Impact of a Low-Carbohydrate Diet on Glycemic Control and Lipids in Pediatric Type 1 Diabetes
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Vanderbilt University Medical Center

Impact of a Low-Carbohydrate Diet on Glycemic Control and Lipids in 
Pediatric Type 1 Diabetes
Protocol Date: 06/25/2020
NCT #: 03997409 

Protocol Version #: 6  
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Impact of a Low-Carbohydrate Diet on Glycemic Control and Lipids in 
Pediatric Type 1 Diabetes 
Sara H. Duffus, MD  
Clinical Fellow 
Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics 
Vanderbilt University Medical Center 
Justin M. Gregory, M.D. 
Assistant Professor of Pediatrics 
Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics 
Vanderbilt University Medical Center 

Protocol Version #: 6  
 
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Protocol Date: 25June2020 
 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 

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1.0 
Background 
 
Chronic hyperglycemia worsens both microvascular and macrovascular 
complications for patients with T1DM1,2. After acute diabetes complications, 
cardiovascular disease (CVD) is the leading cause of death for adult T1DM patients3, 
making the prevention of chronic hyperglycemia critically important. Carbohydrate 
quantity and type affect post-prandial glycemia more than any other dietary factor in 
non-diabetic populations4,5. Additionally, consuming larger meals is associated with 
underestimation of carbohydrate quantity and mealtime insulin dose, leading to 
increased glucose variability5. These findings serve as the theoretical basis for 
implementing a carbohydrate restricted diet to improve HbA1c and decrease glycemic 
variability. Current dietary recommendations from the ADA for patients with T1DM6 align 
with guidelines from the Institute of Medicine for healthful eating in the general 
population7. While the ADA recommends individualization of dietary plans for patients 
with T1DM, most recent guidelines state that “evidence is inconclusive for an ideal 
amount of carbohydrate intake for people with diabetes”6. 
 
While LCDs have been associated with improved HbA1c in adults with T1DM, 
no randomized, prospective studies have evaluated the effect of a LCD on 
outcomes in the pediatric T1DM population.  Cross sectional and prospective 
studies in adults with T1DM have demonstrated improvement in HbA1c after a LCD8-11, 
but these studies have significant limitations including small sample size9 and 
methodologic flaws such as using HbA1c as both a dietary adherence marker and 
outcome measure10. Large observational12 and survey studies13 have revealed 
associations between lower carbohydrate intake and lower HbA1c in pediatric patients 
with T1DM. However, existing studies have major limitations, including significant 
selection bias and methodologic concerns, such as recruiting highly motivated 
participants from a social media group and using self-reported HbA1c as the primary 
outcome13.  No study to date has prospectively investigated the impact of a LCD 
intervention on glycemic control in children with T1DM in a randomized controlled 
design. To fill this knowledge gap, in Aim 1 we will test the hypothesis that a LCD 
intervention will improve HbA1c compared to a SCD in pediatric patients with type 1 
diabetes. 
 
Carbohydrate quantity and type affect post-prandial glycemia while also 
influencing low-density lipoprotein cholesterol (LDL-C)14.  Epidemiologic 
evidence suggests that LDL-C above 100 mg/dL is associated with increased 
cardiovascular disease (CVD) risk in patients with T1DM15. One study surveyed a social 
media group of pediatric T1DM patients who consumed a very low-carbohydrate diet 
(VLCD) and found glycemic control was excellent (HbA1c = 5.7%), but total cholesterol 
and LDL-C were elevated13.  These findings contrast with larger studies showing that 
LCD reduced LCL-C in adult populations of both non-diabetic and diabetic patients16.  
Further, experts have noted that directly measuring the number and size of LDL 
particles (LCL-P) using nuclear magnetic resonance (NMR) may better capture CVD risk17 
as suggested by multiple cross sectional18 and prospective studies 19-22.  In one 
prospective, parallel isocaloric nutrition study in overweight men, the percent dietary 
carbohydrate consumption was directly proportional to smaller (i.e. worse) LDL-P size23. 
No study has yet prospectively investigated the influence of a LCD on lipid profiles in 

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children with T1DM. In Aim 2, we will use NMR spectroscopy to comprehensively 
quantitate the atherogenic lipoprotein load by measuring lipoprotein particle number and 
size in addition to lipoprotein cholesterol concentrations. 
 
Dietary intake influences several life domains that may affect QOL, including 
social interactions, personal satiety, economic, physical, and psychological domains24. 
Significant challenges in prospective dietary intervention trials include high rates of 
attrition and difficulty maintaining participant compliance25, both of which are ultimately 
linked to the impact of the diet on QOL. While improved QOL with LCD interventions has 
been demonstrated in patient populations including obese adults24 and children with 
epilepsy26, findings are often confounded by improvements in the underlying disease 
process such as weight loss or improvement in seizure frequency, respectively. No study 
has prospectively evaluated the impact of a LCD intervention on QOL outcomes in 
pediatric T1DM, which will be investigated in aim 3.   
 
2.0 
Rationale and Specific Aims 
 
We hypothesize that pediatric patients with T1DM who consume a LCD will 
have improved HbA1c compared with T1DM patients who consume a 
standard-carbohydrate diet (SCD).  We further hypothesize that differences in 
lipidemia and quality of life (QOL) between the groups will be minimal. To test 
our hypotheses, we will employ a pragmatic nutrition education intervention. The study 
will randomize adolescent patients (ages 13-21 years) to one of three groups (n = 15 
per group). We will instruct participants to consume a LCD (group 1) or a SCD (group 
2), or provide no specific recommendations regarding diet (group 3). We will prescribe 
isocaloric diets for groups 1 and 2 equaling the estimated energy requirements of the 
Institute of Medicine7. Participants on the SCD intervention will consume 45-65% of total 
daily caloric intake from carbohydrates, 25-35% from fat and 10-30% from protein.  
Participants on the LCD intervention will consume 25-35% of total daily intake from 
carbohydrates, 45-65% from fat and 10-30% from protein. Group 3 will serve as a 
control that receives the same number of education sessions as groups 1 and 2 to teach 
general diabetes management but without specific dietary recommendations. This study 
design will allow for discrimination of the effect of the composition of the diet versus the 
effect of receiving any nutritional prescription. 
 
Nutrition interventions are effective in producing dietary behavior change among 
adolescents27, particularly when information and communication technologies (ICT) are 
incorporated28. Previous brief nutrition interventions teaching LCD or low glycemic index 
diets in T1DM patients have resulted in appropriate dietary adherence29,30. We will 
provide both traditional and ICT-based education and monitor dietary adherence with a 
smart-phone based nutritional tracking tool. 
 
Aim 1 will provide preliminary estimates of improvement HbA1c after a 
nutrition intervention that teaches a LCD versus education reinforcing a SCD 
to families of pediatric T1DM patients. To determine the primary outcome—change 
in HbA1c—we will obtain HbA1c at baseline and at 12 weeks after the nutrition 
intervention.  Additionally, we will quantify glycemic variability using continuous glucose 
monitoring (CGM) as a secondary outcome. Low rates of severe hypoglycemia, diabetic 

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ketoacidosis and growth attenuation have been reported in pediatric T1DM patients on a 
VLCD13, therefore, we anticipate low rates of these adverse events with the LCD 
intervention. 
 
Aim 2 will provide preliminary estimates of the change in the atherogenic 
lipoprotein profile in patients on a LCD versus SCD.  The primary outcome 
measure will be change in total LDL-P from baseline to 12 weeks after the nutrition 
intervention.  As secondary outcomes, we will measure the change in other contributors 
to atherogenic lipoprotein load, such as high-density lipoprotein particle (HDL-P) 
number, small LDL-P number, and LDL size.   
 
Aim 3 will provide preliminary estimates of the change in QOL in patients on a 
LCD versus SCD.  Participants will complete the PedsQL, a validated QOL measure in 
T1DM patients, and Problem Areas in Diabetes-Teen (PAID-T), a validated measure of 
diabetes-specific distress, at baseline (week 0) and at 12 weeks after the nutrition 
intervention31,32.  Additionally, parents of participants will complete the WHO-5 Well-
Being Index, a questionnaire for assessing subjective psychological well-being33, and 
Problem Areas in Diabetes-Parent Revised version (PAID-PR), a validated measure of 
perceived parental burden associated with caring for a child with diabetes.34 
 
We will perform an independent samples t-test to compare outcomes between groups, 
in addition to multilinear regression analysis to account for potentially confounding 
covariates, such as total daily dose of insulin, weight change, glycemic variability as 
measured by continuous glucose monitoring (CGM), and age.  
 
This proposed research will be the first prospective study to determine the effect of a 
LCD intervention on key diabetes outcomes in a pediatric T1DM population. This study 
will also provide a basis of training for a new pediatric investigator in the conduct of 
clinical trials under the mentorship of a highly successful mentorship team including Dr. 
Kevin Niswender and Dr. Justin Gregory.   
 
3.0 
Animal Studies and Previous Human Studies 
3.1 
Previous Human Studies – Adult T1DM Population  
A recent systematic review described eight studies that investigated the 
effect of a low-carbohydrate diet on glycemic control using HbA1c as the 
primary outcome.  Of these studies, four reported non-significant changes 
in HbA1c with a LCD while three reported statistically significant 
reductions8. 
 
3.2 
Previous Human Studies – Pediatric T1DM Population  
Published studies focused on the effects of a low carbohydrate diet on 
outcomes in pediatric T1DM have been limited to observational and 
survey studies.   
 
One study surveyed an online social media group of pediatric T1DM 
patients who consumed a very low-carbohydrate diet (VLCD) with an 
average carbohydrate intake goal of 36 +/- 15 grams of carbohydrates 
per day and found glycemic control was excellent with a reported mean 

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HbA1c of 5.7%13.  There were low rages of adverse events, including 
episodes of diabetic ketoacidosis (1%), hypoglycemia with seizure or 
coma (2%), hypoglycemia requiring assistance from others (12%), and 
hypoglycemia requiring glucagon (4%)13.   
 
A large cross-sectional observational study in 46,010 patients with T1DM 
aged 1 – 18 years in Germany and Austria found that lower carbohydrate 
intake was associated with lower HbA1c (p < 0.001) with the average 
HbA1c being 0.2% lower in the lowest quartile of carbohydrate intake 
than in the highest quartile12. 
 
4.0 
Inclusion/Exclusion Criteria 
 
Table 1: Inclusion and Exclusion Criteria  
Inclusion Criteria 
Exclusion Criteria  
• 
Currently receive care at the Eskind 
Diabetes 
Clinic 
at 
Vanderbilt 
University Medical Center 
• 
Diagnosed with T1DM for at least 
12 months 
• 
Age 13 to 21 years  
• 
Total daily dose of insulin 0.5 to 
1.5 units/kg/day 
• 
Current use of an insulin pump and 
CGM 
• 
Participant or parent of participant 
use of smart phone 
• 
Able to read and speak English  
• 
HbA1c between 7% and 10% 
• 
Any episode of diabetic ketoacidosis 
(DKA) in the last 12 months  
• 
Any 
episode 
of 
severe 
hypoglycemia (defined as requiring 
assistance from another person, 
including 
coma, 
seizures, 
or 
episodes requiring glucagon, IV 
dextrose 
or 
oral 
carbohydrate 
administered by another person1) in 
the last 12 months  
• 
Any prior abnormal fasting lipid 
panel (LDL > 130) 
• 
Additional dietary restrictions  
• 
Following 
a 
weight-loss 
or 
otherwise restrictive diet  
• 
Use of medication or supplements 
other than insulin to control blood 
glucose  
• 
Use 
of 
medication 
or 
other 
supplements to lower lipids  
• 
Pregnancy or breast feeding  
• 
History of hemoglobinopathy  
 
 
5.0 
Enrollment/Randomization 
 
5.1 
Recruitment 
5.1.1 Recruitment Resources 
We will use multiple tools to identify prospective study 
participants.  The PI will contact intramural and extramural 
endocrinology colleagues at Vanderbilt and in the region to 
discuss this study and ask them to refer potential subjects. The 

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Vanderbilt Eskind Diabetes Clinic is a large academic center that 
sees approximately 2,700 patients with T1DM annually. The study 
team will also use additional research tools including Research 
match, Subject locator, and My Research at Vanderbilt.  We will 
post flyers and send an institution-wide mass email through the 
Research Notifications Distribution List. In addition, we will post 
our research flyer on social media platforms (e.g. Facebook and 
Twitter) to target further potential T1DM and control group 
participants. For example, the Middle TN JDRF Chapter Facebook 
page has a large number of followers across the state of 
Tennessee many of whom may participate in our research.  
 
Participants will also be recruited from the Vanderbilt Children's 
Endocrinology Franklin 
 
  IRB-approved flyers will be posted in the 
clinic (both provider workroom and in patient care areas).  I will 
also ask my endocrinology colleagues at Vanderbilt who see 
patients at the Franklin clinic to refer potential subjects.   
 
5.1.2 Initial Contact with Potential Participants 
Once the research team becomes aware of a potential subject, we 
will either telephone the participant (or parents in the case of 
potential pediatric participants) or visit with them in person during 
an endocrinology clinic visit. The initial discussion will aim to make 
a preliminary assessment of whether the subject might be eligible 
to participate in the study.  Study personnel will ask the potential 
subject to share his or her: 
- 
Diagnosis of T1DM  
- 
Age 
- 
Weight 
- 
Height 
- 
Most recent HbA1c  
- 
Diabetes duration  
- 
Medications 
- 
History of severe hypoglycemia in the past 12 months 
- 
History of any episodes of DKA in the past 12 months 
- 
Food preferences and restrictions 
- 
Level of physical activity 
-  
Use of insulin pump and CGM  
-  
Ability to read and speak English 
 
Inclusion and exclusion criteria are listed in table 1. We will invite 
eligible subjects to participate in the initial screening visit. The 
initial screening visit will occur in the Vanderbilt Eskind Diabetes 
Center or Vanderbilt Children’s Endocrinology Franklin clinic. The 
participant will receive an electronic or paper copy of the informed 
consent document to review prior to the initial screening visit.  
 

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5.2 
Enrollment 
A member of the study team (i.e. key study personnel, KSP) will obtain 
written, informed consent or adolescent ascent with parental consent at 
the beginning of the screening visit as detailed in section 6.1.1.1. Once 
consent/assent is obtained, the participant will be enrolled in the study. A 
detailed description of special protection for adolescents as research 
subjects follows in section 7.2 below. 
 
The Vanderbilt Eskind Diabetes Center 
 
 
. 
 
The Vanderbilt Children's Endocrinology Franklin 
 
  The performance site at the Vanderbilt Children's Endocrinology 
Franklin clinic is not engaged in research.  KSP from this study would 
utilize the clinic space to meet with participants for study visits.  
Phlebotomists at this location would be utilized to obtain blood work, 
which would then be handled by KSP. 
 
5.3 
Randomization  
Random permuted blocks with a fixed size of 3 will be used for 
randomization into treatment groups. We will stratify participants based 
on open vs. closed loop insulin pump use and age prior to randomization. 
 
5.4 
Participant Compensation 
Research subjects will be compensated for their time and inconvenience 
in the study in the form money in the amounts specified below. Following 
study completion, participants will be mailed a check equal to the dollar 
amount below. 
 
- Visit 1 (Screening visit): the initial screening visit will last approximately 
2-3 hours. Subjects who complete their screening visit will be 
compensated $25. 
- Visit 2 (Week 1 visit): this visit will last approximately 2-3 hours.  
Subjects who complete this week 1 visit will be compensated $25. 
- Visit 3 (Week 12 visit): this visit will last approximately 1-2 hours.  
Subjects who complete this week 12 visit will be compensated $25. 
 
- Telephone visits (weeks 2, 4, 8): these visits will last approximately 30-
60 minutes.  Subjects who complete these visits will be compensated $10 
per visit. 
 
- 
Participants will receive full compensation for study visits and 
telephone visits only if they have completed all pre-visit tasks, which 
will be outlined in both the consent documentation and included in 
the written instructions participants are given in the preceding visit. 
 

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6.0 
Study Procedures 
 
6.1 
Research visits 
 
 
 
Figure 1: Study Timeline  
 
6.1.1 Study Visit 1, Initial Screening Visit (Week -2) 
Screening visits will take place in a room designated for research in the 
Eskind Diabetes Center or the Vanderbilt Children’s Endocrinology 
Franklin Clinic.  
 
The purpose of the screening visit is to:   
- 
obtain informed, written consent/assent,  
- 
conduct a history and physical exam,  
- 
confirm each participant is able to properly use their insulin pump and 
continuous glucose monitor (CGM),  
- 
calculate the estimated energy requirement to be consumed before 
during the study period,  
- 
show participants how to log their food intake on their digital device. 
 
The screening visit will consist of the following:  
6.1.1.1 
Consent/Ascent 
The PI or designated KSP will obtain consent/assent 
from all participants. Consent/assent will be obtained in 
a private room in the Eskind Diabetes Center or 
Vanderbilt Children’s Endocrinology Franklin clinic prior 
to beginning study procedures. The consent and assent 
form will be provided to the subject and family (if 
applicable) for review prior to the visit. The PI or 
designated Key Study Personnel will review the 
consent/assent forms with the family in detail and 

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provide time for discussing any questions. The study 
team will provide a copy of the consent/assent form to 
the participant and parents if applicable.  
 
6.1.1.2 
History and Physical Exam  
The PI or designee will review each subject’s clinical 
history, 
perform 
a 
physical 
exam, 
and 
take 
anthropometric measurements. 
 
6.1.1.3 
Nutritional Tracking App Instructions 
The study team will use a nutritional tracking 
smartphone 
application, 
such 
as 
Nutrihand, 
MyFitnessPal, or FatSecret, on which participants will 
log their daily caloric intake using the software’s web-
based or Smartphone app interfaces.  Participants will 
be asked to intermittent track intake using this 
smartphone app throughout the study. 
 
Participants may be asked to use their personal email 
to send a CSV file containing data files from the 
smartphone app to the study team.  This CSV file does 
not contain any PHI.  The file will be directly uploaded 
into REDCap, then the email will be permanent 
deleted. 
 
6.1.1.4 
Continuous Glucose Monitor Instructions  
The study team will instruct T1DM participants in the 
use of a continuous glucose monitor (CGM) such as 
Dexcom G6 or Medtronic Guardian for the monitoring 
of glycemia during the study. The team will then show 
T1DM participants how to upload CGM data into a 
HIPAA 
and 
FDA-compliant 
cloud-based, 
data-
integration platform such as Dexcom Clarity or 
Tidepool.  The team will show the control participants 
how to use the CGM device during this time. 
 
Participants in group 3 will also be asked to keep a 
manual blood glucose log intermittently throughout the 
study. 
 
6.1.1.5 
Insulin Pump Instructions 
The study team will instruct T1DM participants in the 
use of an insulin pump such as Medtronic Minimed 
670G, 
Tandem 
T-Slim, 
or 
Omnipod 
Insulim 
Management System for the adminsitration of insulin 
during 
the 
study. 
 
Instructions 
will 
include 
administering all insulin via insulin pump and recording 
all carbohydrates consumed into the insulin pump. The 

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team will then show T1DM participants how to upload 
insulin pump data into a HIPAA and FDA-compliant 
cloud-based, 
data-integration 
platform 
such 
as 
Medtronic Careline or Tidepool.  The team will show 
the control participants how to use the insulin pump 
device during this time. 
 
 
6.1.1.6 
Randomization 
We will then randomize patients to 1 of 3 groups: group 1 is low 
carbohydrate diet, group 2 is standard carbohydrate diet, group 3 
is general diabetes education without dietary recommendation.  
Each group will contain 15 participants.  Random permuted blocks 
with a fixed size of 3 will be used for randomization into treatment 
groups. 
 
6.1.2 Run In Period (Weeks -2 to 0)  
Participants will log all dietary intake in the smartphone nutritional 
tracking app, which will serve as a baseline of dietary habits.  
They will also be instructed to consistently wear the CGM and to 
administer insulin boluses using their pump’s bolus calculator. 
 
Participants in groups 1 and 2 will be asked to complete 
nutritional tracking in the smartphone app during this time.  
Participants in group 3 will be asked to complete a blood sugar 
and exercise log. 
 
6.1.3 Study Visit 2 (Week 0)  
This visit will correspond with the participant’s routine diabetes 
follow up at the Eskind Diabetes Center or Vanderbilt Children’s 
Endocrinology Franklin clinic with their primary endocrinologist. 
Each T1DM participant’s endocrinologist will manage his or her 
glycemic control and insulin doses throughout the study. The 
study team will review data from the nutrition log, CGM, and 
insulin pump.  Participants will be excluded for any of the 
following:  
- 
Tracking < 2 meals per day in the nutritional tracking app 
- 
Entering carbohydrates from < 2 meals per day in their insulin 
pump 
- 
Wearing CGM < 80% of run-in period.   
 
6.1.3.1 
History and Physical Exam  
The PI or designee will review each subject’s clinical history, 
perform a physical exam, and take anthropometric measurements. 
They will ensure the patient has an up to date intramuscular 
glucagon kit for treatment of hypoglycemia as needed. 
 
6.1.3.2 
Blood draw 

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Blood will be drawn from each participant and the following labs 
obtained:  
- 
HbA1c 
- 
Beta hydroxybutyrate 
- 
NMR spectroscopy lipoprofile. 
 
6.1.3.3 
Continuous glucose monitor and insulin pump data 
collection 
Continuous glucose monitor and insulin pump will be downloaded 
into a HIPAA and FDA-compliant cloud-based, data-integration 
platform such as Dexcom Clarity, Medtronic Carelink, or Tidepool.  
 
Information that will be collected from the continuous glucose 
monitor download will include (but not be limited to):  
- 
Percent of time spent above the glycemic target of 140 mg/dL 
- 
Percent of time spent in the glycemic target of 70 – 140 
mg/dL 
- 
Percent of time spent below the glycemic target of 70 mg/dL 
- 
Percent of time spent in hypoglycemia below 50 mg/dL 
- 
Average blood glucose 
- 
Blood glucose standard variation  
 
Information that will be collected from the insulin pump download 
will include (but not be limited to): 
- 
Average total daily dose of insulin 
- 
Average bolus amount of insulin per day 
- 
Average basal amount of insulin per day 
 
6.1.3.4 
Nutritional 
tracking 
smartphone 
application 
data 
collection  
 
Information that will be collected from the smartphone app will 
include (but not be limited to):  
 
- 
Total number of calories consumed  
- 
Average grams of carbohydrates consumed per day 
- 
Average grams of fat consumed per day 
- 
Average grams of protein consumed per day 
- 
Additional macronutrient data 
 
Participants will also be asked to photograph all food consumed in 
the 24 hours prior to the study visit.  At the study visit, they will 
complete a 24 hour dietary recall. 
 
6.1.3.5 
Quality of life survey 
Participants will complete the PedsQL, a validated QOL measure in 
T1DM patients, and Problem Areas in Diabetes-Teen (PAID-T), a 
validated measure of diabetes-specific distress31,32.  They will also 

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complete the Self-Care Inventory, a validated measure of 
adherence with diabetes self-care behaviors35. All surveys will be 
scored by a member of the research team. 
 
Additionally, parents of participants will complete the WHO-5 Well-
Being 
Index, 
a 
questionnaire 
for 
assessing 
subjective 
psychological well-being34, and Problem Areas in Diabetes-Parent 
Revised version (PAID-PR), a validated measure of perceived 
parental burden associated with caring for a child with diabetes33. 
All surveys will be scored by a member of the research team. 
 
6.1.3.6 
Diet Instructions 
From weeks 0 to 12, research participants in groups 1 and 2 will 
consume a weight-maintaining diet designed by the Vanderbilt 
Diet, Body Composition, and Human Metabolism Core and the 
research team.   
 
The research team will discuss food preferences with each 
participant to design diet plan with standard macronutrient 
contents. The Institute of Medicine formula7 or similar formula will 
be used to calculate the estimated energy requirement (EER).  
EER for males (kcal/day) = 662 – (9.53 × age [y]) + PA × (15.91 × 
weight [kg] + 539.6 × height [m]). 
Where PA is the physical activity coefficient: 
PA = 1.00 if PAL is estimated to be ≥ 1.0 < 1.4 (sedentary)  
PA = 1.11 if PAL is estimated to be ≥ 1.4 < 1.6 (low active)  
PA = 1.25 if PAL is estimated to be ≥ 1.6 < 1.9 (active)  
PA = 1.48 if PAL is estimated to be ≥ 1.9 < 2.5 (very active) 
 
EER for females (kcal/day) = 354 – (6.91 × age [y]) + PA × (9.36 × 
weight [kg] + 726 × height [m]) 
Where PA is the physical activity coefficient:  
PA = 1.00 if PAL is estimated to be ≥ 1.0 < 1.4 (sedentary)  
PA = 1.12 if PAL is estimated to be ≥ 1.4 < 1.6 (low active)  
PA = 1.27 if PAL is estimated to be ≥ 1.6 < 1.9 (active)  
PA = 1.45 if 
PAL 
is 
estimated to 
be ≥ 1.9 < 
2.5 
(very 
active) 
 
 

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Figure 2: Macronutrient Content of SCD and LCD  
 
The study team will devise two isocaloric diet plans for each 
participant in groups 1 and 2. One plan, the standard 
carbohydrate diet (SCD), will reflect the acceptable macronutrient 
distribution range of the Institute of Medicine’s Recommendations 
for Nutrition: carbohydrate (45%–65% of energy), protein (10%–
30% of energy), and fat (25%–35% of energy) (figure 2).7 The 
other plan, the low carbohydrate diet (LCD), will reduce the 
percent caloric intake from carbohydrates and replace that amount 
with calories from dietary fat. Thus with the LCD, 45%–65% of 
energy will come from fat, 10-30% of energy will come from 
protein, and 25%–35% of energy will come from carbohydrates 
(figure 2).  
Group 3 will serve as a control that receives the same number of 
education sessions as groups 1 and 2 to teach general diabetes 
management but without specific dietary recommendations. This 
study design will allow for discrimination of the effect of the 
composition of the diet versus the effect of receiving any 
nutritional prescription. 
 
6.1.3.7 
Quality Assurance of Interventions 
In order to ensure consistency in the education provided to each 
group, we will audio record 20% of study visit 2 in each group. Key 
study personnel who did not perform the educational intervention 
will review the audio recording and score for fidelity. These audio 
recordings will be strictly used to ensure consistency of the 
intervention, will not be used to collect data.  Audio files will be 
contained within REDCap.  
 
6.1.4 Management between study visit 2 and 3 

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Each T1DM participant’s will manage his or her glycemic control 
before and between study visits using insulin as prescribed by 
their primary endocrinologist. Participants will be instructed to 
contact the research team and will be removed from the research 
protocol in the event of any of the following: weight loss more 
than 10% from baseline or any episode of DKA or severe 
hypoglycemia. 
 
6.1.4.1 
Adherence monitoring  
The study team will monitor adherence by reviewing each 
participant’s dietary log, CGM data, and insulin pump data in an 
ongoing fashion. Should the research team detect suboptimal 
adherence a member of the team will contact the participant to 
help troubleshoot the reason for the suboptimal adherence. 
 
6.1.4.2 
Text Messaging 
Participants will receive text messages 2 to 4 times per week36 
that will provide reminders regarding key components of the 
dietary 
intervention, 
encouragement 
regarding 
diabetes 
management, and general positive quotes. The study team will 
create a bank of 50 text messages for each dietary intervention 
(LCD and SCD), and participants will receive 2 to 4 of these text 
messages per week.  Examples of message content include: “Try 
a breakfast high in protein! An omelet with a side of bacon would 
be a great choice” and “The only way of finding limits of the 
possible is by going beyond them and into the impossible – Arthur 
C. Clarke.”  The text message will be sent using the text 
messaging feature in RedCap with the Twilio messaging service 
and will contain no protected health information.  Text messaging 
will continue until participants have completed study visit 3. 
 
6.1.5 Telephone Visits (Weeks 2, 4, and 8)  
The study team will monitor adherence by reviewing each participant’s 
dietary log, CGM data, and insulin pump data.  The team will conduct a 
30 to 60-minute telephone session (either via Facetime, Skype, or phone 
call) with the participant. The study team will review with the participants 
their nutritional intake and reinforce key concepts from the diet to which 
they are assigned (LCD or SCD).  If the CGM is being worn less than 80% 
of the time or insulin pump is not being used to record more than 2 
meals per day, the study team will troubleshoot the reason for suboptimal 
adherence with the participant. 
 
Participants in groups 1 and 2 will be asked to complete nutritional 
tracking in the smartphone app during this time.  Participants in group 3 
will be asked to complete a blood sugar and exercise log. 
 
In the event that study visit 3 occurs more than 14 weeks after study visit 
2, we will conduct an additional telephone visit at week 12.  We will 

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continue to conduct a telephone visit every 4 weeks after week 12 until 
the participant has completed study visit 3. 
 
6.1.6 Study Visit 3 (Week 12)  
This visit will again correspond with the participant’s routine 
diabetes follow up at the Eskind Diabetes Center or Vanderbilt 
Children’s Endocrinology Franklin clinic with their primary 
endocrinologist. 
 
6.1.6.1 
History and Physical Exam  
The PI or designee will review each subject’s clinical history, 
perform a physical exam, and take anthropometric measurements. 
 
6.1.6.2 
Blood draw 
Blood will be drawn from each participant and the following labs 
obtained:  
- 
HbA1c 
- 
Beta hydroxybutyrate 
- 
NMR spectroscopy lipoprofile. 
 
6.1.6.3 
Continuous glucose monitor and insulin pump data 
collection 
Continuous glucose monitor and insulin pump will be downloaded 
into a HIPAA and FDA-compliant cloud-based, data-integration 
platform such as Dexcom Clarity, Medtronic Carelink, or Tidepool.  
 
Information that will be collected from the continuous glucose 
monitor download will include (but not be limited to): 
- 
Percent of time spent above the glycemic target of 140 mg/dL 
- 
Percent of time spent in the glycemic target of 70 – 140 
mg/dL 
- 
Percent of time spent below the glycemic target of 70 mg/dL 
- 
Percent of time spent in hypoglycemia below 50 mg/dL 
- 
Average blood glucose 
- 
Blood glucose standard variation  
 
Information that will be collected from the insulin pump download 
will include (but not be limited to): 
- 
Average total daily dose of insulin 
- 
Average bolus amount of insulin per day 
- 
Average basal amount of insulin per day 
 
6.1.6.4 
Nutritional 
tracking 
smartphone 
application 
data 
collection  
 
Participants in groups 1 and 2 will be asked to complete 
nutritional tracking in the smartphone app during this time.  

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Participants in group 3 will be asked to complete a blood sugar 
and exercise log. 
 
Information that will be collected from the smartphone app will 
include (but not be limited to): 
 
- 
Total number of calories consumed  
- 
Average grams of carbohydrates consumed per day 
- 
Average grams of fat consumed per day 
- 
Average grams of protein consumed per day 
- 
Additional macronutrient data  
 
Participants will also be asked to photograph all food consumed in 
the 24 hours prior to the study visit.  At the study visit, they will 
complete a 24 hour dietary recall. 
 
6.1.6.5 
Quality of life survey 
Participants will complete the PedsQL, a validated QOL measure in 
T1DM patients and Problem Areas in Diabetes-Teen (PAID-T), a 
validated measure of diabetes-specific distress31,32.  PedsQL will be 
scored by a member of the research team. 
 
Additionally, parents of participants will complete the WHO-5 Well-
Being 
Index, 
a 
questionnaire 
for 
assessing 
subjective 
psychological well-being34, and Problem Areas in Diabetes-Parent 
Revised version (PAID-PR), a validated measure of perceived 
parental burden associated with caring for a child with diabetes33. 
All surveys will be scored by a member of the research team. 
 
 
7.0 
Risks 
 
7.1 
The following risks associated with participation are considered: 
7.1.1 Suboptimal growth  
Adherence to a low carbohydrate diet has the potential to result in a low 
total caloric intake and lead to suboptimal growth. One small case series 
describes outcomes in 6 pediatric patients who consumed between 22 – 
75 grams of carbohydrates per day, including poor linear growth 
velocity13. However, both diet plans will be designed to maintain weight 
by using the Institute of Medicine or similar formula to calculate each 
participant’s individual estimated energy requirement and will provide a 
significantly larger number of grams of carbohydrates per day than the 
previously described case series.  Anthropomorphic measures will be 
taken at each study visit and participants will be removed from the study 
if they experience weight loss more than 10% from baseline. 
 
7.1.2 Hypoglycemia 

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Hypoglycemia is encountered intermittently by patients with T1DM as 
part of the natural consequence of diabetes management with exogenous 
insulin administration, and we do not anticipate that this risk will be 
increased by consuming a low carbohydrate diet. 
 
One study surveyed an online social media group of pediatric T1DM 
patients who consumed a very low-carbohydrate diet (VLCD) with an 
average carbohydrate intake goal of 36 grams per day and found low 
rages of adverse events, including hypoglycemia with seizure or coma 
(2%), hypoglycemia requiring assistance from others (12%), and 
hypoglycemia requiring glucagon (4%)13.  We anticipate that the rates of 
these events will be considerably lower in the current study given that the 
carbohydrate intake in both the low-carbohydrate and standard-
carbohydrate groups will be substantially higher than in the previously 
mentioned study. 
 
We will use the following safety provisions to minimize risk of 
hypoglycemia: Participants will wear a continuous glucose monitor 
throughout the study period and will be instructed to contact the study 
team for any episode of hypoglycemia (blood glucose <70). If 
hypoglycemia occurred, the study team would instruct the patient to be 
treated orally (administer 15 grams of carbohydrates in liquid form or 
with glucose tablets) if the patient is responsive and able to consume the 
treatment orally.  If the patient is unresponsive, the study team would 
instruct the participant’s caretaker to administer intramuscular glucagon.  
The study team will ensure that the participants have an up to date 
glucagon kit at time of enrollment.  
 
7.1.3 Diabetic Ketoacidosis  
During very low carbohydrate intake, the transition to utilizing fatty acids 
as a fuel source leads to production of ketone bodies in state known as 
dietary ketosis37.  In severely uncontrolled T1DM (ie when exogenous 
insulin is not adequately supplied), ketone bodies are produced in 
supranormal quantities and cause ketoacidosis37. In the T1DM population, 
consuming a low carbohydrate diet could potentially lead to dietary 
ketosis.  However, the low carbohydrate diet that we are utilizing in this 
study is not intended to induce ketosis. Participants will continue to 
consume enough carbohydrates at each meal to necessitate insulin 
administration, which suppresses ketosis.  
 
However, we anticipate that rates of ketoacidosis will be low given low 
observed rates of DKA in a population of adolescent T1DM patients on a 
very low carbohydrate diet (about 1%)13. Carbohydrate intake was 
significantly restricted in the very low carbohydrate study to less than half 
of the amount that we propose in the current study.  Therefore, we 
anticipate that rates of DKA will be equivalent to that typically 
experienced by patients with T1DM. 
 

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To monitor for ketosis, we will measure beta hydroxybutyrate levels at 
study visits 2 and 3.  Participants will additionally be instructed to contact 
the study team if they have any clinical signs of developing ketoacidosis, 
including abdominal pain, vomiting, and presence of urine ketones at 
home.  
 
7.2 
Special Protections for Adolescents as Research Subjects 
Because the study includes adolescent T1DM subjects between ages 15-
18, special consideration has been given to provisions designed to protect 
children as outlined in 45 CFR 46, Subpart D. 
 
7.2.1 Justification and rationale for inclusion of adolescent subjects with 
T1DM 
Chronic hyperglycemia worsens both microvascular and macrovascular 
complications for patients with T1DM1,2. After acute diabetes  
complications, cardiovascular disease (CVD) is the leading cause of death 
for adult T1DM patients3, and it is clear that the mechanisms that 
contribute to macrovascular disease are present early in the natural 
history of T1DM38.  The atherosclerotic changes of macrovascular disease 
in T1DM appear to begin in childhood and adolescence39,40. Therefore, 
identifying strategies for the prevention of chronic hyperglycemia to 
prevent micro- and macrovascular complications is critically important in 
the childhood and adolescent T1DM population. 
 
Carbohydrate quantity and type affect post-prandial glycemia more than 
any other dietary factor in non-diabetic populations4,5. Additionally, 
consuming larger meals is associated with underestimation of 
carbohydrate quantity and mealtime insulin dose, leading to increased 
glucose variability5. These findings serve as the theoretical basis for 
implementing a carbohydrate restricted diet to improve HbA1c and 
decrease glycemic variability with the ultimate goal to prevent CVD. 
 
7.3 
Assessment of risk to adolescent participants relative to 45 CFR part 46, 
subpart D 
It is our impression that T1DM subjects would fall under 45 CFR 46.406, 
as outlined in Vanderbilt’s Human Research Protections Program Policy 
Number IX.A, section II.C.  The proposed research is likely to yield 
generalizable knowledge about these adolescents’ condition. Specifically, 
 
7.3.1 The risk represents a minor increase over minimal risk. 
7.3.2 The procedure presents experiences to participants that are 
reasonably commensurate with those inherent in their actual or 
expected medical situation. 
7.3.3 The procedure is likely to yield generalizable knowledge about the 
participants’ disorder or condition, which is of vital importance for 
the understanding or amelioration of the participants’ disorder or 
condition. 

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7.3.4 Adequate provisions are made for soliciting assent of the children 
and permission of their parents or legal guardians as detailed in 
the present IRB application. 
 
7.4 
Discussion of Risks as Part of the Consent Process  
The study team will discuss all procedures, risks, and benefits with 
potential study participants, as part of the consent process. An IRB 
approved written informed consent document will be required for 
participation in this study. It is understood that consent is a process and 
not a discrete event.  A participant’s decision to withdraw consent will be 
respected throughout the duration of each subject’s participation in this 
study. It is also understood that there may be as-yet unknown or 
unanticipated adverse effects of this study. The study team will 
continually monitor for these effects and consider altering the protocol as 
needed to ensure patient safety.  Changes in the procedures of the study, 
as well as any change(s) in the risks and/or benefits will be presented to 
and discussed with the subjects upon approval from the IRB for 
implementation of such revision(s), and any IRB revised written consent 
will be signed, as appropriate.   
 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
 
8.1 
Serious Adverse Events 
8.1.1 Defining Serious Adverse Events 
Consistent with FDA guidelines, serious adverse events (SAEs) will 
be defined as any untoward medical occurrence that: 
- 
requires inpatient hospitalization 
- 
results in persistent or significant disability 
- 
is suspected to cause a congenital anomaly or birth defect in a 
subject's unborn child 
- 
is life-threatening 
- 
results in death 
- 
is considered to be an important medical event based on 
appropriate medical judgement (e.g. bronchospasms requiring 
emergency department referral, seizures that might not result 
in hospitalization). 
 
8.2 
Assessing relationship between a SAE and relationship to study 
procedures 
An SAE's relationship to the study procedures will be assessed and 
graded as either: not related, unlikely, possible, probable, or definite. 
 
8.3 
Assessing whether an AE is an anticipated problem 
Any AE will be assessed for whether or not it was an anticipated problem. 
In accordance with Department of Health and Human Services guidance 
and consistent with 45 CFR part 46, an "unanticipated problem" will 

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include any incident, experience, or outcome that meets all of the 
following criteria: 
1. unexpected (in terms of nature, severity, or frequency) given  
a. the research procedures that are described in the protocol-
related documents, including the IRB-approved research 
protocol and informed consent document; and  
b. the characteristics of the subject population being studied; 
related or possibly related to participation in the research; and 
2. suggests that the research places subjects or others at a greater risk 
of harm. 
3. related or possibly related to participation in the research; 
4. suggests that the research places subjects or others at a greater risk 
of harm than was previously known or recognized. 
 
8.4 
Unanticipated, non-serious AEs 
All unanticipated, non-serious AEs and the study team’s response to the 
non-serious AE will be included in a report at the time of annual 
continuing review.  The PI will review the AEs and notify the Data Safety 
Monitor (DSM) and the IRB of any changes needed to the protocol. If 
needed, appropriate changes will be made to the consent form.   
 
8.5 
Unanticipated SAEs 
In accordance with IRB policy, any unanticipated SAE that is considered 
possibly related to participation in the study will be reported within 7 
calendar days of the PI's notification of the event to the IRB and DSM. 
The study team will continue to follow or obtain documentation of the 
resolution of any SAE.   
 
8.6 
Adverse Event Reporting 
The annual summary of all unanticipated adverse events and any audit 
reports will be sent to the IRB at the time of continuing review. A copy of 
this report will also be sent to the NIH who currently funds the PI on a 
T32 grant.   
 
Data and safety monitoring activities for this study will continue until all 
subjects have completed their participation and until a sufficient amount 
of time has passed beyond which any study-related AEs are unlikely.   
 
This protocol will be reviewed annually (at a minimum) by the Vanderbilt 
IRB.  The goal of this process is to determine the risks and benefits of the 
study in the actual experience of subjects and that measures taken to 
minimize risks are adequate 
 
9.0 
Study Withdrawal/Discontinuation 
 
Subjects will be free to withdraw from the study at any time, which will be made clear at 
enrollment. Subjects will be withdrawn from the study if:  
- 
Pregnancy is detected 

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- 
The PI’s (or designated MD, NP, or PA KSP) medical judgement is that 
participation places the subject at risk for harm 
 
10.0 Statistical Considerations 
 
10.1 
Recruitment and Sample Size Justification  
We have targeted an accrual of 40 participants in this pilot study to 
achieve two goals. First, we require a sufficient number of participants to 
estimate the effect size and variance of the LCD as a means to reduce 
HbA1c in T1DM in a future definitive trial. We utilized the method of 
Whitehead et al. to estimate our pilot study’s optimum accrual, which 
proposes stepped increases in sample size based on the anticipated 
standard difference, d, between interventions41,42.  We defined the 
minimum important difference (MID) in ΔHbA1c between LCD and SCD 
interventions as 0.3% and estimated a pooled SD of 0.8% based on our 
literature review9.  If d=MID/SDpooled=0.3%/0.8%=0.38, a sample size 
of 20 participants per arm will optimize future sample size calculations for 
the definitive study, while allowing for up to 40% dropout.  Second, this 
sample size allows for up to 4 degrees of freedom in multivariable linear 
regression analysis. 
 
10.2 
Statistical Analysis  
Statistical analysis will be performed using an independent samples t-test 
to compare change from baseline to 3 months post-intervention values 
from each aim (∆HbA1c, ∆LDL-P, and ∆QOL score) between the two 
groups.  We will also perform a series of multivariable linear regression 
analyses with change in primary outcomes from each aim (∆HbA1c, 
∆LDL-P, and ∆QOL score) from baseline to 12 weeks post-intervention as 
the dependent variable. Explanatory variables in the multivariable linear 
regression modeling will include mean total daily dose of insulin 
normalized for body mass, weight change, coefficient of variation of 
glucose as measured by CGM, and age.   
 
 
11.0 Privacy/Confidentiality Issues 
 
A database will be designed for this study using REDCap (Research Electronic Data 
Capture) tools. REDCap is a secure, web-based application designed to support data 
capture for research studies, providing validated data entry, audit trails, seamless data 
downloads to common statistical packages, and mechanisms for importing data from 
external sources. It will reside on a secure server with access provided exclusively to the 
research personnel. Subjects will be identified with a study identification number. A key 
to the subject identification number will be kept in a separate locked file drawer to 
which only the Principal Investigator and research coordinators have access. Reports will 
thereby be generated without Protected Health Information (PHI) data, and access will 
be restricted so that statisticians, etc. don't have access to all data. 
 

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Risk of leakage of PHI is minimized by keeping paper records in a locked cabinet and 
maintaining computerized records in the password protected REDCap data base. The 
principal investigator and the research staff are trained in HIPAA privacy regulations. 
The participant's identification is concealed, and a number is used as the identifier 
instead of the subject's name.  Only the principal investigator or members of the 
research team will have the list of study patient's names as the correlate with the study 
number. 
 
12.0 Follow-up and Record Retention 
 
The study is anticipated to last for up to three years.  The study results will be 
maintained indefinitely for research purposes. 
 
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