Impact of Meal Timing on Glycemic Profile in Latino Adolescents With Obesity
Phase: NA
Conditions: Pediatric Obesity, Meal Timing
Sponsor: Children's Hospital Los Angeles

Official Title:  Impact of Meal Timing on Glycemic Profile in Latino Adolescents with Obesity 
Brief Title:  Impact of Meal Timing on Glycemic Profile in Latino Adolescents with Obesity 
NCT Number:  NCT05391438 
Unique ID:  CHLA-22-00119 
Date of Document:  7/22/2024 
PI:  Alaina P. Vidmar, MD   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
PROTOCOL TITLE: 
Impact of Meal Timing on Glycemic Profile in Latino Adolescents with Obesity. 
  
PRINCIPAL INVESTIGATOR: 
Alaina P. Vidmar, MD 
The Center of Endocrinology, Diabetes and Metabolism 
323-361-3385 
avidmar@chla.usc.edu 
  
STUDY ABSTRACT  
  
In adolescents, conventional obesity treatment comprehensively addresses nutritional, activity, 
and behavioral topics. Due to limited resources in historically marginalized communities, 
implementation of nutrition-based interventions that require easy access to fresh food and ability 
to change the home environment is difficult, which may exacerbate health disparities. It is 
critical to find nutrition strategies and recommendations that are impactful, sustainable, and cost 
effective across all communities. There is growing interest in time-based interventions focusing 
on “when” food is consumed rather than on prescribed macronutrient composition. Time-
restricted eating (TRE) is a type of meal-timing which involves fasting for at least 14-hours per 
day and eating over a 10-hour eating window initiated in the morning, mid-day, or afternoon. 
TRE recommendations are simple in merely dictating when eating occurs and thus may represent 
a more straightforward approach for adolescents than other caloric restriction regimens relying 
on numeracy (kilocalories and macronutrients) and goal setting. In adults, early-day TRE has 
been shown to reduce body weight, fasting glucose, and insulin resistance. By contrast, 
restricting food intake to the evening has produced mostly null results or even worsened post 
prandial glucose levels and β-cell responsiveness. To date, there has been no trial comparing 
early vs. late TRE on glycemic profiles in adolescents, and it is unclear how meal-timing impacts 
glycemic profiles in youth.  The optimal timing of food intake for adolescents may be very 
different than adults due to increasing sex steroids and growth hormone levels overnight which 
may contribute to increased insulin resistance in the early morning. The proposed proof-of-
concept study addresses this question by measuring metabolic response to a test meal consumed 
in the morning, afternoon, and evening among 30 adolescents with obesity using a within 
participant design. These findings will provide the needed research base for the refinement of 
TRE interventions in adolescence. 
  
SPECIFIC AIMS 
The prevalence of type 2 diabetes in adolescents is steadily increasing, specifically 
among Latino youth. Unfortunately, there is a lack of effective preventative treatments available 

to delay the progression to type 2 diabetes in youth living with obesity and pre-diabetes. 
Specifically, it is challenging for many adolescents to maintain adherence to multicomponent 
interventions resulting in high attrition which then decreases efficacy. There is growing interest 
in time-based interventions focusing on “when” food is consumed rather than on prescribed 
macronutrient composition. In the adult population there has been increasing evidence that time-
restricted eating (TRE), which consists of limiting daily food intake to an 8 to 10-hour period 
or less may improve insulin sensitivity and β-cell responsiveness. However the results of TRE in 
adults appear to depend on when eating occurs. Early TRE (last eating event prior to 16:00) has 
been shown to reduce body weight, fasting glucose and insulin, and insulin resistance. However, 
restricting food intake to the evening produced mostly null results or worsened post prandial 
glucose level. One possible explanation is that consuming food early in the day synchronizes the 
central and peripheral circadian clocks involved in energy expenditure and fat oxidation and 
minimizes glycemic excursions and endogenous glucose production via enhanced insulin 
secretion. It has been proposed that the enhanced insulin secretion may be secondary to 
corresponding diurnal variations in the release of incretin hormones such as glucagon, glucagon-
like-peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and pancreatic 
peptide (PP).  
Because of its simplicity, TRE may represent a more feasible approach for adolescents 
than other caloric restriction regimens. Our team recently conducted the first study examining the 
feasibility of TRE in adolescents with obesity. In this study, fifty adolescents were randomized to 
a self-selected 8-hour TRE compared to a prolonged eating window.  TRE was found to be 
feasible, safe, and acceptable but there was no difference in glycemic profiles or weight loss 
between groups. These null findings may be due to the late eating window that was selected. To 
date, there have been no trial comparing early vs. late TRE on glycemic profiles in adolescents 
and it is unclear how meal-timing impacts glycemic profiles in youth. It remains unknown how 
the timing of meal consumption directly effects glycemic profiles and cardiometabolic endpoints 
in this age group. Thus, to address this question, in our proof-of-concept study, we aim to 
measure glycemic and metabolic responses to a test meal (controlled for macronutrient profile 
and caloric amount) at various meal-timings (early vs. afternoon vs. late) in thirty Latino 
adolescents (ages 13-19 years), with obesity, without diabetes. All participants will consume 
three standard test meals administered in random order at different times of day over a two-week 
period: (1) Early: test meal consumed at 8 AM; (2) Afternoon: 12 PM; (3) Late: 4 PM. Test 
meals will be consumed on different days at least three days apart after a minimum of a 16-hour 
fasting period. A continuous glucose monitor (CGM) will be placed on the participant for the 
duration of the 2-week period. The primary endpoints will be frequently sampled glucose, 
insulin, and c-peptide area under the curve (AUC) collected after consumption of a standard test 
meal, insulinogenic index (IGI: change in insulin/change in glucose over the first 30 min after the 
load), and glucose variability as captured by percent time in range on CGM. We hypothesize 
that adolescents with obesity will have reduced AUC and IGI following the later meals compared 
to the early meal.  We will test these hypotheses with the following aims:  

Aim 1: Identify how timing of meal consumption after a prolonged 16-h fast affects glucose 
and insulin response in Latino adolescents with obesity. We will measure insulin secretion, 
clearance rates, and sensitivity assessed with a) 3-h frequent sampling of glucose, insulin, and c-
peptide post meal, b) calculated insulinogenic index, and c) percent time in range measured by 
CGM. We expect that meal consumption at 12 and 4 PM will be associated with lower post 
prandial glucose excursions, decreased AUC and IGI, and increased percent time in range 
compared to that same meal consumed at 8 AM. 
Aim 2: Examine the association between timing of meal consumption and incretin and 
pancreatic hormones in Latino adolescents with obesity. We will collect frequent sampling of 
glucagon, total GLP-1, GIP, and PP concentrations post-meal to explore how diurnal variation in 
these hormones impact insulin sensitivity. We expect that meal consumption at 12 and 4 PM will 
in greater change in incretin and pancreatic hormones concentrations compared to that same 
meals consumed at 8 AM.  
Future Direction:  The data collected during this pilot will inform the design of a randomized 
clinical trial to test the feasibility, safety, and efficacy of early vs. late TRE in adolescents with 
obesity to reduce glycemic and insulin response for the prevention of type 2 diabetes. 
  
RESEARCH STRATEGY  
i. Significance:  
In the United States, 1 in 5 adolescents has obesity, and 30-50% of those go on to 
develop early onset type 2 diabetes. Increased pediatric obesity has been accompanied by a 
rising incidence of type 2 diabetes in adolescents, specifically among Latino youth. With 
increasing prevalence and increasing cost for care, obesity in adolescents is expected to result in 
extensive financial costs, and significant life limiting complications. In adolescents, conventional 
obesity treatment comprehensively addresses nutritional, physical activity, and behavioral topics 
with the goal of achieving clinically meaningful weight loss. Adherence to comprehensive 
lifestyle interventions is challenging for adolescents, in part because these approaches require 
frequent monitoring and engaging in multiple behavioral targets continuously. Therefore, there is 
a growing interest in simplifying intervention recommendations to decrease reliance on 
numeracy (Kilo calories and macronutrients), goal setting and complex skillsets. One simpler 
and promising approach is based on timing of eating.  
Time-restricted eating (TRE) involves shortening the eating window to a pre-
specified number of hours per day and fasting for the remaining of the day without 
necessarily altering diet quality and quantity. TRE has been shown to promote weight loss, 
improve fasting glucose and postprandial glucose levels, mean daily glucose, and insulin 
resistance, as well as blood triglyceride, total cholesterol, LDL cholesterol levels and overall 
well-being. Because of its simplicity, TRE may represent a more feasible approach for 
adolescents because it removes the need for intensive counting of daily caloric intake and 
focuses on a straightforward task of consuming food during a pre-specified time. Our 

preliminary data, collected in 50 adolescents, shows the feasibility, acceptability, and safety of 
implementing 8-hour TRE in adolescents. 
The results of TRE in adults appear to depend on when eating occur. Early TRE (last 
eating event prior to 16:00) has been shown to reduce body weight, fasting glucose and insulin, 
insulin resistance, and inflammation. However, restricting food intake to the afternoon and/or 
evening produced mostly null results or worsened post prandial glucose levels and β-cell 
responsiveness. Thus, many adult trials have promoted TRE early in the day because it has been 
hypothesized to synchronize the central and peripheral circadian clocks involved in energy 
expenditure and fat oxidation and minimizes glycemic excursions and endogenous glucose 
production. In adults, previous evidence has shown glucose tolerance, skeletal muscle fatty acid 
oxidation, and diet-induced thermogenesis are higher in the morning than in the evening and that 
an evening meal induces higher postprandial glucose concentrations and different secretion of 
insulin and incretins compared with the same meal consumed in the morning. These findings 
suggest that eating earlier in the daytime might be more optimal for food consumption in adults, 
whereas delayed eating may predispose to more metabolic dysfunction. It has been proposed that 
the enhanced insulin secretion seen in response to a morning meal may be secondary to 
corresponding diurnal variations in the release of incretin hormones such as glucagon-like 
peptide 1 and glucose-dependent insulinotropic peptide. 
An early eating window may not align with many adolescents’ development and 
social schedules that often shift their food consumption to later in the day. This shifting 
chronotype, coupled with increasing sex steroids and growth hormone levels overnight, has been 
shown to cause increased insulin resistance in the early morning for this age group, contrary to 
what is seen in adults. Given the changing metabolic state of many adolescents living with 
obesity, it remains unknown how the timing of meal consumption directly effects glycemic 
profiles and cardiometabolic endpoints in this age group. In the proposed proof-of-concept study 
we aim to measure glycemic and metabolic responses to a test meal (controlled for macronutrient 
profile and caloric amount) consumed in the morning, afternoon or evening using a cross-over 
design in 30 Latino adolescents with obesity. These findings will provide metabolic evidence to 
inform what eating window is most appropriate for adolescents with obesity utilizing TRE. 
  
ii. Innovation: 
The proposed study is theoretically and clinically innovative for the following reasons: 
This is the first study to evaluate the relationships between the timing of food intake and 
insulin sensitivity in adolescents with obesity. This study will determine if the timing of the 
first meal of the day alters the glycemic profile in adolescents with obesity. These findings will 
provide metabolic evidence to guide the recommendation of when time-based interventions 
should occur in this age group as a non-pharmacological intervention to delay conversion to type 
2 diabetes. New insight into the relationship between insulin secretion and incretin release 
in adolescents. By evaluating the difference in incretin hormone response by time of meal 
consumption, this study will investigate the relationship between insulin secretion, incretin 

release, and diurnal variation in adolescents with obesity. Expand our understanding of the 
use of CGM in adolescents with obesity. There is very limited experience of the use of CGM 
among underserved racial/ethnic minority populations at risk for type 2 diabetes. Current CGM-
based metrics provide a clinically meaningful macroscopic perspective on an individual’s 
glycemia. This study aimed to gain data-driven insights from the postprandial glucose response 
to meal consumption at various times throughout the day to determine if changes in glucose 
peaks shift by the time of first meal consumption. Results from this study could potentially 
change the way adolescents with obesity are treated in the future by incorporating meal-timing 
behaviors as part of their medical regimen. 
  
PROCEDURES INVOLVED 
Overview of Proposed Study Design: We propose a cross-over, proof-of-concept study 
to measure glycemic and metabolic responses to a test meal (controlled for macronutrient profile 
and caloric amount) administered at various times of the day (early vs. afternoon vs. late) in 
thirty Latino adolescents (ages 13-19 years), with obesity, without diabetes, to determine how 
timing of eating impacts glycemic response to the test meal after a 16-h fasting period. All 
participants will consume three standard test meals administered in random order at different 
times of day over two-weeks: (1) Early: test meal consumed at 8 AM; (2) Afternoon: test meal 
consumed at 12 PM; (3) Late: test meal consumed at 4 PM. A continuous glucose monitor 
(CGM) will be placed on the participant for the duration of the 2-week period. Baseline and post-
meal samples will be assayed for glucose, insulin, c-peptide, GLP-1, GIP, PP at times -10, , 10, , 
30, , 60, 90, 120, and 180 minutes after glucose. The proposed protocol is modified to include 
multiple samples during the initial 30 minutes when glucose is rapidly increasing, allowing for 
modeling of glucose stimulated insulin secretion. The primary endpoints will be glucose, insulin, 
and C-peptide area under the curve, insulinogenic index, and glucose variability as captured by 
percent time in range on CGM following the test meal.  
The implementation steps of the proposed RCT are as follows: (1) The staff will introduce the 
study to all eligible participants either in person or virtually and consent interested families for 
the study; (2) All participants and their families will complete baseline study surveys in REDcap; 
(3) All participants and their families will receive training on the use and application of the 
CGM, which is FDA approved in patients 2 years and older. All equipment required for the 
duration of the study will be distributed to the participants in-person. (4) All participants will be 
randomized to the order in which they consume their test meal. Test meals will be consumed on 
different mornings at least three days apart after a 16-h fasting period. Outside of study visits, 
participants will purchase all their meals as they would normally without alternation to food 
quality or quantity; (5) The study staff will conduct study assessments with participants at 
baseline and during each test meal study visit (3 total). Participant will be given the option to 
redo visits with missing lab results (up to 6 total); (6) The study staff will perform weekly phone 
encounters with the participants to assess barriers to study visit attendance and to record any 

medication changes or health issues that have occurred in the last 7 days; (7) The PI and research 
team will meet bi-weekly to monitor all study procedures and oversee data management and 
analysis. 
  
The implementation steps of the proposed test meals and blood collection are as follows: 
1) Subjects without a port will have an IV inserted; 
2) -10 min pre-meal blood sample (5 mL) will be collected from the port or IV for fasting 
labs; 
3) Subjects will consume meal; and 
4) 10 min post-meal blood sample (5mL), 30 min post-meal blood sample (5mL), 60 min 
post-meal blood sample (5mL), 90 min post-meal blood sample (5mL), 120 min post-
meal blood sample (5mL), and 180 min post-meal blood sample (5mL) will be collected 
from the port or IV post-meal test. 
  
Sharing of Testing Results with Subjects 
Study endpoints will be shared with participants upon request via email or over the 
phone. The PI will review any tests results and if additional medical evaluation nis warranted 
will refer to the primary care providers. 
  
Study Timelines 
Intervention: For the 14 days study period, all participants will maintain their usual 
lifestyle, including food consumption, physical activity, and sleep patterns.  Physical activity and 
sleep recommendations consistent with the American Academy of Pediatrics guidelines for 
adolescents will be encouraged but not formally prescribed. Test Meal Composition: Each 
participant will consume three test meals over the study period, administered at three different 
times of the day. The test meals will be prepared by the dietetic staff at CHLA. The test meal 
will consist of 770 calories total (one-third of the recommended total daily caloric intake for age, 
30% protein, 10% fat, and 60% carbohydrates [CHO]). The test meal will be comprised of a deli 
sandwich (560 calories, 84 grams of CHO, 10 grams of added sugar) snack bar (100 calories, 17 
grams of CHO, 9 grams sugar), and Greek yogurt (110 calories, 16 grams CHO, 7 grams sugar). 
Timing of Test Meal Consumption: There will be three time periods in which the test meal is 
administered over the study period: 8 AM, 12 PM, and 4 PM. To mimic a TRE model, in which 
the daily fasting period is extended to 14-16 hours or more all participants will be asked to fast 
for at least 16-hs prior to their test meal visit. Participants will be asked to not consume any food 
for 3 hours after the test meal is completed. Continuous Glucose Monitor. All participants will 
be trained to wear a blinded continuous glucose monitor sensor using manufacturer educational 
materials under the supervision of research staff. Participants will be asked to wear the CGM for 
14 days after enrollment. During each study visit, the CGM reader will be connected to the site 
database to create an individual participant report.  
  

Study Timeline 
Q1 Q2 Q3 Q4 
Study Start Up 
  
  
  
  
Hire and train study personnel 
X   
  
  
Finalize protocol, obtain Institutional Review Board (IRB) approval 
X   
  
  
Data & document review 
X   
  
  
Design Test Meal 
X   
  
  
Apply for CHLA CTSI Biostats Core Pilot Grant 
X   
  
  
Create Testing Protocol with CTU 
X   
  
  
Study implementation 
X X X   
Data Handling 
  
  
  
  
Data entry/cleaning and analysis 
  
X X X 
Publications and presentations 
  
  
X X 
Future Grant Preparation   
  
  
  
  
R01 and ADA 
  
  
  
X 
  
Measurements: The study team will conduct all assessments baseline and each meal 
consumption visit (3 total). Participant will be given the option to redo visits with missing lab 
results (up to 6 total). All data will be collected and stored in REDCap. 
  
Aim 1: Identify how timing of meal consumption after a prolonged 16-h fast affects glucose and 
insulin response in Latino adolescents with obesity.  
Quantifying glycemic profile after test meal from venous sample: Baseline and post-
meal samples will be assayed for glucose, insulin, and c-peptide at times -10, , 10, , 30, , 60, 90, 
120, and 180 minutes after the meal is consumed. The proposed protocol is modified to include 
multiple samples during the initial 30 minutes when glucose is rapidly increasing, allowing for 
modeling of glucose stimulated insulin secretion. Using this approach to model glucose kinetics 
without the need to administer insulin is a safe and cost-effective surrogate of β-cell function and 
can be more easily implemented in youth. Insulinogenic index (change in insulin/change in 
glucose over the first 30 min after the load) will be calculated. IGI has been widely used as an 
index of early phase insulin secretion in clinical studies. It is highly correlated with the acute 
insulin response on intravenous glucose tolerance test and is considered a reasonable surrogate.  
Quantifying glycemic profile on CGM: Four parameters will be computed from CGM 
data for each test meal segment:  Starting glucose: The glucose value at the start of the meal.  
Time to peak: The time difference between the start of the meal response and the meal response 
peak in minutes.  Maximum glucose rise: The difference between the glucose levels at the start 
of the meal and post-meal peak in mg/dL.  Glucose incremental area under curve: The positive 

area under the post-meal glucose curve after subtracting the glucose value at the start. We will 
capture glucose readings every 5 minutes and obtain the weekly %TIR over the course of the 
study.  
  
Aim 2: Examine the association between timing of meal consumption and incretin and 
pancreatic hormones in Latino adolescents with obesity to explore if the enhanced insulin 
secretion is secondary to corresponding variations in the release of incretin hormones.51  
Quantifying incretin hormones after test meal from venous sample: Following 
baseline sampling (0 min), a test meal will be administered. glucagon, GLP-1, GIP, and PP 
concentrations will be measured in duplicate from plasma samples using Millipore Enzyme-
linked Immunosorbent Assays (ELISA) or multiplex assays according to the recommendations 
of the manufacturer (Birmington, MA). Total area under the cure (AUC) will be calculated for 
venous glucagon, GLP-1, GIP, and PP concentrations using the trapezoid methods using 
GraphPad Prism (Version .01, GraphPad Software Inc, San Diego, CA, USA). 
  
Statistical Consideration: The sample size estimates, and analytical plans were 
developed under the guidance of Dr. Ramon Durazo-Arvizu who is the Director of the TSRI 
Biostatistics core and who will also be a mentor on this award. Descriptive statistics, including 
graphical depictions, will be utilized to assess the degree of symmetry/normality of continuous 
outcomes and identification of outliers. A ladder of powers approach will be applied to identify 
the best easy-to-interpret transformation of the continuous outcome variable. The statistical 
approach will be implemented with and without transformations when appropriate. Data for this 
3-treatment, 3-period cross-over design will be analyzed using linear mixed effects model as 
described in the literature and implemented in STATA 17.1 (College Station, TX) Sensitivity 
analysis applying weighted least squares regression will follow. Areas under curves (AUC) will 
be calculated by the trapezoid rule for levels after meal ingestion. Separate AUC will be 
calculated for the early (initial 30-min) and the total (entire 300-min) responses. This separation 
of responses in early and total was decided based on previous findings that insulin secretion is 
progressively increased during these first 30 min after oral nutrient ingestion. Wilcoxon matched 
paired test will be used for tests of significance between variables obtained during morning, 
afternoon, and evening meal ingestion. Spearman regression coefficients will be obtained to 
estimate correlation.  
  
Potential Challenges and Alternative Approaches: 1) Study Design: We considered utilizing 
a comparison study based on time of day of meal consumption. However, given this is a proof-
of-concept proposal we felt a cross-over design would be more feasible and inform that design of 
a larger trial for a future grant application. 2) Assessment:  The hyperglycemic clamp and FSIGT 
have been the most widely reported and acceptable methods to evaluate β-cell function. 
However, given this is a limited resources proposal in adolescents, we elected to utilize a 
multiple sample approach following a test meal to characterize glycemic variability in a more 

real-life scenario, which is both more cost- effective and tolerable for pediatric participants.  3) 
Intervention: Ideally this study would be conducted as a controlled feeding study, in which all 
food was provided to participants over the study period.  This design would ensure equal daily 
caloric intake and equal fasting window for all test meals. However due to resource constraints 
and anticipated participant burden that is outside the scope of this proposal and thus we selected 
to conduct this in a more real-life setting. We will adjust our analysis based on fasting window to 
control for length of fasting before meal consumption.  4) CGM Use: We considered utilizing 
real-time CGM feedback during the two-week period. However, given CGM use is not standard 
of care we opted to utilize blinded CGM for outcome monitoring to lower participant burden and 
enable more clear assessment of the primary intervention component of meal-timing 
 
Inclusion and Exclusion Criteria 
• We will recruit 30 Latino adolescents (age 13-19 years at enrollment, all gender expressions) 
from clinical programs at CHLA. Inclusion criteria are: (1) age 13-19 years; (2) Hispanic or 
Latino defined by the NIH as a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race; (3)Tanner stage III and 
above; (4) body mass index > 95th percentile; (5) participant must be willing and able to 
adhere to the assessments, visit schedules, and eating/fasting periods. To limit confounding 
factors, individuals will be considered ineligible to participate if they meet any of the 
following exclusion criteria: (1) diagnosis of Prader-Willi Syndrome, brain tumor or  
hypothalamic obesity; (2) serious intellectual disability; (3) parent/guardian-reported 
physical, mental of other inability to participate in the assessments; (4) previous bariatric 
surgery; (5) current use of an anti-obesity or other diabetes medication (e.g., phentermine, 
topiramate, orlistat, GLP-1 agonist, naltrexone, buproprion, or insulin); or (6) current 
participation in other interventional weight loss studies. Randomization tables will be first 
generated using SAS and fed into the study REDCap database. Participants will be randomly 
allocated to the sequence of meal-times consumed over the study period. 
• Inclusion Criteria: Participants must meet all of the following criteria to be enrolled in the 
trial: 
o Age 13-19 years 
o Hispanic or Latino defined by the NIH as a person of Cuban, Mexican, Puerto Rican, 
South or Central American, or other Spanish culture or origin, regardless of race  
o Tanner stage III and above 
o Body mass index greater than or equal to the 95th percentile 
o Willing and able to adhere to the assessments, visit schedules, eating/fasting windows 
• Inclusion of Women: We will enroll adolescents of all gender expressions, with obesity. We 
expect approximately 60% of the study participants will be female.  
• Inclusion of Minorities: The study site will make it possible to recruit an ethnically and 
racially diverse sample. Sixty-five percent of patients seen at CHLA self-identify as Latinx, 

compared to 47.5% of the population in Los Angeles. The anticipated racial and ethnic 
composition of the study reflects the population at CHLA. 
• Inclusion Across the Lifespan: Children constitute the target population for this study as we 
aim to evaluate the impact of meal timing on glycemic profile in adolescents. In our 
experience, children younger than 13 years of age and older than 21 years would require 
different intervention/counseling strategies. Therefore, we can develop a more consistent 
“age-neutral” approach if we limit the age range to 13-19 years. In addition, based on our 
ongoing experience, this age range incorporates the general window of late pubertal 
development and we will limit recruitment to participants who are Tanner stage 3 or greater 
to exclude the potential confounding effects of early pubertal transition. Puberty will be 
determined by Tanner staging during examination by a physician and included as a co-
variate. The IRB has strict regulations for the approach to and documenting of assent by 
minors and consent by their parents/guardians. Documentation of assent/consent is done via 
IRB-approved study-specific forms. 
• Exclusion Criteria: Participants will not be eligible to participate if they meet any of the 
following criteria:  
o Previous diagnosis of Prader Willi Syndrome, brain tumor or hypothalamic obesity 
o Serious developmental or intellectual disability 
o Diagnosis of eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge-eating 
disorder) 
o Parent/guardian-reported physical, mental of other inability to participate in the 
assessments (e.g., inability to wear CGM, inability to be in the imaging modality 
without sedation) 
o Previous or planned bariatric surgery 
o Current planned use of an anti-obesity or T2D medication (e.g. phentermine, 
topiramate, orlistat, glucagon like peptide-1 agonist, naltrexone, bupropion, SGLT-2 
Inhibitor, etc.) or insulin 
o Current participation in other interventional weight loss studies.  
  
Number of Subjects 
• We will recruit 30 Latino adolescents (age 13-19 years at enrollment, all gender expressions) 
from clinical programs at CHLA. 
  
Recruitment Methods 
• Recruitment: We will combine three recruitment pools (community outreach, general 
pediatric, and sub-specialty populations) to reach our goal of 120 participants over 2 
years (1-2 participant per week), which is like what we have achieved in prior studies 
with similar funding. CHLA and its academic partner USC, has a long history of 
successful investigator-initiated studies in youth with obesity. The CHLA 
endocrinology clinic currently cares for over 500 children and adolescents with 

obesity annually. We receive an additional 700 referrals annually from providers all 
across Southern California. Of those, 50% meet eligibility criteria for this study. The 
demographics of our patient population are mean age 16.9 years, 60% female, 
mean age of diagnosis 13.2 ± 2.3 years. Sixty-five percent of our patients self-
identify as Latino, compared to 47.5% of the population in Los Angeles. We will elicit 
support from community partners, patient and family advocates, and patients living 
with obesity to ensure the study design and execution aligns with- and promotes 
ideas and interests of all stakeholder partners.    
• The CHLA endocrinology clinic currently cares for over 250 adolescents with obesity each 
year. Of those, 50% meet eligibility criteria. We will also recruit from affiliate hospitals and 
pediatric clinics in the area. The demographics of our patient population are mean age 16.9 
years, 60% female. Sixty-five percent of our patients self-identify as Latino, compared to 
47.5% of the population in Los Angeles.62 At CHLA, the recruitment rate in this population 
is between 50-60% with a retention rate of 60-80%. Based on our recruitment history in 
adolescents with obesity, we anticipate a consent rate of 50-60%, retention rate of 75-80%, 
and recruitment of 30 adolescents within the first 9 months of the award period.  
• Participants will be recruited from Children’s Hospital Los Angeles (Los Angeles, CA). The 
typical approach will be through direct involvement with the treating physician. In their 
clinics, they will introduce the study to their patients and connect interested participants with 
the study staff. Research staff will carefully review the full consent form with the participant 
and parent or guardian in person or via phone, answering the participant’s questions about 
the study. Participants will be allowed to electronically sign consent forms online using 
DocuSign, REDCap, or printed forms in-person. Alternatively, research staff will review 
medical records of potential participants in order to identify participants who may be eligible. 
CHLA has natural language processing algorithms that allows for rapid searches of electronic 
medical records to identify patients with specified criteria for recruitment into studies. 
Research staff will first discuss potential participants with the PI and treating physician 
before making contact. After the initial recruitment process, a follow-up phone call will be 
made by a trained recruiter within one week to answer questions and solicit participation.  
  
Withdrawal of Subjects 
Principal investigator will not withdraw participants from the study without their consent. 
However, the researchers may end subject’s participation in this study for a number or reasons, 
such as if subjects’ safety and welfare are at risk, if study instructions are not being followed. 
Adolescents who experience psychiatric emergencies will be withdrawn from the study. 
Adolescents who experience psychiatric emergencies such as suicidal behavior will be 
withdrawn from the study. If patient requests to be withdrawn from the study, they can either 
stop all study tasks and visit or they can select what components they no longer want to continue 
and that data will be drafted as missing data. 
  

Risks to Human Subjects: 
a. Human Subject Involvement, Characteristics and Design: In our proof-of-concept 
study, we aim to measure glycemic and metabolic responses to a test meal (controlled for 
macronutrient profile and caloric amount) at various meal-timings (early vs. afternoon vs. 
late) in thirty Latino adolescents (ages 13-19 years), with obesity, without diabetes, to 
determine how timing of eating impacts glycemic response to a test meal after a 16-hour 
fasting period. We will enroll 30 adolescents, of all gender expressions, aged 13-19 years, 
with a BMI > 95th percentile. In this cross-over design, each participant will act as their 
own control. The order of the meal timings consumed will be randomized across 
participants. A random block stratified randomization scheme will be used. 
Randomization tables will be first generated using SAS and fed into the study REDCap 
database. 
b. Study Procedures, Materials, and Potential Risks: 
Sources of Material. Data sources include questionnaires, blood samples, and anthropometric 
data. Privately identifiable information will therefore be collected. All data will be kept 
confidential and used only for research purposes. 
• Questionnaires, and Medical Chart Abstractions. Participants will be asked to complete 
standard/validated questionnaires data using web-based (Research Electronic Data Capture, 
REDCap) or paper-based forms. Demographic variables include age, race, ethnicity, 
marital status, education, and income level. The baseline questionnaire will also ascertain 
data on a variety of potential risk factors, including family history, medical history, 
supplement use, and medication use. We will measure weight and height. Assessments will 
be conducted at all three study visits.   
• Blood Collection: We will collect, process, and store blood according to standard protocols 
for the hemoglobin A1c, C-peptide, insulin, and glucose levels. Blood will be collected at 
all three study visits and stored at -70°C. DPP-4 and Aprotinin inhibitors will be added into 
test tubes for analysis. 
Potential Risks/Adverse Events Monitoring and Procedures Used to Minimize the Risks:  
Participants will be queried about adverse events at each phone call and study visit and will 
additionally be instructed to report adverse events as they occur. Participants will be provided 
with (A) a phone number and email address to report non-urgent adverse events to the research 
coordinator; and (B) a phone number to directly reach the study physician, in case of serious 
adverse events. The study physicians will immediately refer participants to the appropriate 
medical care (e.g., urgent care or non-urgent care) should any pressing concerns arise during the 
study period. In case of emergency, participants will be instructed to call 911 before calling the 
study physician. Should a participant require urgent or emergency care, the study physician will 
follow up with the participant’s healthcare provider to determine whether it is safe for the 
participant to continue in the trial. 
Adverse events will be subsequently documented and reported as described above. The 
severity of the event is graded as follows: 

• Mild (Grade 1): the event causes discomfort without disruption of normal daily 
activities. 
• Moderate (Grade 2): the event causes discomfort that affects normal daily activities. 
• Severe (Grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
• Life-threatening (Grade 4): the patient is at risk of death at the time of the event. 
• Fatal (Grade 5): the event causes death. 
  
Risks Related to prolonged fasting prior to study meal consumption. Adverse events are unlikely 
as a result of participation in this study. The PI, co-investigators, and study team will monitor 
participants for mild symptoms associated with prolonged fasting prior to study meal 
consumption, such as thirst, headaches, and gastrointestinal issues. To reduce the risks of 
increased thirst, headaches, and gastrointestinal issues, participants will be encouraged to stay 
hydrated by drinking water.  
  
Attitudes and practices around food and eating. None is anticipated. We will continuously 
monitor for unforeseen or unanticipated events and risks. If a participant reports unhealthy 
compensatory eating behavior (i.e., binge eating, excessive restraint, purging, etc.) during the 
research visits, we will refer them to their primary provider to have an official psychological 
evaluation. If we suspect that the adolescent is purging or placing themselves in immediate 
medical danger, we will contact their parent or guardian and create a safety plan and instruct 
them to go the local emergency room for evaluation. In addition, the PI will contact the primary 
care provider to ensure appropriate referrals for psychiatric support are obtained. Adolescents 
who experience psychiatric emergencies will be withdrawn from the study. Dr. Salvy is a clinical 
behavioral psychologist and will provide oversight, monitoring, and guidance to the PI regarding 
the monitoring of any adverse events related to behavior changes that may occur during the study 
period.  
  
Progression to diabetes requiring escalation of care. All participants will have obesity and thus 
increased risk of conversion to youth onset type 2 diabetes. If during the study visits any of the 
biochemical analysis is suggestive of new onset type 2 diabetes, they will be referred to their 
primary care provider for confirmatory lab testing and referral to a pediatric endocrinologist as 
needed.  
  
Risks Related to Blood Draws. A small minority of participants will likely experience transient 
discomfort, pain, bleeding, and/or bruising from the needle insertion and/or IV. This poses 
minimal risk. Infection is also possible in rare cases. This risk will be minimized by having 
trained nursing and phlebotomy staff use sterile techniques to draw blood. 
  

Risks Related to Biohazards. All staff will follow the Code of Federal Regulations on the 
handling of biospecimens (29 CFR Part 1910-1030) and hazardous chemicals (29 CFR Part 
1910-1450). Human biospecimens (serum blood collected to measure: HbA1c, C-Peptide, 
Insulin, and Glucose) will be collected by doctors, nurses, or other trained personnel, and the 
collected samples will be processed and analyzed by trained technicians. All blood samples and 
reagents will be handled in approved areas using established guidelines set by Children’s 
Hospital Los Angeles Occupational Health and Safety Offices. The collected blood specimens 
will be documented and stored in monitored and locked facilities. Blood, chemicals, and any 
materials that encounter biospecimens will be disposed of in designated biohazard waste 
receptacles, following federal and local biohazard regulations. All staff members who will 
encounter blood samples and chemical reagents are trained to safely handle these biospecimens 
and are retrained annually.  
  
Risks Related to Privacy and Confidentiality. To protect privacy, each study participant will be 
assigned a unique identification (ID) number. Data forms, participant information, and biological 
specimens will be coded using these ID numbers. Personal, identifiable information will not 
appear on these materials; instead, the key linking the participant’s identity to their unique 
identification number will be stored separately in a secure location. Records that identify study 
participants will be kept confidential as required by law, and every effort will be made to 
maintain the confidentiality of participants’ study records. Except when required by law or if 
necessary, to protect their rights or welfare, study participants will not be identified by name or 
any other identifying characteristics in records disclosed outside of the investigational team. To 
manage study data, we will use REDCap, a secure web application that meets both HIPAA and 
21 CFR Part 11 requirements. REDCap leaves a pristine audit trail by documenting all changes 
to data, and data access is strictly controlled with password authentication and user controls. 
Data from the medical chart and clinical outcomes and adverse events will be electronically 
uploaded to the database, and all questionnaires will be coded into and administered through 
REDCap. Such electronically stored data will be protected through stringent security measures 
assured by Children’s Hospital Los Angeles technical departments and with coded ID numbers 
and electronic security systems required by HIPAA. Paper documents will be scanned and saved 
on each site’s secure network and stored in locked cabinets in locked offices. Biological 
specimens will be stored and analyzed in locked areas with restricted access. Access to 
participants’ data and biological specimens will be limited only to the study’s investigators, 
clinical support staff for this study, the overseers of clinical facilities, and the study sponsor—all 
on a need-to-know basis. The study team has significant experience with the operation of clinical 
trials and safeguarding confidentiality 
  
Trauma, Bullying, and Domestic Violence Risks. None anticipated. We will continuously 
monitor unforeseen or unanticipated events and risks. If trauma and/or domestic violence is 
suspected, either through completion of the questionnaires or through participants’ report or staff 

observation, we will implement the following procedures: (1) we will make participants aware of 
resources available to them in their communities, such as shelters; (2) we will work with 
participants to develop a safety plan for addressing violence and seeking shelter; and (3) we will 
ascertain risk to the child(ren) in the household. If we suspect that the child(ren) has/have been 
abused or witnessed domestic violence, we will report the incident to child protective services. 
Participants who are victims of domestic violence will be allowed to remain in the study if they 
wish to do so. 
  
Suicidal Behavior Risks. None anticipated. We will continuously monitor for unforeseen or 
unanticipated events and risks. We follow the Substance Abuse and Mental Health Services 
Administration SAFE-T: Suicide Assessment Five-Step Evaluation and Triage approach to 
determine risk and the appropriate clinical response. The five steps are Identify Risk Factors, 
Identify Protective Factors, Conduct Suicide Inquiry, Determine Risk Level/Intervention, and 
Document (which includes intervention and follow-up).  As per practice guidelines, we will 
estimate suicide risk as low, moderate, or high. All potentially suicidal participants will be given 
an emergency plan with numbers to call (e.g., local hospital emergency rooms, suicide hotlines, 
staff, and study physicians). Each plan will be individually tailored to the needs and resources of 
the participants. Family members will be incorporated into the plan. Adolescents who experience 
psychiatric emergencies such as suicidal behavior will be withdrawn from the study. 
  
Alternative Treatments. Participants will be informed that the alternative option is not to enroll in 
the trial and their decision whether to enroll will not affect the quality or extent of medical care 
that they receive. 
  
Handling Incidental Findings. If any clinically abnormal result or illness is uncovered, or if 
participants exhibit signs of depression or mental illness, the affected participant will be notified 
and referred to his/her physician or an appropriate health professional for treatment. Participants 
will be offered copies of any tests or incidental findings. 
  
2. Adequacy of Protection Against Risk  
  
a. Informed Consent: Participants will be recruited from Children’s Hospital Los Angeles (Los 
Angeles, CA). The typical approach will be through direct involvement with the treating 
physician. In their clinics, they will introduce the study to their patients and connect interested 
participants with the study staff. Research staff will carefully review the full consent form with 
the participant and parent or guardian in person or via phone, answering the participant’s 
questions about the study. Participants will be allowed to electronically sign consent forms 
online using DocuSign, REDCap, or printed forms in-person. Alternativley, research staff will 
review medical records of potential participants in order to identify participants who may be 
eligible. CHLA has natural language processing algorithms that allows for rapid searches of 

electronic medical records to identify patients with specified criteria for recruitment into studies. 
Research staff will first discuss potential participants with the PI and treating physician before 
making contact. After the initial recruitment process, a follow-up phone call will be made by a 
trained recruiter within one week to answer questions and solicit participation. Consent can be 
withdrawn from at any time. Potential participants will have the following carefully explained: 
(1) the investigational nature of the research; (2) the objectives of the research; (3) the 
procedures involved in the research; (4) any and all risks and discomforts due to participation; 
and (5) alternative options to participation that are currently available. Clarification questions 
will then be elicited from the potential participants and their parents/guardians. Only after the 
above will an IRB-approved document recording informed consent be signed as per institutional 
guidelines with a copy to be given to the participant and the original stored with the research 
record in a secure location. Data protection will be ensured by storing on an IS-approved 
university database on encrypted servers. All participants will be issued a study ID with data 
entered in de-identified manner. All databases will be password-protected with access only to the 
study team. All paper/documentation/research charts will be maintained in locked locations 
accessible only to the study team. 
  
b. Protection Against Risk: 
  
Safety Reviews: The PI (Vidmar) and Primary Mentors (Goran, Raymond), and Advisory 
Committee (Salvy, Espinoza and Durazo-Arvizu) will review this protocol on a continuing basis 
for participant safety. The annual reports will include a list of adverse events and will address: 
(1) whether adverse event rates are consistent with pre-study assumptions; (2) reasons for 
dropouts from the study; (3) whether all participants met entry criteria; and (4) whether 
continuation of the study is justified on the basis that additional data are needed to accomplish 
the stated aims of the study. 
  
Monitoring plan: Data monitoring will focus on performance (participant follow-up and 
retention, participant privacy and confidentiality, protocol adherence, and data quality) and safety 
(adverse events and required action/response). The PI and Mentoring team will be responsible 
for the regular monitoring of data and safety issues and will maintain the record of any reported 
adverse events and other concerns. The study data safety and monitoring plan will entail several 
components, overseen by the PI: 
1. All CHLA IRB policies and continuous reporting requirements will be followed in 
conducting the study. Any actions taken by the IRB as part of its continuing review 
will be immediately reported to the NIH. 
2. The PI will implement procedures to ensure that each participant provides informed 
consent, and that all data remain confidential. This will also include a rigorous data 
management protocol to optimize data entry, accuracy/checking, and retrieval. Data 
will be stored in password-protected files accessible only to the investigators and 

staff under their supervision. In the database, only an ID code number will identify 
subjects. A list linking names and other identifiers with their ID codes will be stored 
in a separate file with a separate password. All original paper surveys and case 
report forms will be stored in locked file cabinets. The PI will review all data 
collection forms for completeness and accuracy and for protocol compliance. In the 
case of a breach of confidentiality or other adverse event, the PI will report the 
event to the IRB and the appropriate NIH officials, and appropriate procedural 
changes will be implemented to prevent future breaches or adverse events.  
3. An internal committee comprised of the PI, Mentoring team, and consultants will 
meet quarterly to assess participant recruitment, accrual, and retention; data quality 
and timeliness; participant risk versus benefit; and the development of external 
conditions that could potentially affect the study.  
All personnel who will interact with subjects will receive training on adverse event reporting. In 
response to any adverse event, forms will be completed promptly and returned to the study 
physicians for review and implementation of an appropriate action plan. 
Potential Benefits of the Proposed Research to Research Participants and Others 
  
Research participants may expect benefits from learning about their health. All participants will 
be offered copies of test results from procedures performed during the study. In the case of an 
abnormal test result or other incidental finding, participants will be instructed to visit their 
physician or other appropriate health care provider. Finally, participants may benefit from better 
understanding nutritional strategies. Overall, this clinical trial may inform future interventions 
for adolescents with obesity. 
  
As the known risks to participants from the intervention (i.e., increased thirst, headaches) and 
procedures like blood draws (e.g., bruising, temporary pain) are minor, we believe that these 
benefits outweigh the risks, as the risks to participants are minimal and will be monitored by 
regularly assessing participant safety 
  
4. Planned Inclusion Enrollment Report 
Racial Categories  
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
To
tal 
Female 
Male 
Female  Mal
e  
  
American Indian/Alaska Native 
0 
0 
0 
0 
  
Asian 
0 
0 
0 
0 
  

Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
  
Black or African American 
0 
0 
2 
2 
4 
White 
0 
0 
10 
6 
16 
More than One Race 
0 
0 
6 
4 
10 
Total 
0 
0 
18 
12 
30 
  
  
Dissemination Plan:  
Public Access Plan  
We will comply with the NIH Policy on the Dissemination of NIH-Funded Clinical Trial 
Information in Notice NOT-OD-16-149. Dr. Vidmar will register the trial in ClinicalTrials.gov 
no later than 21 days after the first subject is enrolled. The consent form will state that 
information on the trial will be posted on the ClinicalTrials.gov website and that no information 
that can identify any participants will be posted. The specific wording will be: “A description of 
this clinical trial will be available on ClinicalTrials.gov, as required by U.S. Law. This website 
will not include information that can identify you. At most, the website will include a summary 
of the results. You can search this website at any time.” We will report summary results 
(including adverse events) no later than one year after the completion date. Children’s Hospital 
Los Angeles has internal policies in place to ensure that all clinical research at the university 
complies with the dissemination requirements in NOT-OD-16-149. 
  
Dissemination to the Scientific Community and Health Care Professionals 
Our dissemination plan is four-pronged. We aim to generate scientifically interesting data 
for the scientific community, as well knowledge that can be readily scaled-up and exported for 
professionals and other end-users. First, findings from this study will be presented at key 
scientific meetings. I will develop poster presentations under the supervision of my mentor 
committee. Targeted forums include annual scientific meetings focusing on diabetes and obesity 
management, including American Diabetes Association, Endocrine Society, Pediatric Endocrine 
Society, and The Obesity Society. Once the study is underway, we will publish interim findings 
and summaries and, subsequently, the final findings and reports. The most appropriate scientific 
outlets of the study findings will be journals dedicated to obesity, diabetes, and lifestyle and 
nutrition interventions more broadly (e.g., Obesity, Pediatric Obesity, International of Obesity, 
Diabetes Care, American Journal of Clinical Nutrition). Third, study results will be shared with 
researchers and professionals interested in diabetes and obesity. We expect that these findings 
may be of greatest interest to colleagues who provide care to adolescents with obesity.  Finally, 
aside from dissemination to the scientific community and health professionals, we intend to 
generate knowledge that can readily be integrated into the refinement of widely available, 

commercial weight management programs already available and used by youth with obesity that 
incorporate time-based recommendations. The long-term goal of this research is to generate 
knowledge regarding how time-based dietary programs can benefits pediatric patients with 
obesity. This work can inform the development of potentially low-cost, scalable, and sustainable 
interventions to optimize treatment recommendations for this high-risk population.  
  
Costs to Subjects 
There will be no cost to subjects. Subjects will not be accountable for any research costs.  
  
Consent Process 
The implementation steps of the proposed randomized controlled trial (RCT) are as 
follows:  
  
1.  Study staff will introduce the study to all eligible subjects and recruit and consent interested 
families.  
  
2. All participating subjects and their parent/legal guardian/family member will receive training 
on the use, application, and equipment for CGM. All equipment required will be distributed to 
the subject, and they will download the Dexcom app onto their personal smartphone setting up 
an account with a codename.  
  
3. Consented participants wear the CGM prior to being randomized to begin with one of three 
meal times (Early: test meal consumed at 8 AM; Afternoon: test meal consumed at 12 PM; Late: 
test meal consumed at 4 PM  (<30% protein, 10% fat, and 60% carbohydrates [CHO]) + blinded 
CGM. 
  
5. The study staff will conduct in person/virtual study assessments of subjects and their 
parent/legal guardian/family member at 3 time points throughout the study period. 
  
6. The study staff will perform weekly calls to assess barriers to adherence, review CGM data 
and perform dietary recall.  
  
7. The principal investigator (PI) will complete and oversee data management and analysis. 
  
  
Schedule of Study Procedures 
Visit 0 
Visit 1 
Visit 2 
Visit 3  
Study Visit 
Consent 
Visit 
Day 1 
Day 7 
Day 14 
Study Window 
NA 
+/-7 days 
+ /- 7 days 
+ /- 7 days 

**Consent Session 
X 
  
  
  
Randomization in mealtime 
assignment 
X 
X 
  
  
Weight and height measured 
  
X 
X 
X 
**CGM Use and Data Review: 
X 
X 
X 
X 
Time in range 
X 
X 
X 
X 
Education and equipment 
X 
  
  
  
CGM Placed 
X 
  
  
  
**24-hour Dietary Recall Collection 
  
X 
X 
X 
Research blood draw/fasting labs: 
glucose, insulin, c-peptide, glucagon, 
GLP-1, GIP, PP: -10, minutes. 
  
X 
X 
X 
Lab Testing: at post-meal samples 
glucose, insulin, c-peptide, glucagon, 
GLP-1, GIP, PP 
  
X 
X 
X 
Meal Test: 10, , 30, , 60, 90, 120, , 180 
minutes 
  
X 
X 
X 
**Surveys 
  
X 
X 
X 
Demographic information 
Parent/family member/guardian 
X 
  
  
  
Pittsburg Sleep Index 
Adolescent 
  
X 
X 
X 
Satisfaction Survey 
Adolescent 
  
  
  
X 
Compensation 
  
X 
X 
X 
  
**Subjects have the option of completing these procedures virtually via WebEx or over phone. If 
subject and/or parent/family member/guardian opts for this option, the study team will 
coordinate this with the subject.  
  
Process to Document Consent in Writing 
Participants will be recruited from Children’s Hospital Los Angeles (Los Angeles, CA). 
The typical approach will be through direct involvement with the treating physician. In their 
clinics, they will introduce the study to their patients and connect interested participants with the 
study staff. Research staff will carefully review the full consent form with the participant and 
parent or guardian in person or via phone, answering the participant’s questions about the study. 
Participants will be allowed to electronically sign consent forms online using DocuSign, 
REDCap, or printed forms in-person. Alternatively, research staff will review medical records of 
potential participants in order to identify participants who may be eligible. CHLA has natural 
language processing algorithms that allows for rapid searches of electronic medical records to 
identify patients with specified criteria for recruitment into studies. Research staff will first 
discuss potential participants with the PI and treating physician before making contact. After the 

initial recruitment process, a follow-up phone call will be made by a trained recruiter within one 
week to answer questions and solicit participation. Consent can be withdrawn from at any time. 
Potential participants will have the following carefully explained: (1) the investigational nature 
of the research; (2) the objectives of the research; (3) the procedures involved in the research; (4) 
any and all risks and discomforts due to participation; and (5) alternative options to participation 
that are currently available. Clarification questions will then be elicited from the potential 
participants and their parents/guardians. Only after the above will an IRB-approved document 
recording informed consent be signed as per institutional guidelines with a copy to be given to 
the participant and the original stored with the research record in a secure location. Data 
protection will be ensured by storing on an IS-approved university database on encrypted 
servers. All participants will be issued a study ID with data entered in de-identified manner. All 
databases will be password-protected with access only to the study team. All 
paper/documentation/research charts will be maintained in locked locations accessible only to 
the study team.  
  
The IRB has strict regulations for the approach to and documenting of assent by minors and 
consent by their parents/guardians. Documentation of assent/consent is done via IRB-approved 
study-specific forms. 
  
  
Setting 
• All research procedures will be conducted in Children Hospital Los Angeles (Los Angeles, 
CA). 
• The USC DORI may be utilized to collect study endpoints. At USC, study staff may 
complete study procedures during visits 1, 2, and 3 (refer to the Schedule of Study 
Procedure table). Additionally, research blood draws (baseline and post-meal samples will 
be assayed for glucose, insulin, c-peptide, GLP-1, GIP, PP at times -10, , 10, , 30, , 60, 90, 
120, and 180 minutes after glucose) will be completed.  
  
Resources Available 
  
  
  
  
  
  
  
  
  

  
  
  
  
  
  
  
 
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Statistical analysis  
Descriptive statistics and graphical depictions were utilized to assess the distribution of outcome 
variables. The primary outcome variables in this analysis were glucose, insulin, and c-peptide 
profiles and the main independent variables of interests were the time of meal consumption.  
  
Mixed-effects linear regression model was used to assess changes in glucose, insulin, and c-
peptide profile over the course of 180 minutes and the difference of first mealtime at 8:00AM, 
12:00PM, and 4:00PM univariately.  The difference of mealtime over the course of 180 minutes 
on glucose, insulin and c-peptide levels was assessed by including mealtime as an interaction 
term in the mixed-effects linear regression model. Due to the skewness of the distribution, 
differences in glucose, insulin, and c-peptide AUCs over 180 minutes and the insulinogenic 
index by mealtime were assessed on a logarithmic scale. Profiles that were significantly differ 
across meal timing were subjected to pairwise comparisons using the false discovery rate 
based on Simes' method. Changes in profiles were described using beta estimates (β) with its 
associated 95% confidence intervals and p-values. Pairwise comparisons were presented as 
percent changes with its associated 95% confidence intervals, unadjusted and adjusted p-
values.  
  
The secondary outcome variables included incretin levels and pancreatic hormones, which 
includes glucagon, pancreatic polypeptide, glucagon-like-peptide-1 (GLP-1), and glucose-
dependent-insulinotropic polypeptide (GIP).  Mixed-effects linear regression model was used to 
assess the changes in incretin levels and pancreatic hormones between pre- and post- 
intervention timepoints. Additionally, mealtime difference on the changes in incretin levels and 
pancreatic hormones was assessed by including an interaction term in the model, and these 
variables were analyzed on logarithmic scale. The distributions of incretin levels and pancreatic 
hormones were described in median and interquartile range by pre- and post- intervention 
timepoints.  The paired difference of pre and post was described using median and 95% 
confidence intervals by mealtime. Statistical significance was set at 0.05 with two-sided test and 
all statistical computations were performed in Stata/SE 18.0 (StataCorp, College Station, TX).