Accelerating Solutions to Optimize Glycemic Control and Weight Management In Young Adults With Type 1 Diabetes
Phase: NA
Conditions: Diabetes Mellitus, Type 1, Overweight and Obesity
Sponsor: University of North Carolina, Chapel Hill

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Advancing Care for 
Type 1 Diabetes and Obesity Network (ACT1ON) 
 
 
 
NCT number  NCT03651622 
Document Date   06/15/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY PROTOCOL 
 
 
Complete Title: 
 
 
 
Short Title: 
 
 
Sponsor: 
 
 
 
 
 
 
Original Protocol Date: 
 
 
 
Accelerating Solutions to 
Optimize Glycemic Control 
and Weight Management in 
Young Adults with Type 1 
Diabetes 
 
ACT1ON Phase 2 (SMART 
Pilot) and Phase 3 (Efficacy 
trial development) 
 
National Institutes of 
Health/NIDDK DP3DK113358-
01 
 
May 30, 2018 
 
 
 
 
 
 
Study Principal Investigators (Multi-PI): 
 
 
 
 
 
 
 
 
Elizabeth J Mayer-Davis, PhD 
UNC Chapel Hill 
245A Rosenau Hall, CB 7461 
Chapel Hill, NC, 27599 
919-966-1991 
mayerdav@email.unc.edu 
 
David Maahs, MD, PhD 
Stanford University 
 
Richard Pratley, MD 
Translational Research 
Institute for Metabolism and 
Diabetes 
Orlando, FL 

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Contact PI: 
Elizabeth Mayer-Davis, PhD 
University of North Carolina at Chapel Hill 
Protocol Version: 7 
Version Date: June 15, 2020 
 
I confirm that I have read this protocol and understand it. 
 
Principal Investigator Name: 
_____Beth Mayer-Davis_____________________ 
 
Principal Investigator Signature: ___
_________ 
 
Date:  
 
 
 
June 15, 2020____________________________ 
 
 
 
Complete Title: 
 
 
 
Short Title: 
 
 
 
 
Accelerating Solutions to Optimize Glycemic Control 
and Weight Management in Young Adults with Type 1 
Diabetes 
 
ACT1ON Phase 2 (SMART Pilot) and Phase 3 
(Efficacy trial development) 
 
 
 

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List of Modifications 
Version 8, June 15, 2020 
Our team has made the decision to cease recruitment and enrollment of new subjects. 
We have changed our target enrollment numbers in the protocol and IRB application to 
reflect this. 
 
We are adding an incentive of $50 as compensation for the extra time that participants 
have spent in the study due to COVID-19 related delays. 
 
We are amending the protocol to reflect a change to microbiome collection. Currently 
enrolled participants who agreed to microbiome and delivered a sample at baseline, will 
be eligible to collect a sample at M3 and M4 as well for an additional incentive. 
 
We are making it clear that now that we are no longer doing a blood draw and not 
collecting stored whole blood and plasma, and therefore are not asking participants to 
fast, that we will not ask participants to report their blood sugar or whether or not they 
have had anything to eat in the last 8 hours. The only fields of the ‘specimen collection 
form’ that we will complete are those that pertain to the HbA1c collection, that is, time 
and date of collection along with any problems the participant may have had.  
 
List of Modifications 
Version 7, April 27, 2020 
Continued response to COVID-19: moving entire study to virtual measurement 
visits. 
As it becomes clear that the ramifications of the COVID-19 will hinder our ability to 
conduct study processes as originally designed for the indefinite future, the study team 
has decided to transition all data collection to remote conduct. All measurement visits 
will be accomplished virtually, as described in the protocol, and new participants at each 
site will be enrolled into the study via a virtual visit in order to meet our original 
recruitment goals.  
o Some elements of data collection that were not necessary for 
randomization cannot be accomplished remotely. This includes: 
 DXA body scan 
 Stored whole blood for future analysis 
These elements of the study will be discontinued. 
We are reinitiating microbiome stool collection at Baseline and 3-months for 
eligible participants, as this can be done remotely. Additionally, we will add 
microbiome collection at 6- and 9-months for those participants who have provided 
baseline samples. This will allow for achievement of our originally intended sample 
size, given the need to stop recruitment in light of COVID-19. Incentives will 
increase and be $70.00 for 6-month stool samples and $90.00 for 9-month samples. 
Included, but separate from COVID-19 Provisions 
Additionally, we are adding a physical activity tracking part of the study, described in 
Appendix 1. All participants will be given the opportunity to participate in this new 
addition to the study.  

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Ketone data collection will also be discontinued as participants are not monitoring their 
ketones even though kits are being provided.  
 
List of Modifications 
Version 6, March 19, 2020 
AMENDMENT TO CLARIFY PROCEDURES IN LIGHT OF COVID-19 
Due to efforts to minimize the spread of Coronavirus, as of 3/19/2020, all form collection 
will be done online (or Zoom/phone interview if participants need help with completing). 
For the in-person part of the visit, this will be limited to A1c draw only and physical 
measures. We are stopping DXA, microbiome, and CGM for the time being, as these 
are not necessary to participant's safety and well-being. 
The only procedures that will be conducted at in-person visits are: 
• 
Height/weight/waist (completion of physical exam form by staff) 
• 
A1C draw (completion of specimen form by staff) 
Should the University move to restrict all participant in-person visits, we will promptly 
inform our participants utilizing the attached letter that they will remain on their current 
diet for an extended period of time and resume measurement visits and potential re-
randomization only when it has been deemed safe to do so. 
In this scenario, participants will remain on the diet they are currently assigned to and 
have virtual check-ins every other week with their study RD. 
RDs will use their skills and rapport with participants to work through issues related to 
the diet, anticipating that this is a time of increased stress due to financial, health, and 
other concerns. 
If it is necessary for participants to remain on diets for longer than the predetermined 
intervention period, analysis will take time difference into account.  
We will resume regular visit protocol once the University’s guidance changes and we 
are permitted to conduct measurement visits in-person again. 
List of Modifications 
Version 5, January 17, 2020 
• Protocol amendment to include that screening A1C must be from within last 6 
mos (not formally stated) 
• We are making a change in the protocol that we will replace people who dropped 
out of the study before randomization. This will change our total number to be 
enrolled at UNC from 42 to 44. 
List of Modifications 
Version 4, March 18, 2019 
• Changes throughout protocol to update with new screening process 

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• Changed order of inclusion and exclusion criteria 
• Reordered information about the participant targets at each site to improve 
protocol flow 
• Added that we will use EPIC and a subscription service ‘Accurint’ will be used to 
search for updated contact information if previously obtained contact info is not 
working 
• May use messaging through MyChart for recruitment (TraCS is checking study 
eligibility). 
 
List of Modifications 
Version 3, October 10, 2018 
• Protocol Synopsis and Intervention section: edited dietary fat information in the 
low carb diet 
• 
Protocol Synopsis and Recruitment section: Exclusion criteria- Added exclusion criteria 
of having lost 10 or more pounds in the last 6 months. (Note: this is already on the IRB-
approved screening form, but language is being added to the protocol). Updated 
inclusion criteria to reflect BMI of 27-39.9 (revised from 27-39) 
• 
Section 6. Process of Obtaining Consent 
o Added description of the consent comprehension checklist, which will be used to 
guide the conversation between study coordinators obtaining consent and 
participants. The purpose of this form is to ensure participant understanding of 
what they are consenting to and informed consent itself. 
• 
Recruitment – exclusion criteria: took out that those with prohibitive dietary restrictions 
would be excluded as this has been subsumed by those unwilling to follow study diet will 
be excluded. 
o Added emailing as an option to deliver recruitment materials to participants at all 
stages of recruitment, beginning with the initial mailing. 
• 
Section 12: Edited blood volume from DNA storage from 8.5 ml tube to 10 ml tube. Total 
blood volume drawn at baseline visit increased from 20.5 to 22 ml. 
List of Modifications 
Version 2, August 2018 
Abbreviation List 
• Changed DEXA to DXA in abbreviation list and throughout. Added DXA-related 
abbreviations (LM, FM, VAT, AG, and FFM) to list of abbreviations. 
Protocol Synopsis 
• Edited total study time to be 10.5 months (this change comes from adding 14-day 
wear time for CGM following each measurement visit) 
• Updated inclusion criteria to reflect BMI of 27-39 (revised from 25-39) 
• Updated exclusion criteria to remove exclusion based on celiac disease. Edited 
language related to diet-related exclusion. Edited language to exclude individuals 
that have delivered a baby in the last 12 months. Edited exclusion criteria to 
reflect individuals unwilling to follow any of the three study diets (rather than 
unwilling to adjust insulin dosing to accommodate the three study diets) 
• Updated Efficacy Evaluations to reflect 14-day CGM wear time (changed from 7-
day CGM wear time) 

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Section 1. Executive Summary 
• Edited total study time to be 10.5 months 
Section 3. Study Objectives 
• Edited total study time to be 10.5 months 
Section 5. Selection & Recruitment of Subjects 
• Updated exclusion criteria to remove exclusion based on celiac disease.  
Edited language related to diet-related exclusion.  Edited language to exclude 
individuals that have delivered a baby in the last 12 months.  Edited exclusion 
criteria to reflect individuals unwilling to follow any of the three study diets 
(rather than unwilling to adjust insulin dosing to accommodate the three study 
diets) 
• Updated inclusion criteria to reflect BMI of 27-39 (revised from 25-39) 
• Added email as option to share materials during the recruitment process 
Section 6. Process of Obtaining Consent 
• Added language to detail providing instructions to participants accessing the 
online data management system for self-administered forms 
• Added language regarding completion of study forms prior to the baseline 
visit if consent is provided via an online consent form 
• Added clarification on involuntary withdrawal to include difficulties with 
glycemic control (per investigators’ discretion). 
Section 7. Randomization 
• Edited total study time to be 10.5 months 
Section 8. Standardized Measurements 
• Updated CGM wear time to 14 days (from 7 days) and CGM procedures to 
reflect initiation of CGM at each in person visit 
• Clarified DXA scan will be full body scan and added details regarding scan 
procedures and outcomes of interest 
• Moved waist circumference under additional measures (from primary 
measures) 
• Removed insulin dosing from measurements 
• Listed Demographics separate from Health History (now on separate form) 
• Stored blood will now be collected as a fasting sample 
• Adding collection of blood ketones (weekly for individuals on a low 
carbohydrate diet) 
Section 9: ACT1ON SMART Pilot Intervention 
• Edited total study time to be 10.5 months 
• Corrected intervention description to show 8 in person sessions and 15 phone 
“check-in” 
• Edited the fidelity description to clarify details of fidelity review 
Section 12: Potential Risks, Discomforts, Inconveniences and Precautions 
• Updated blood draw volume to reflect total amount of 20.5 ml per visit at the 
baseline visit and 12 ml at other study visits. 

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• Remove that study HbA1c results will be shared with participants and 
providers 
• Changed time for storage of blood/plasma from 5 to 10 years after study has 
ended. 
Section 15: Privacy and Confidentiality 
• Added details regarding local Microsoft Access database to track participant 
contact information and contacts. 
Section 16: Study Timeline 
• Updated study timeline to reflect recruitment beginning in September and 
data collection ending in November 2020 
 
 
 
CONTENTS 
List of Abbreviations: .................................................................................................................. 7 
Protocol Synopsis ...................................................................................................................... 7 
1. 
Executive Summary ...........................................................................................................11 
2.  Background and Significance ...............................................................................................12 
3.  Study Objectives ..................................................................................................................15 
4.  Site Descriptions and Targets ..............................................................................................15 
5.  Selection & Recruitment of Subjects ....................................................................................16 
6.  Process of Obtaining Consent ..............................................................................................18 
7.  Randomization .....................................................................................................................18 
8.  Standardized Measurements ...............................................................................................20 
8a. Primary Outcomes ........................................................................................................... 20 
8b. Secondary outcomes: ...................................................................................................... 20 
8c. Dietary Intake and Physical Activity ................................................................................. 23 
8d. Potential Mediators .......................................................................................................... 23 
8e. Additional Measures ........................................................................................................ 23 
8f. Study Acceptability ........................................................................................................... 25 
9.    ACT1ON SMART Pilot Intervention ....................................................................................25 
9a. SMART Pilot Overview .................................................................................................... 25 
9b. SMART Pilot Procedures ................................................................................................. 26 
9c. Intervention Components ................................................................................................. 27 
10. Data management ...............................................................................................................28 
11.  Statistical Considerations ...................................................................................................28 
12.  Potential Risks, Discomforts, Inconveniences, & Precautions: ...........................................31 
13. Risk/Benefit Analysis ...........................................................................................................35 

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14.  Data Safety & Monitoring: ..................................................................................................36 
15.  Privacy & Confidentiality .....................................................................................................38 
16.  Study Timeline ...................................................................................................................41 
 
List of Abbreviations:  
AE – Adverse Event 
AG – Android/Gynoid 
BF% - Body Fat Percentage 
CGM – Continuous glucose monitoring 
DCCT – Diabetes Control and Complications Trial 
DXA – Dual-Energy X-ray Absorptiometry  
DKA – Diabetic Ketoacidosis 
DSMB – Data Safety and Monitoring Board 
FDA – Food and Drug Administration  
FFM – Fat Free Mass 
FM - Fat Mass 
LM - Lean Mass 
MI – Motivational Interviewing 
PSST – Problem Solving Skills Training 
SAE – Serious Adverse Event 
SMBG – Self Monitored Blood Glucose 
SMART– Sequential, Multiple Assignment Randomized Trial  
T1D – Type 1 Diabetes 
TRI-MD – Translational Research Institute for Metabolism and Diabetes 
VAT - Visceral Adipose Tissue 
Protocol Synopsis 
Study Title 
Accelerating Solutions to Optimize Glycemic Control and Weight Management 
in Young Adults with Type 1 Diabetes 
Funder 
National Institutes of Health/NIDDK 
Clinical Phase 
Phase 1 
Study Rationale 
The prevalence of overweight and obesity among individuals with type 1 
diabetes now parallels that of the general population and contributes to 
cardiovascular disease. There is a compelling need to develop behavioral 
interventions that are designed to optimize not just one, but two key 
outcomes—glycemic control and weight status—and that are responsive to the 
unique metabolic, clinical, and behavioral context of T1D. Upon completion of 
the work, we will have established a rigorous adaptive design for an efficacy 
trial of behavioral interventions that will be acceptable to young adults with 
T1D. 
Study 
Objectives 
Primary 
• 
To assess acceptability and adherence to three distinct, evidence-
based dietary approaches designed to address weight management 
and glycemic control. 
• 
To generate data required to inform and develop a fully powered 
SMART design trial. 

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Test Article(s) 
o Diet 1: hypocaloric, moderate low fat (30% calories from fat) weight 
management based on the Look AHEAD study  
o Diet 2: hypocaloric, low carbohydrate (15-20% calories from 
carbohydrate with fats being at least 37% monounsaturated fat and 
<10% as saturated fat)  
o Diet 3: advice to select a healthy Mediterranean dietary pattern with no 
caloric restriction  
Behavioral counseling strategies, use of carbohydrate counting for insulin 
dosing, and encouragement of usual level of physical activity will be the same 
across the 3 diets. 
Study Design 
This is an initial pilot and feasibility study using a Sequential, Multiple 
Assignment, Randomized Trial (SMART) design to identify acceptable and 
effective dietary strategies to optimize both glycemic control and weight 
management. This pilot study will be done at UNC and Stanford.   
Sequential randomization will occur following the baseline, 3 months, and 6 
months.  Following the baseline data collection and a short run-in period, 
participants will be randomized to one of the three diets (stratified by site with 
block size of 4). Using a priori decision rules following the 3 and 6 month visit 
post-initial randomization, those for whom the diet assigned is not acceptable 
or is not effective will be re-randomized. A total follow-up time of 10.5 months 
allows for evaluation of the effect of the diets on initial weight loss and on early 
maintenance of initial weight loss. The decision criteria for re-randomization will 
incorporate both clinical outcomes (glycemic control and weight change) and 
acceptability of the diet to the participant. 
Subject 
Population 
Key Criteria for 
Inclusion and 
Exclusion 
Inclusion Criteria 
1. Individuals ages 19-30 years old 
2. History of type 1 diabetes for greater than one year 
3. HbA1C less than 13% within the last 6 mos.  
4. BMI of 27-39.9 at time of phone screening 
 
Exclusion Criteria 
The study will exclude based on the following criteria: 
1. Individuals with other metabolic disorders, diagnosed eating disorder, 
prohibitive strict dietary restrictions, or those with other serious condition 
that renders participation inappropriate. 
2. Individuals that have experienced DKA or severe hypoglycemia 
requiring outside assistance in the last 6 months. 
3. Females who are pregnant, breast feeding, planning to become 
pregnant during the study period or delivered a baby in the last 12 
months 
4. Individuals unwilling to follow any of the three study diets. 
5. Individuals who are unwilling to monitor blood glucose at least three 
times a day. 
6. Individuals who have lost 10 or more pounds in the last 6 months. 
Number of 
Randomized 
Subjects  
84 randomized subjects (42 at UNC, 42 at Stanford) 
Participants withdrawn from the study before randomization will be replaced. 
Study Duration 
Each subject’s participation will last approximately 10.5 months. 

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Study data collection is expected to end by November 2020. Grant funding 
ends April 2021. 
Study Phases 
1. Screening: screening for eligibility, recruiting and obtaining consent 
2. Intervention: study intervention (randomization to diets) 
(Note: Each clinical site will recruit approximately four participants a month 
over 12 months.  Intervention will be ongoing once enrollment has begun.) 
Efficacy 
Evaluations 
Glycemic control: HbA1c and percent time in hypoglycemia (continuous glucose 
monitor worn for 14-days at each measurement visit). Change in weight. 
Safety 
Evaluations 
Participants will be asked about hypoglycemic events at each study visit and RD 
session (in person and telephone). The RDs will communicate regularly with the 
study endocrinologist to review labs and self-monitored blood glucose (SMBG) 
data to ensure appropriate insulin dosing. 
Statistical and 
Analytic Plan 
We will primarily compare the 3-month response rates to each of the 3 initial 
diets using standard statistical comparison procedures (e.g., t-tests and 
ANOVA) for differences in glycemic control (HbA1c and percent time in 
hypoglycemia) and change in weight. 
 
In addition, we will conduct a series of secondary, hypothesis-generating 
analyses using standard statistical approaches as well as more complex fixed 
and mixed effect regression methods such as generalized additive models and 
random forests for these outcomes plus body fat and fat free mass.  
Data and Safety 
Monitoring Plan 
Data quality and safety monitoring will occur both within the research team 
(data quality committee) (monthly) and a 4-member DSMB (to meet twice 
yearly). 
 
Participant accrual and retention, progress, completeness of standardized 
measures, and attendance at intervention sessions will be monitored. All 
aspects of data collection and data storage will be carefully monitored to 
ensure rapid detection of errors, inconsistencies or other problems.  
Distributions of key variables will be monitored for data quality and safety. 
AE and SAE, as defined by NIH, will be reported to the local site 
investigator and corresponding IRBs. AE/SAEs will be reviewed 
monthly. 
 
Summary of changes related to COVID-19 Provisions, submitted with Protocol Version 
7: 
As of April 2020, we are transitioning the entire study to a virtual format. All follow-up visits will 
be conducted virtually, and we will continue to enroll new subjects remotely as well. We are 
making changes according to the following table, described in detail in the protocol document: 
Data element 
Method and 
timepoint 
conducted 
previously 
Method and 
timepoint 
conducted now 
Major changes 
Anthropometrics 
Height 
In-person, all visits At home, baseline 
only 
For existing participants, will use 
baseline height (avg of 2 closest). For 
new participants, the home height 
procedures (Section 8a) will be used. 
Weight 
In-person, all visits At home, all visits 
Participants will use their BodyTrace 
scale provided as part of their study 
participation to measure their weight 

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according to the home weight 
procedures (Section 8a). 
Waist 
circumference 
In-person, all visits At home, all visits 
Participants will be mailed a tape 
measure and provided with instructions 
as to how to collect this measurement 
at home (Section 8e). 
Lab-based 
HbA1c 
In-person, all visits At home, all visits 
At home collection kits will be used 
(Section 8a). 
Fasting stored 
blood  
In-person if fasting 
and consented, all 
visits 
No longer 
collecting 
This was not a primary outcome 
measure and is not feasible to collect 
at home (Section 8e). 
Stool sample 
collection/storage 
(gut microbiome) 
Kit offered for 
home collection at 
baseline, Meas  2, 
Meas 3, and Meas 
4 
Kit shipped for 
home collection, 
Baseline, Meas 2, 
Meas 3, and Meas 
4 
The only change to procedure is that 
the kit will be shipped directly to 
participants and they will receive their 
instructions remotely (Section 8e). 
BG/Ketones 
Blood ketones  
Weekly at-home 
monitoring by 
participants on 
low-carb diet 
No longer 
collection 
Participants have not been doing data 
collection for the most part and this 
data is not essential for outcomes 
(Section 8e). 
CGM (% time in 
hypoglycemia 
and other 
measures of 
glycemia 
CGM sensor 
inserted by staff at 
all visits 
CGM inserted at 
home by 
participant, all 
visits 
The Libre Pro Reader and sensor, 
along with all other necessary supplies 
for insertion, will be shipped to 
participants ahead of each virtual visit 
for at-home insertion. Participants will 
be provided with an instructional video 
link and written instructions (Section 
8a). 
Self-Admin Questionnaires 
All Self-Admin 
Questionnaires, 
including diet 
acceptability 
Completed online 
or in-person at all 
visits by 
participant 
Completed online 
at the time of each 
measurement visit 
by participant or 
via phone or zoom 
interview with 
staff 
Participants will now complete the 
CES-D online. This form was 
previously completed by participants 
on paper at the in-person 
measurement visit (Section 8e). 
COVID-19, 
Stress, 
Resilience, Food 
Security Form 
NEW 
Completed online 
This form will be administered via 
CDART as an interview and completed 
at each virtual visit (Section 8e). 
Physical Activity 
24-Hour Diet and 
Physical Activity 
Recalls 
Phone interview by 
NORC staff after 
each meas visit 
No change 
No change except participants will now 
be mailed the Food Amounts Booklet 
at their baseline visit or ahead of any 
visit if they have misplaced it (Section 
8c). 
Global Physical 
Activity 
Questionnaire 
In-person 
interview, all visits 
Phone or Zoom 
interview, all visits 
Completed at time of ‘virtual visit.’ 
Showcards will be emailed to 
participants (Section 8c). 
Garmin Wearable 
Component 
NEW 
Home setup and 
wear 
Participants will receive written 
instructions and be guided through the 
setup process during a phone or zoom 
call (Section ?). 

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Other 
 
 
 
DXA (Body 
composition) 
In-person, all visits 
Discontinued  
Cannot do virtually (Section 8b). 
Urinalysis 
Pregnancy Test  
In-person, ahead of 
DXA scan, all visits 
Female participants 
will be asked to 
self-report 
pregnancy at the 
time of each virtual 
visit. 
Pregnancy result will be recorded on 
DXA form. Participants will simply be 
asked if they are pregnant, no 
urinalysis will be required. Safety 
concerns of pregnancy are lessened 
now that DXA is discontinued (Section 
8b). 
 
1. Executive Summary 
 
Young adults with type 1 diabetes (T1D) commonly struggle with both glycemic control 
and weight. The prevalence of overweight and obesity among individuals with T1D 
now parallels that of the general population and contributes to central obesity, 
dyslipidemia, elevated blood pressure, and insulin resistance, increasing risk for 
cardiovascular disease. There is a compelling need to develop a program of research 
designed to optimize not just one, but two key outcomes – glycemic control and weight 
status – and to address the underlying metabolic processes and behavioral challenges 
unique to T1D. Accordingly, our main objective is to develop a rigorous adaptive 
design to test the efficacy of a behavioral intervention to simultaneously 
optimize glycemic control and facilitate weight management among overweight 
young adults with T1D. The intervention must be appropriate to the unique metabolic 
phenotype in T1D, and to biological and behavioral responses to glycemia (including 
hypoglycemia) that relate to weight management. The intervention must be safe, 
feasible to implement, and accepted by overweight young adults with T1D. In June 
2015, we established a consortium called ACT1ON: Advancing Care for Type 1 
Diabetes and Obesity Network, which includes a transdisciplinary team of scientists at 
three institutions: University of North Carolina at Chapel Hill (UNC), Florida Hospital 
Translational Research Institute for Metabolism and Diabetes (TRI), and the Division 
of Pediatric Endocrinology and Diabetes at Stanford University. Together, we propose 
Specific Aims in three phases focused on young adults (age 19-30 years) with T1D. 
This protocol covers one aim of the funded grant: Aim 2 (Phase 2).  
Aim 2, Phase 2: In Phase 2, an initial pilot and feasibility study will be conducted 
using a Sequential, Multiple Assignment, Randomized Trial (SMART) design to identify 
acceptable and effective dietary strategies to optimize both glycemic control and 
weight management in young adults with T1D. This pilot trial will include 84 
randomized participants (42 at UNC, 42 at Stanford) in a 10.5 month behavioral 
intervention, with co-primary outcomes of glycemic control (HbA1C and hypoglycemia) 
and weight loss. (Note: data from Aim 1, Phase 1 approved under separate IRB 
approval will be utilized to inform the SMART pilot. Phase 1 Study 1 will inform calorie 
goals. Phase 1 Study 2 will inform potential counseling strategies related to dietary 
response to hypoglycemia). 

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2.  Background and Significance 
Young adults with type 1 diabetes (T1D) commonly struggle with both glycemic control 
and weight. The prevalence of overweight and obesity among individuals with T1D 
now parallels that of the general population1,2 and contributes to central obesity, 
dyslipidemia, elevated blood pressure, and insulin resistance,3–5 increasing risk for 
cardiovascular disease.4,5 There is a compelling need to develop a program of 
research designed to optimize not just one, but two key outcomes – glycemic control 
and weight status – and to address the underlying metabolic processes and behavioral 
challenges unique to T1D. 
Glycemic Control in Young Adults with T1D: The benefits of intensive glucose 
control were demonstrated by the DCCT,6,7 with persistent benefit over 30 years later.8 
Higher HbA1c in teens/young adults as compared to adults over age 30 was well 
documented in the DCCT trial.9 Recent T1D Exchange data demonstrate elevated 
HbA1c with a peak mean of over 9% in 17-year-olds, which remains elevated above 
8% until a mean age of 30 years.10 Thus, a significant number of young adults with 
T1D have glucose control similar to and even worse than DCCT participants in the 
conventional glycemic control arm, despite advances in technology and therapeutics. 
Prevalence and Consequences of Overweight and Obesity in T1D: Historically, 
people with T1D were thin or of normal weight, in part due to poor glucose control. 
Many participants in the DCCT intensive treatment arm experienced weight gain,11,12 
which was associated with a poorer cardiometabolic profile.3 Now, with common use of 
intensive insulin therapy, and paralleling trends in the U.S. population, there is a high 
prevalence of overweight and obesity among people with T1D.1,2 Among young adults 
in the T1D Exchange Registry, 31% were overweight and 15% were obese.10 
Longitudinal studies show that obesity increases in people with T1D as they age.13,14 
Obesity is now accepted as an important contributor to long term cardiovascular risk in 
people with T1D.4,5,15 
Determinants of Energy Balance in T1D: Standard equations for estimating energy 
expenditure and dietary requirements in healthy individuals are not adequate for those 
with T1D. First, in patients with uncontrolled T1D, glucosuria can account for 300-400 
kCal/day in obligate energy losses.16 Second, most studies demonstrate a modest 
increase in resting energy expenditure (REE; range=100-300 kCal/day) in people with 
T1D relative to healthy controls or predicted values.16–20 The REE increase in T1D 
appears to be proportionate to the degree of hyperglycemia and has been attributed to 
increased hepatic gluconeogenesis, driven by hyperglucagonemia.21 Other factors, 
including increased sympathetic nervous system activity, increased protein turnover 
and substrate transport across cellular membranes, alterations in the gut microbiome, 
22 and increases in size of metabolically active organs,23 may contribute to alterations 
in T1D energy expenditure. While exploration of these factors is beyond the scope of 
this proposal, there is an urgent need for a new and comprehensive assessment of the 
24-hour energy requirements in people with T1D.  
In addition to alterations in energy balance, T1D is characterized by 
impairments in metabolic flexibility, which is the ability of an organism to shift substrate 
oxidation rates to accommodate changes in substrate availability24 and is important in 
the development of metabolic syndrome.25 Compared to controls, people with T1D had 

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marked differences in substrate oxidation rates – with increased lipid oxidation during 
basal conditions – blunted ability to shift to carbohydrate oxidation during meals, and 
decreased thermic effect of food.16–21 Metabolic inflexibility is implicated in the 
development of insulin resistance in obesity and T2D, and may similarly contribute to 
the metabolic syndrome and increased risk of CVD in T1D.24,25  
Weight Loss and Eating Behaviors Unique to T1D: Successful weight loss 
strategies address both behavioral and psychosocial elements,26,27 grounded in 
established theoretical frameworks to promote behavior change, such as the Health 
Belief Model,28 Transtheoretical Model,29–31 and Theory of Reasoned Action.27,32 Self-
monitoring of dietary intake and weight, use of caloric restriction, fewer calories from 
fat, and high levels of physical activity contribute to sustained weight loss and weight 
gain prevention in the general population.12,26,27,33 Conditions unique to T1D – 
including fear of hypoglycemia,34 diabulimia,35 or hypoglycemia-induced binging – may 
interfere with weight loss and maintenance efforts.5 
The process of glycemic management in T1D may interfere with achieving and 
maintaining healthy weight via unintended consequences of dietary restriction. Dietary 
restraint refers to intentional and sustained restriction of caloric intake to achieve 
weight loss or maintenance.36,37 T1D is described as a food culture of dietary restraint 
in that a strict dietary regimen38,39 characterized by carbohydrate counting drives 
imposed food preoccupation.40 Self-report measures of dietary restraint in T1D 
patients showed higher dietary restraint was associated with poorer glycemic control.41 
Recurrent hypoglycemia and its associated intense hunger and permission to eat 
forbidden sugary foods may lead to over-eating, guilt, restriction, and possibly more 
episodes of hypoglycemia, creating a self-perpetuating cycle of disordered eating 
behavior resembling binge eating disorder and bulimia.42 As this restrictive-excess 
intake cycle repeats, individuals may increase their risk for weight gain43–46 and 
worsening glycemic control. Thus, models for disordered eating behaviors in T1D have 
expanded from insulin manipulation for weight loss to identify hypoglycemia as an 
important part of a cycle of dietary restraint39,40,47 in which hypoglycemia and its 
treatment can disrupt physiological hunger cues and result in a net surplus of calories 
with potential weight gain and worsened glycemic control.48 
Dietary Approaches to Weight Loss: According to the American Diabetes 
Association (ADA)’s Nutrition Therapy Recommendations, individualization of 
dietary recommendations is recommended to account for metabolic status, clinical 
goals, preferences, and sociocultural considerations.49 Optimal dietary approaches to 
weight management and metabolic control are highly controversial: studies (essentially 
all in T2D) vary in dietary approach, sample population, T2D duration and T2D 
treatment regimen, and importantly, in participant retention, particularly in the more 
restrictive dietary approaches.50,51 As reviewed by Evert et al.,(2013)49 weight 
management approaches in Look AHEAD52 (low fat diet) and a Mediterranean dietary 
pattern approach53 were effective in weight loss and HbA1c improvement. Both 
approaches incorporated relatively high carbohydrate intake (~50-55% of calories). 
Current ADA Standards of Medical Care54 emphasize that, for T2D patients, weight 
loss can be achieved with hypocaloric diets with macronutrient composition based on 
the individual patient’s medical status and preferences. However, in a subset of 

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individuals with T2D from PREDIMED, a Mediterranean diet supplemented with either 
olive oil or nuts, but not explicitly calorically restricted, led to significant weight loss.55   
On average, people with T1D consume 45% of calories from carbohydrates,51,56 
significantly less than the general US population.53 Further, in T1D, higher intake of 
carbohydrate is associated longitudinally with higher HbA1c.57 In T2D, a one-year 
hypocaloric low carbohydrate (14%) diet was effective in promoting weight loss, 
improving glycemic control and variability, and improving CVD risk factors.58 Thus it is 
reasonable to consider that, in T1D, a lower carbohydrate diet may be acceptable and 
beneficial in promoting weight loss and glycemic control. Randomized controlled 
clinical trials that evaluate dietary approaches to optimize both weight 
management and glycemic control in T1D have not been conducted. Our 
proposed work will provide critically needed information to optimally design 
such a trial.  
Sequential, Multiple Assignment Randomized Trial (SMART) Designs: Sequential 
multiple assignment randomized trials (SMARTs) have become increasingly important 
tools in biomedical research because of their ability to efficiently address practical 
treatment comparison questions in clinically realistic settings. SMART designs address 
intervention decisions that unfold over time and can adapt dynamically based on 
patient response,59–61 as is crucial in T1D treatment. The proposed pilot SMART 
design will evaluate the effectiveness of experimental diets in the context of 
anticipated variation in patient response, both across patients and within patients over 
time.  
 
 

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3.  Study Objectives 
Our main overall objective is to develop a rigorous adaptive design to test the efficacy 
of a behavioral intervention to simultaneously optimize glycemic control and facilitate 
weight management among overweight young adults with T1D. We propose Specific 
Aims in three phases focused on young adults (age 19-30 years) with T1D. This 
protocol covers Aim 2 (Study Phase 2).  
Aim 2, Phase 2:  Phase 2 is an initial pilot and feasibility study using a Sequential, 
Multiple Assignment, Randomized Trial (SMART) design to identify acceptable and 
effective dietary strategies to optimize both glycemic control and weight management 
in young adults with T1D. This pilot trial will include 84 randomized participants (42 at 
UNC, 42 at Stanford) in a 10.5 month behavioral intervention, with co-primary 
outcomes of glycemic control (HbA1C and hypoglycemia) and weight loss. (Note: data 
from Aim 1 Phase 1, approved under separate IRB approval, will inform the SMART 
pilot. Phase 1 Study 1 will inform calorie goals. Phase 1 Study 2 will inform potential 
counseling strategies related to dietary response to hypoglycemia.) 
Specific objectives of SMART pilot work are as follows: 
• To assess acceptability and adherence to three distinct, evidence-based 
dietary approaches designed to address weight management and glycemic 
control. Behavioral counseling strategies, use of carbohydrate counting for insulin 
dosing, and encouragement of the participant’s usual level of physical activity will 
be the same across the 3 diets. Diets are as follows: 
o Diet 1: hypocaloric, moderate low fat (30% calories from fat) weight 
management based on the Look AHEAD study52  
o Diet 2: hypocaloric, low carbohydrate (15-20% calories from carbohydrate, 59-
63% as total fat (<10% saturated fat, at least 37% monounsaturated fat, 
remaining as polyunsaturated fat)58 
o Diet 3: advice to select a healthy Mediterranean dietary pattern49,55 with no 
caloric restriction  
 
• To generate data required to inform a fully powered SMART design by:  
o estimating the reduction in weight and body fat for each of the three diets 
o estimating the improvement in glycemic control (HbA1c, hypoglycemia) for each 
of the 3 diets 
o comparing the effectiveness and acceptability of the 3 dietary approaches to 
concurrently optimize weight and glycemic control outcomes 
4.  Site Descriptions and Targets 
The two clinical sites include the 1) University of North Carolina at Chapel Hill (UNC-
CH) and 2) Division of Pediatric Endocrinology and Diabetes at Stanford University. 
Both clinical sites are well-established academic medical centers with vast experience 
in diabetes translational research. UNC-CH will also oversee coordination of the 
SMART pilot. Northwest Lipid Research Laboratory in Seattle, Washington will 
complete the required laboratory (blood sample) analysis for the SMART Pilot. COVID-
19 PROVISIONS: Due to ramifications of the COVID-19 Pandemic, we are no longer 
able to have samples assayed with Northwest Lipid Metabolism and Diabetes 

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Research Laboratories in Seattle, Washington. We will be using the Diabetes 
Diagnostic Laboratory at the University of Missouri. Existing specimens stored at the 
Northwest Research Laboratories will be transferred to the Stanford University School 
of Medicine for storage. 
 
Participant Recruitment: Stanford: The recruitment goal for Stanford will be 42 
participants (~ 4/month over 12 months). Among the current patient population at 
Stanford, approximately 300 are between the ages of 19-30 and meet study inclusion 
criteria for weight and HbA1c.  
 
Participant Recruitment: UNC: The recruitment goal for UNC is 42 (~4/month over 12 
months). The number of patients in the UNC Health Care System who meet our 
inclusion criteria is approximately 150 and in addition, the UNC Student Health center 
follows about 100 T1D patients. If necessary, UNC-CH may also recruit from T1D 
patients seen at the nearby Duke Diabetes clinic.   
 
Only those participants who withdraw from the trial before randomization will be 
replaced.  
5.  Selection & Recruitment of Subjects 
Inclusion criteria 
Males and females ages 19-30 years old with a diagnosis of type 1 diabetes for 
greater than one year. Individuals must have most recent HbA1c (measured within last 
6 months at time of phone screening) of less than 13% and BMI of 27-39.9 at time of 
phone screening.   
 
Exclusion criteria 
The following individuals will be excluded from study participation: individuals with 
other serious metabolic disorders that would render participation unwise, diagnosed 
eating disorder, or those with other serious conditions that renders participation 
inappropriate. Individuals who have experienced DKA or severe hypoglycemia 
requiring outside assistance in the past 6 months will be excluded. Females who are 
currently pregnant, breastfeeding, planning to become pregnant during the study 
period or who have delivered a baby in the last 12 months will be excluded. Individuals 
who are unwilling to follow any of the three study diets will be excluded. Individuals 
who are unwilling to self-monitor blood glucose levels at least three times a day will be 
excluded. Individuals who have lost 10 or more pounds in the last 6 months will be 
excluded. 
 
Medical records will be used to identify patients who potentially meet the eligibility 
criteria for this study. Medical records will also be used to collect information related to 
the participant’s diabetes care, as well as demographic information. For individuals 
contacting us about study participation, medical record review will not be required; 
instead, we will rely on self-report of relevant screening criteria. 
 

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Participants may reach out to us after seeing the study on Join the Conquest or 
through another Type 1 diabetes support network. We will work with NC TraCS to 
establish recruitment through MyChart. 
 
Strategies to Optimize Recruitment and Retention: Study staff at UNC-CH and 
Stanford will be responsible for local recruitment activities. Recruitment will use a 
combination of targeted mailings/emails with phone follow-up and in-person clinic-
based strategies. Our recruitment process will utilize the highly successful two-step 
recruitment strategy used in the FLEX study, consisting of sending an informative 
recruitment letter/email to eligible participants and following with a series of phone 
calls by research staff.  
 
COVID-19 VIRTUAL VISIT TRANSITION (4/2020) - All recruitment of new subjects 
will be conducted electronically. The protocol has been altered to reflect this. 
 
Recruitment Step 1: Initially, prospective participants will be emailed an invitation letter 
with an electronic study brochure. Research staff will follow-up with a brief telephone 
call to explain the study and ascertain participant interest. If participants are interested, 
research staff will schedule a second follow-up call (described in recruitment step 2).  
If we are unable to reach participants because of what seems to be outdated or 
incorrect contact information, we may use EPIC and a subscription service ‘Accurint’ to 
search for updated contact information.  
 
Recruitment Step 2:  Potential participants who remain interested following the 
initial telephone contact will be emailed a document providing additional details about 
the study (“Frequently Asked Questions” (FAQ)), which will include common barriers 
or issues that could impede participation in the study. This mailing/email will also 
include the Participant Study Flowsheet, which displays the schedule of measurement 
activities and RD encounters, and the Microbiome Information Sheet, which provides 
information about the optional stool collection activity in the study. Staff will review 
these documents and specific barriers or concerns for the potential participant during a 
follow-up telephone call with the potential participant. The conversation will be 
individualized and will incorporate strategies of motivational interviewing as a way to 
allow the potential participant to identify, express, and discuss any of their concerns 
about participation. This two-step recruitment process will help ensure the participant 
understands the study fully before deciding to participate. 
 
Recruitment materials will also be prominently displayed in the diabetes clinic 
waiting area and exam rooms at both sites. ACT1ON study personnel may also utilize 
in-person recruitment of eligible participants during usual care visits.  
 
COVID-19 VIRTUAL VISIT TRANSITION (4/2020) – Recruitment materials will no 
longer conducted in-person.  
Additionally, we will incorporate successful retention strategies from FLEX (e.g., 
offering flexible visit options, incentives that increase over time {baseline: $100, 3-mo: 
$150, 6-mo: $200, 9-mo: $250}. 

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6.  Process of Obtaining Consent 
Participants will have opportunity to provide informed consent following the two-step 
recruitment process detailed above. For participants who agree to participate and 
schedule a baseline visit, the study consent form will be emailed to the participant prior 
to the Baseline Visit, so that the individual has ample time to review it on their own 
ahead of the visit. Participants will also be provided with instructions on how to use 
CDART, the data management system that we will employ to house participant data 
and house self-administered questionnaires. This email will also include a 
personalized link to a Qualtrics questionnaire, which provides participants the chance 
to read a consent form specific to completing baseline forms ahead of the virtual visit 
with the ACT1ON team coordinator. 
 
COVID-19 VIRTUAL VISIT TRANSITION (4/2020) - Participants will have opportunity 
to provide informed consent following the two-step recruitment process detailed above. 
Prior to the virtual visit, study staff will review the full study consent via Zoom or 
telephone in detail before standardized data collection begins. For participants who 
agree to participate and schedule a baseline visit, the study consent form will be 
emailed prior to the consent conversation so that the individual has ample time to 
review it on their own ahead of the visit. The participant will be given as much time as 
needed to review the consent form and ask any questions prior to signing it. 
Participants will be informed that participation in the study is voluntary and they are 
free to withdraw their consent and discontinue participation in this research at any 
time. Study staff obtaining consent will utilize the tailored Consent Comprehension 
Checklist to guide a conversation with the participant that aims to ensure that she or 
he understands what she or he is consenting to and the nature of informed consent 
itself. Following the consent conversation, participants will be provided with 
instructions on how to use CDART, the data management system that we employ to 
house participant data and house self-administered questionnaires.  
 
We will reconsent all currently enrolled participants using the consent addendum. This 
will be completed with participants prior to the beginning of any data collection for their 
next upcoming measurement visit.  
 
Following consent, participants may be involuntarily withdrawn from the study per the 
investigator’s discretion if they develop a serious condition that would render 
participation unwise, including difficulties with glycemic control and/or serious physical 
or psychiatric conditions. Females who become pregnant will also be withdrawn from 
study participation.     
 
7.  Randomization 
Sequential randomization (Baseline, ~3 months, and ~6 months).  At the start of the 
study, diet randomization schemes will be determined by computer for each individual.   

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Permuted block randomization with blocks of size 24 will be used to assign all 12 
potential treatment regimes using R statistical software. This will be confidentially 
generated by the statistician and placed into CDART data management software to be 
revealed only at the point of treatment (diet) assignment for each patient.  
Following the baseline data collection and a short run-in period, the initial diet 
randomization will be revealed to the participant. Based on a priori decision rules at 3 
and 6 months post-initial randomization, those for whom the diet assigned is not 
acceptable or is not effective will have the next diet assignment revealed (be re-
randomized). A total follow-up time of 10.5 months allows for evaluation of the effect of 
the diets on initial weight loss and on early maintenance of initial weight loss. The 
decision criteria for re-randomization (Table 7.1) will incorporate both clinical outcomes 
(glycemic control and weight change) and acceptability of the diet to the participant as 
indicated on the Diet Acceptability Form.  
 
Following Measurement Visit 2, participants meeting one or more criteria for re-
randomization will have the next diet in their individual randomized diet scheme 
revealed (one of two diets not yet experienced); otherwise, participants will continue 
their original diet assignment. Following Measurement Visit 3, decision criteria will be 
applied again. Participants meeting re-randomization criteria will have the next diet in 
their individual randomized diet scheme revealed (for participants who had continued 
on the original assignment at the 3-month mark, this will be one of the two remaining 
diets; for those who received a new diet, the only remaining untried diet will be 
assigned). By the end of the study, each participant will have either been on a diet that 
was acceptable and effective for a period of time or will have tried all 3 diets. For 
individuals assigned to one of the hypocaloric diets (low carbohydrate or Look 
AHEAD), at Measurement Visit 2 and/or Measurement Visit 3 the calorie prescription 
will be re-calculated to incorporate body weight and composition at that time. Note that 
at 3 and 6 months, if weight loss has been achieved that classifies participant as 
“normal weight” then ‘weight change’ criteria (see Table 7.1) does not apply for re-
randomization. For these individuals, the RD will advise the participant regarding 
weight loss maintenance in the context of their assigned diet. 
 
Table 7.1 Re-Randomization Criteria.  Re-assignment of diet will occur if one or more 
criteria are met. 
Time post-
initial 
randomization 
Diet 
acceptability 
Weight change 
Glycemic control since 
baseline 
3 and 6 
months 
Unacceptable 
based on Diet 
Acceptability 
Form 
Not achieving at least 2% 
loss in body weight from 
previous measurement 
visit. Exception: if weight 
loss has been achieved 
that classifies participant 
as “normal weight” then 
this criteria does not 
apply 
Self-report of increased 
hypoglycemia 
or 
HbA1c ↑ ≥ 0.5% 

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8.  Standardized Measurements 
8a. Primary Outcomes    
Anthropometric Measurements:  
The primary outcome of weight change will be assessed through measurement of 
anthropometrics. Study visits completed prior to the virtual transition included a height 
and weight measurement at each study visit utilizing standardized methods described in 
the SEARCH study protocol (available online, www.searchfordiabetes.org).  
 
COVID-19 VIRTUAL VISIT TRANSITION (4/2020) - Height will be obtained either from 
medical record or via self-report. Weight will be measured at home using the BodyTrace 
scale provided by the study for intervention support. We will calculate body mass index 
(BMI) from these measurements. 
 
Glycemic control: HbA1c (assayed at the Diabetes Diagnostic Laboratory at the 
University of Missouri as of virtual visit transition, using HPLC) will be used as a 
measure of long-term glycemic control. Continuous Glucose Monitoring (CGM): The 
Freestyle Libre Pro CGM will be used to collect short-term glycemia, including 
frequency and time spent in hypoglycemia. Study visits completed prior to the virtual 
transition included use of CGM applied by a study staff member. With transition to 
virtual visits (4/2020), the CGM will be applied at home by participants at the time of 
each virtual visit. Participants will be provided with written instructions as to how to 
apply the CGM, along with a link to a video outlining and demonstrating the process. 
The CGM will continue to be worn for 14 days. At the baseline visit, the participant will 
have been instructed on the use of the study CGM (for participants enrolled remotely, 
this will occur at the virtual baseline visit), namely duration of wear and how to remove 
the CGM after the wear period. During CGM wear, participants will be instructed to 
perform blood glucose measurements as they normally do according to physician 
guidance. Participants who are already using a CGM for glucose management will be 
advised to continue to do so. 
 
Additionally, participants will be queried regarding occurrence of both non-severe and 
severe hypoglycemia by their RD at each encounter (check-in and longer remote 
sessions). Participants will also be queried regarding increased hypoglycemia on the 
short and long diet acceptability forms, completed between and at measurement visits. 
Consistent with a recent report on consensus guidelines for the use of continuous 
glucose monitoring, contributed to by MPI Maahs,62 we define hypoglycemia as CGM-
based glucose <70mg/dl for more than 10 min, not requiring help from another person.  
 
8b. Secondary outcomes: 
Body Composition:  
Body composition will be assessed via a full body dual energy x-ray absorptiometry 
scan. For female participants, a urinalysis pregnancy test will be performed at each in-
person measurement visit prior to the DXA measurement. Participants who become 
pregnant will be withdrawn from the study. Participants will be asked to remove any 

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clothing that might contain metal, hard plastic, or any other materials that could interfere 
with the DXA scan. A trained DXA technician will enter the height, weight, gender, and 
ethnicity of each subject into the device’s default software prior to performing each 
scan. During each scan, participants will rest in a supine position in the center of the 
scanning table with their hands at their sides, while minimizing movement as much as 
possible. Outcomes of interest for the current study included lean mass (LM), fat mass 
(FM), body fat percentage (BF%),visceral adipose tissue (VAT), android/gynoid (AG) fat 
mass ratio, and fat free mass (FFM). To ensure the accuracy of this measurement, 
participants will be advised to arrive at all DXA measurement visits having fasted and 
avoided exercise for at least 2 hours prior. 
 
COVID-19 PROVISIONS-VIRTUAL VISITS:  
Body composition will no longer be assessed as of modifications submitted in April of 
2020, as DXA scans cannot be completed virtually. For participants attending in-person 
visit prior to the virtual transition, body composition was assessed via a full body dual 
energy x-ray absorptiometry scan. For female participants, a urinalysis pregnancy was 
performed at each in-person measurement visit prior to the DXA measurement for 
safety purposes. With transition to virtual visits (4/2020), participants will no longer 
be tested for pregnancy. Rather, female participants will be queried at each 
measurement visit regarding current pregnancy status.  
 
Other Glycemia Measures: We will use CGM data to explore additional measures of 
glycemic variability.62 
 
As we are no longer doing a blood draw and not collecting stored whole blood and 
plasma, and therefore are not asking participants to fast, that we will not ask 
participants to report their blood sugar or whether or not they have had anything to eat 
in the last 8 hours. The only fields of the ‘specimen collection form’ that we will complete 
are those that pertain to the HbA1c collection, that is, time and date of collection along 
with any problems the participant may have had.  
 
Table 8.1 
Outcome/Measure 
Meas. Visit 1 
(Baseline;  
-14 days) 
~ 1 
mo 
Meas. 
Visit 2 
~ 4 
mo 
Meas. 
Visit 3 
~ 7 
mo 
Meas. 
Visit 4 
(End of 
Study) 
Conducted 
remotely? 
Anthropometric 
Measurements  
Height 
X 
 
X 
 
X 
 
X 
Baseline only 
Weight 
X 
 
X 
 
X 
 
X 
Yes 
Waist 
X 
 
X 
 
X 
 
X 
Yes 
Glycemic Control 
HbA1c 
X 
 
X 
 
X 
 
X 
Yes 
% time in 
hypoglycemia (CGM) 
X 
 
X 
 
X 
 
X 
Yes  
Secondary Outcomes 
 
DXA (Body 
composition) 
X 
 
X 
 
X 
 
X 
No 
CGM (Other measures 
of glycemia) 
X 
 
X 
 
X 
 
X 
Yes 

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Urinalysis Pregnancy 
Test (biologically 
female participants 
only, prior to DXA) 
X 
 
X 
 
X 
 
X 
No 
Dietary Intake and Physical Activity 
24-Hour Diet and 
Physical Activity 
Recalls 
X 
 
X 
 
X 
 
X 
Yes 
Global Physical Activity 
Questionnaire  
X 
 
X 
 
X 
 
X 
Yes 
Potential Mediators 
 
Diet History 
Questionnaire III  
X 
 
X 
 
X 
 
X 
Yes 
Diabetes Eating 
Problem Survey  
X 
 
X 
 
X 
 
X 
Yes 
Weight Related Eating 
Questionnaire  
X 
 
X 
 
X 
 
X 
Yes 
Barratt Impulsiveness 
Scale  
X 
 
X 
 
X 
 
X 
Yes 
Food Craving 
Inventory 
X 
 
X 
 
X 
 
X 
Yes 
Nutrition Knowledge 
Questionnaire 
X 
 
X 
 
X 
 
X 
Yes 
Additional Measures 
Demographics 
X 
 
 
 
 
 
 
Yes 
Health History  
 
X 
 
X 
 
X 
 
X 
Yes 
Diabetes-Specific 
Quality of Life  
X 
 
X 
 
X 
 
X 
Yes 
Generic Quality of Life 
X 
 
X 
 
X 
 
X 
Yes 
Low Blood Sugar 
Survey  
X 
 
X 
 
X 
 
X 
Yes 
Sleep Disorders 
Questionnaire 
X 
 
X 
 
X 
 
X 
Yes 
Centers for 
Epidemiologic Study - 
Depression Scale 
(CES-D) 
X 
 
X 
 
X 
 
X 
Yes 
Diabetes Stigma 
Assessment Scale 
X 
 
X 
 
X 
 
X 
Yes 
Fasting stored blood  
(future assessment of 
genetics, lipids and 
other parameters TBD) 
X 
 
X 
 
X 
 
X 
No 
Stool sample 
collection/storage (gut 
microbiome) 
X 
 
X 
 
X 
 
X 
 
Yes 
Blood ketones  
At home weekly check for those on a low carbohydrate diet. 
Discontinued 
4.8.2020 
Study Acceptability 
Diet Acceptability-Long 
Form 
 
 
X 
 
X 
 
X 
Yes 
Diet Acceptability-
Short Form 
 
X 
 
X 
 
X 
 
Yes 
Exit Interview 
 
 
 
 
 
 
X 
Yes 
Added after virtual transition 
Stress/Resilience/Food 
Security/COVID-19 
questions 
X 
 
X 
 
X 
 
X 
Yes 
Pregnancy self-report 
X 
 
X 
 
X 
 
X 
Yes 

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8c. Dietary Intake and Physical Activity 
Dietary adherence will be monitored via 24-hour dietary recalls. Recalls will be done on 
two unannounced days during the 14-day CGM wear time after each measurement visit.   
These recalls will be obtained by telephone by trained and certified interviewers from 
the UNC NIH/NIDDK Nutrition Obesity Research Center (NORC) staff (P30DK056350; 
MPI Mayer-Davis) under the direction of Dr. Mayer-Davis (Diet Assessment Core 
Director), using the Nutrient Data System for Research (NDSR) software and the 
multiple pass interviewing method.63,64  
 
The validated65,66 Previous Day Physical Activity Recall (PDPAR) will be under the 
direction of the UNC NORC, to be administered concurrent with the 24-hour dietary 
recalls, as we have done previously.67 The PDPAR divides the day into half-hour time 
blocks and queries the dominant activity and the approximate intensity of that activity for 
that period, categorized as ‘‘light,’’ ‘‘medium,’’ ‘‘hard,’’ or ‘‘very hard.’’  
 
As an additional measure of physical activity, we will administer the Global Physical 
Activity Questionnaire (GPAQ), via interview during virtual measurement visits. The 
GPAQ is an adaptive, interview-based questionnaire developed by the World Health 
Organization (WHO), collects information on physical activity in three areas: activity at 
work, traveling from place to place, and recreational activities. It also collects 
information on sedentary time.68 
 
8d. Potential Mediators 
We will assess food frequency and habitual dietary patterns using the Diet History 
Questionnaire III (DHQ III).69,70 To capture disordered eating behavior, the Diabetes 
Eating Problem Survey71 will be combined with non-T1D specific ingestive behavior 
questionnaires. The Weight-Related Eating Questionnaire (WREQ) assesses emotional 
eating, disinhibition, and restrained eating behavior/cognitive restraint.72 The Barratt 
Impulsiveness Scale73 (BIS-15), assesses trait impulsivity, including non-planning, 
motor impulsivity, and attention impulsivity.74 The Food Craving Inventory75 assesses 
the degree of craving for a variety of foods. Finally, the Nutrition Knowledge Survey, 
validated in people with T1D,76 assesses healthful eating knowledge, carbohydrate 
counting, blood glucose response to foods, and nutrition label reading. 
 
8e. Additional Measures 
Anthropometric Measurement:  
Waist circumference will be measured at each study visit utilizing standardized methods 
described in the SEARCH study protocol (available online, www.searchfordiabetes.org). 
COVID-19 PROVISIONS - VIRTUAL VISITS - Waist circumference will be measured at 
home at the time of each virtual study visit by the participant. Participants will be 
provided with instructions as to how to measure their natural waist by holding the tape 
level and using the aid of a mirror. 
 
At the Baseline (Measurement 1) virtual visit, participants will complete the 
Demographics Form to collect basic demographics, including birthdate, gender, 

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ethnicity, race, date of diabetes diagnosis, and information about education and 
employment. Also at baseline, participants will complete the Health History Baseline 
Form to ascertain information related to health history, diabetes care, and health 
insurance.  
 
The Health History Follow-Up form will be administered at Measurement Visits 2, 3, and 
4, to update information related to health history, diabetes care, and health insurance as 
needed.   
 
To assess diabetes-related quality of life, we will administer the DCCT-validated 
measurement form Diabetes-Specific Quality of Life (DQOL).77 We will assess non-T1D 
specific quality of life using the MOS 36-item short form (SF-36), created as part of the 
Medical Outcomes Study (MOS)78 to assess health-related quality of life. We will also 
assess behaviors and worries related to hypoglycemia using the Low Blood Sugar 
Survey.79  
 
The Sleep Disorders Questionnaire will be used to obtain sleep duration and quality 
over the preceding month.80 We will assess depressive symptoms using the Centers for 
Epidemiologic Study Depression Scale (CES-D).81 The Diabetes Stigma Assessment 
Scale (DSAS-1) will assess experience and views related to stigma and T1D.82   
We will administer the four part data collection form: COVID-19, Stress, Resilience, 
Food Availability Form, which is a combination of questions based of the newly 
developed World Health Organization Survey Tool and Guidance: Rapid, simple, 
flexible behavioural insights on COVID-19112; a globally validated 14-item Perceived 
Stress Scale (PSS)113; and the Connor-Davidson Resilience Scale 25 (CD-RISC-
25)©114; and USDA Food Security Screener (2019).115 
 
Fasting blood will be collected at each study visit to allow for storage of blood and 
plasma for future testing. Samples will be stored for future testing of lipids and other 
analyses. We will also include storage of whole blood from the baseline visit only for 
future DNA/genetics work. 
 
COVID-19 PROVISIONS-VIRTUAL VISITS: With the transition to virtual visits, fasting 
blood and plasma for storage will no longer be collected. 
 
Participants will complete at home stool collection after the Baseline (Measurement 1) 
Visit and Measurement Visit 2. Stool samples will be analyzed using 16s rRNA 
sequencing and analysis of short chain fatty acids using liquid-chromatography mass-
spectrometry. 
 
COVID-19 PROVISIONS-VIRTUAL VISITS: Participants who have not taken antibiotics 
in the past 4 weeks will still be eligible to complete a stool sample at the time of the 
baseline and measurement visit 2. The stool kits and written instructions with step-by-
step photographed procedures will be mailed directly to participants and further 
instructions will may be provided remotely, through a phone/zoom call. 

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Participants on the low carbohydrate diet may be asked to check their blood ketones 
once weekly using the Nova Max© Plus glucose monitoring system, along with Nova 
Max ketone testing strips, provided by the study. Note: as of 4/2020, the study is 
discontinuing weekly checks of blood ketones for participants on the low carbohydrate 
diet due to lack of participation by study participants.  
 
8f. Study Acceptability 
Diet Acceptability: An appropriate instrument with known psychometric properties to 
systematically assess acceptability of specific diets could not be identified in the 
literature. Therefore, we developed and piloted a simple five-item assessment for this 
purpose. From a pre–test, Chronbach’s alphas were 0.89 and 0.87 for weeks four and 
ten, respectively, indicating high internal consistency among questionnaire items. 
Two versions of the diet acceptability will be utilized in this study. The Diet Acceptability 
Long Form includes the five-item assessment of diet acceptability along with five items 
associated with blood glucose management and hypoglycemia relative to the study diet.  
This form will be used to assess acceptability of diet at Measurement Visits 2, 3, and 4. 
The Diet Acceptability Short Form includes only the five questions relative to study diet 
acceptability. Participants will be asked to respond to this form approximately one 
month after beginning a study diet period (months 1, 4, and 7). 
Overall study acceptability will be ascertained at the conclusion of the intervention 
period. Study staff will conduct an exit interview with study participants to gather 
feedback on the study, including intervention design, process, and education materials.    
9.    ACT1ON SMART Pilot Intervention  
 
9a. SMART Pilot Overview  
Intervention Arms: Through the sequential randomization process, three evidence-
based diets will be evaluated. Diets were selected purposefully to vary substantially in 
macronutrient composition and in whether or not calories are explicitly restricted.   
Diet 1: Look AHEAD (hypocaloric): The Look AHEAD “intensive lifestyle intervention” 
will be followed, except that the calorie prescription will be T1D-specific and 
individualized based on findings from energy balance modeling in Phase 1 Study 1, 
calculated to attain the Look AHEAD weight loss goal of 7% body weight loss/1 year. 
The caloric distribution will be <30% fat, <10% saturated fat, and ≥15% protein.83 
Diet 2: Low Carbohydrate (hypocaloric): We will implement a low carbohydrate diet 
similar to the diet described by Tay et al.,(2015)58 which resulted in significant weight 
loss and improved metabolic status with no adverse impact on LDL cholesterol in 
patients with T2D over 12 months. The caloric distribution will be: 15-20% from 
carbohydrate, 22-27% from protein, with fats being at least 37% monounsaturated fat and 
<10% as saturated fat). Individualized calorie goals will be established in the same 
manner as for Diet 1.  
Diet 3: Healthy (Mediterranean) Dietary Pattern (not calorically restricted): This 
approach is justified by the PREDIMED diet, which employed Mediterranean diets 
without caloric restriction and resulted in reduced weight and waist circumference 

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among people with T2D, despite supplementation with either olive oil or nuts.55 Current 
ADA guidelines also support use of healthy dietary patterns such as the Mediterranean 
diet.49 In patients with T1D, common current clinical practice for weight loss is to advise 
reduced consumption of energy dense, nutrient poor foods and encourage consumption 
of healthy foods with ongoing carbohydrate counting for glycemic management. Diet 3 
will use this approach and clarify appropriate food choices consistent with PREDIMED 
dietary guidance, but without the direct provision of olive oil or nuts, which is not 
practical. Dietary guidance includes: (1) abundant use of olive oil for cooking and 
dressing; (2) increased consumption of fruits, vegetables, legumes and ﬁsh; (3) 
reduction in total meat consumption, recommending white meat instead of red or 
processed meat; (4) preparation of homemade sauce with tomato, garlic, onion, and 
spices with olive oil to dress vegetables, pasta, rice and other dishes; (5) avoidance of 
butter, cream, fast food, sweets, pastries and sugar-sweetened beverages; and (6) in 
alcohol drinkers, moderate consumption of red wine.55  
9b. SMART Pilot Procedures  
All RD sessions are conducted remotely following the restrictions placed on in 
person visits due to COVID-19. 
The initial counseling session, following baseline measurement but prior to initial 
randomization, will be designed to explore the participant’s past experiences with both 
glycemic control and weight management. An overview of healthy diet and general 
concepts related to weight management will be discussed. Motivational interviewing will 
be used to facilitate discussion of the participant’s perceptions of challenges and 
strengths related to diabetes self-management, including glycemic control, dietary 
choices, and weight management. Problem-solving skills training will be initiated. This 
initial session will establish the MI/PSST process, which will be used for all diets. 
Depending on results of Phase 1 Study 2 project on hypoglycemia, this initial counseling 
session will incorporate a discussion of problem-solving related to dietary response to 
hypoglycemia. Because self-monitoring will be used for all diets, we have designed a 
simple, one-week run-in period during which participants will monitor carbohydrate 
grams and weight. Participants will be shown how to use “MyFitnessPal,” an app 
commonly used by individuals with T1D for carbohydrate counting. Participants will also 
be provided with a Body Trace scale for home use. This scale transmits weight using 
the cellular network, through which we can confirm self-monitoring.84  
 
Further virtual counseling sessions will provide specific instruction and ongoing MI and 
PSST related to dietary adherence and glycemic control in the context of diet 
assignment. Self-monitoring of dietary intake and weight as relates to goal setting and 
attainment will be reviewed, and problem-solving skills developed to address barriers to 
adherence will be encouraged. The participant will be queried and any difficulties 
related to blood glucose management in the face of the experimental diet will be 
addressed.   
Periodic shorter phone check-in sessions will focus on review of goal attainment and 
problem-solving strategies. 
For an overview of measurement and intervention contacts, see Figure 9.1. 

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9c. Intervention Components 
Behavioral Framework for Dietary Interventions: We will deploy the behavioral 
framework established and refined by the FLEX study team as an adaptive method to 
help individuals accomplish individualized goals that improve self-management.85 
Theories of health behavior,86,87 and analysis and integration of theory in social and 
health psychology,88,89 suggest a conceptual framework positing knowledge, motivation, 
and skills as necessary for behavior change. Our application of this theory is to integrate 
motivational interviewing (MI) and problem-solving skills training (PSST) approaches 
into a coherent intervention and to supplement these with pragmatic tools tailored to 
overcome specific barriers to adherence. MI, an effective,90–92 patient-centered 
approach to health behavior change, is used to help individuals resolve ambivalence 
about change and to enhance intrinsic motivation by creating a motivational frame for 
change.93–95 Once this motivation for change is achieved, PSST, a systematic approach 
to problem-solving, is presented as a way to make desired changes.91–100 
Registered Dietitian (RD) Counseling: Shown in Figure 9.1, RDs will conduct 18 
sessions over 10.5 months: 8 longer virtual counseling and education sessions and 15 
phone “check-in” sessions, a framework similar to the ADA guidelines for intensive 
lifestyle counseling for weight management.54 Study RDs will be centrally trained and 
certified to deliver the proposed intervention, including use of the MI and PSST 
counseling strategies, and delivery of education related to adherence to the specified 
experimental diets. All RD sessions will be documented, including audio-recording of 
the in-person sessions to enable ongoing assessment of fidelity of intervention delivery. 
For all 3 diets, self-monitoring of diet and weight will be encouraged in the context of 
individual goal-setting. Participants will be encouraged to continue on with their usual 
level of physical activity throughout the study, as this study is focusing on changes to 
diet. Counseling related to glucose management and physical activity will be provided 
as needed, and carbohydrate counting will be reinforced for insulin dosing. Participants 
on the low carbohydrate diet will learn about necessary insulin dosing adjustments 
related to higher protein and fat intake. The participants will be queried and any 
difficulties related to blood glucose management in the face of the experimental diet will 
be addressed.  
 
Intervention Materials: The study team developed intervention materials for each of the 
study diets. Materials will utilize motivational interviewing (MI) techniques and problem 
solving skills training (PSST). MI94 is a collection of patient-centered interviewing 
techniques that can be used as the context for virtually any psychological or behavioral 
intervention. MI is designed to create a collaborative environment in which patients can 
develop arguments for change, understand and resolve their ambivalence to change, 
develop strategies for change, and increase their confidence in their coping abilities.93,94 
PSST teaches problem-solving as a behavior process through which individuals can 
accomplish the task of self-management.95,96 
 
The initial RD session focuses on providing an overview of healthy eating strategies, 
reviewing use of MyFitnessPal and the BodyTrace scale, use of nutrition labels, and an 
introduction into PSST strategies. Additional intervention sessions will utilize study diet 
materials to teach use of the specific diet to help the study participant achieve a healthy 

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diet within the guidelines of the specific study diet. Materials will include guidance on 
insulin dosing, caloric intake (for the two hypocaloric study diets), self-monitoring of 
dietary intake and weight, modification of a typical daily intake to meet guidelines of the 
specific study diet, use of nutrition labels, and PSST to identify specific goals within the 
context of use of the study diet in day-to-day life. Additional materials to be provided 
include guidance for eating out, recommendations for exercise for individuals with T1D, 
sample meal plans for each of the study diets, guidance for alcohol intake for individuals 
with T1D, and recognition of signs and symptoms for hyperglycemia, hypoglycemia, and 
diabetic ketoacidosis. 
 
Fidelity: All full-length intervention sessions will be audio-taped. Fidelity assessment will 
include review using a content fidelity checklist. Initially, the first two of each session 
type (initial, introduction to each diet, follow-up to each diet) by each RD will be 
reviewed. A random sample of other sessions will be reviewed in a timely fashion to 
provide feedback to the interventionists throughout the intervention.  
 
10. Data management  
 
An online data management system utilizing CDART from the Collaborative Studies 
Coordinating Center will be developed for this SMART pilot. The system will include 
online data collection and tracking of participant randomization. CDART has robust 
security features including unique user logins with expiration dates and complex 
password requirements; storage of hashed passwords only; granular permissions based 
on user requirement; and encrypted data transmission. The secure server environment 
where the systems that host CDART reside is located within a hardened data center on 
the UNC campus, and is governed by standard UNC information security guidelines. 
Weekly vulnerability detection scans are performed by a third-party vendor, which 
include full administrative credentials to perform maximum detection techniques. Real-
time virus protection software is implemented, and weekly full system virus scans are 
performed. Daily backups of the data are made and stored in an off-site 
location. CDART is 21 FDA Part 11 compliant. 
 
Upon entry into the study, a unique identifying number will be assigned to each 
participant. This number will be used to identify the information and specimens collected 
and stored during this study. Specimens collected and transferred to the central 
laboratory will have no identifier other than the unique identifying number assigned to 
the participant. The roster containing the unique identifying number and direct 
participant identifiers will be kept in a local password-protected database on a secure 
network drive at the clinical sites. 
 
11.  Statistical Considerations 
 
We will primarily compare the 3-month response rates to each of the three initial diets 
using standard statistical comparison procedures (e.g., t-tests and ANOVA) for 
differences in glycemic control (HbA1c and percent time in hypoglycemia) and change 

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in weight. In addition, we will conduct a series of secondary, hypothesis-generating 
analyses using standard statistical approaches as well as more complex fixed and 
mixed effect regression methods such as generalized additive models101 and random 
forests102 for these outcomes plus body fat and fat free mass. We will compare all diet 
sequences (there are 12) using the same outcomes and will incorporate evaluation of 
measures of ingestive behaviors. After adjusting for multiple comparisons, the proposed 
sample size of n=84 is sufficient to ensure 60% power to detect a moderate effect size 
(Cohen h=0.68) and 80% to detect a large effect size (Cohen h=0.85) at a significance 
level of 0.10 for comparing response rates among the 3 diets. Based on data reported in 
Wing et al (2016)103 and Russell et al (2014)104 and other preliminary data, we estimate 
for the same significance level and with 80% power that we will be able to detect a 
difference of about 3.0kg for weight change, 1.3% for HbA1c change, and 1.3 
percentage point change in percent time <70mg/dl. Here we emphasize that, by design, 
our primary goal for this pilot work is to inform the final efficacy design, and we have 
therefore not designed this pilot SMART to be fully powered for all analyses.  
An advantage of SMARTs is that they allow for efficient estimation of precise (i.e., 
deeply tailored) diet strategies. A precise diet strategy adapts treatment to the evolving 
health status of each participant. We will use a regression-based approximate dynamic 
programming algorithm known as Q-learning61,105,106 to estimate the precise diet 
strategy that maximizes weight loss while improving suboptimal or maintaining good 
glycemic control over the duration of the trial. The form of this estimated optimal diet 
strategy will generate hypotheses about how best to choose and adapt diets to 
individual patients. This will require the use of SMART analysis methods for balancing 
competing outcomes.107 
For treatment assignment, permuted block randomization with blocks of size 24 will be 
used to assign all 12 potential treatment regimes using R statistical software. This will 
be confidentially generated by the statistician and placed into CDART software to be 
revealed only at the point of treatment (diet) assignment for each patient. The 12 
possible regime sequences are (1,2,2), (1,2,3), (1,3,2), (1,3,3), (2,1,1), (2,1,3), (2,3,1), 
(2,3,3), (3,1,1), (3,1,2), (3,2,1), and (3,2,2). To illustrate, suppose a patient is assigned 
treatment sequence (1,3,3). Then, at baseline, only the initial diet (Diet 1) will be 
revealed. At 3 months, if the response is positive, the patient will continue with the same 
diet (Diet 1) for the next 3 months to the 6-month follow-up time. If at 6 months the 
patient is not responding, the new diet (Diet 3) will then be revealed. At 6 months, if the 
patient response is positive, the patient will continue with the most recently assigned 
diet (either Diet 1 or 3 depending on the outcome at 3 months yielding one of the two 
treatment paths (1,1,1) or (1,3,3)). If, at 6 months, the patient response is not positive, 
the new diet will be revealed. The new diet is Diet 3 if the patient had a positive 
response at 3 months (yielding the diet sequence (1,1,3)), otherwise the patient will 
receive the only unused diet, Diet 2 (yielding the diet sequence (1,3,2)). Thus a single 
regime will provide for four treatment paths depending on patient response. Moreover, 
all treatment assignments remain hidden in CDART until it becomes time to reveal the 
new diet. We recognize that patients who do not respond at either the 3 or 6 month time 
points will be able to anticipate their third diet, but all other patients will not. This is as 
unblinded as possible for this open label setting. 

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Effect sizes with accompanying confidence intervals will be estimated using mean 
outcome at 3 months and standard ANOVA methods will be used for confidence interval 
construction. We have no reason to think that diets will be differentially acceptable or 
effective for men compared to women; however, exploratory analyses will consider sex 
differences in response to the three diets. 
We also note that there are 21 possible diet sequences, but there are only 12 treatment 
regimes based on the randomization scheme. The distinction between regimes and 
sequences is described in Chapter 2 of Adaptive Treatment Strategies in Practice: 
Planning Trials and Analyzing Data for Personalized Medicine (Kosorok and Moodie, 
2016),108 but this can be illustrated by example. One treatment regime is the following: 
treat initially with Diet 1, then, if the patient responds favorably after 3 months, continue 
with the same diet, otherwise switch to Diet 3. After 6 months, if the patient responds 
favorably, continue with the same diet as given in the previous period. Otherwise, if they 
were on Diet 1, switch to Diet 3; If they were on Diet 3, switch to Diet 2.  Although this is 
a single treatment regimen (reflecting a single treatment choice at each decision time), 
this regime is consistent with the following four treatment paths: (1) if the patient 
responds favorable at both time points, they will experience Diet 1 repeated three times. 
(2) If they respond favorably at 3 months but not at 6 months, then their diet sequence 
would be Diet 1, Diet 1, and Diet 3. (3) If they responded unfavorably at 3 months but 
favorable at 6 months, then their diet sequence would be Diet 1, Diet 3, Diet 3. (4) If 
they respond unfavorably at both 3 and 6 months, their diet sequence would be Diet 1, 
Diet 3, and Diet 2. The issue is that a regime focuses on the decision a clinician can 
make either initially, or when the patient experiences an unfavorable response, at either 
3 or 6 months. The remaining decisions are made automatically since favorable 
responses do not lead to changes in diet. Note that this means that some diet 
sequences are consistent with more than one treatment regime, and thus the data from 
same patients will sometimes be used for estimating more than one of the 12 regimes. 
With balanced randomization, at least 6 patients will be assigned to each treatment 
regime.  
Moreover, we will in fact be able to make valid intent-to-treat comparisons across the 
three starting diets using the outcomes at 9 months, based on the fact the SMART 
designs have greater power for intent-to-treat hypotheses than traditional randomized 
designs (see Chapter 3 of Kosorok and Moodie, 2016).109 In a standard, randomized 
trial, failure of a diet would lead to either patient drop-out or switching of diet by the 
clinician. Thus two sources of bias arise: one from drop out and one from change in 
treatment. In contrast, with our design, we make additional diet assignments at 3 and 6 
months based on diet success. We use randomization instead of ad hoc reassignment. 
Thus, our design more formally addresses both patient drop out and treatment changes 
by including diet changes in our design in a balanced way. There may still be some drop 
out, but it will be lower since patients do not have to leave the study to have their diet 
changed. Thus the design is adequate to achieve the stated objectives. 
In addition, the Q-learning methodology will permit us to pool the data for regression 
models across similar branches among the possible treatment paths. To illustrate this, 
we point out that, as described in Chapter 17 of Kosorok and Moodie, 2016,106 Q-
learning is done through a backwards iteration of regression model fitting, with different 

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regression models at each potential randomization point. In our setting, we can 
integrate the multiple possible regression models at the third decision time (6 months) 
into one regression model by including past diets in the history variables as well as by 
allowing for four treatment options, one for each of the three diets and one for those 
patients who stay on with the previous diet. We can similarly integrate across the 
regression models at the 3 month decision time and also at baseline, resulting in the 
need for only three regression models. We will therefore have sufficient power for all of 
our proposed analyses. In addition, we will have sufficient sample size to use the pilot 
data to sample size a full SMART design using the methods described by Laber et al., 
(2016).110  
12.  Potential Risks, Discomforts, Inconveniences, & Precautions:   
Potential Risks 
Psychological and social risks are expected to be minimal (e.g., potential 
embarrassment about answering questions related to adherence). 
Venipuncture: Drawing blood from a vein in the lower arm may cause mild pain and 
occasionally minor bruising at the site of the blood draw. Fainting can also occur. There 
is a remote chance of infection or peripheral venous phlebitis or thrombosis. For study 
subjects with diabetes, the requirement of a fasting blood sample may precipitate a 
temporary blood glucose level that is somewhat lower or higher than usual. 
DISCONTINUED AS OF 4/2020. DXA scanning exposes subjects to a small dose of 
ionizing radiation. This dose of radiation is comparable to that obtained on a 
transcontinental airplane flight. 
Continuous glucose monitoring (CGM). This procedure is routinely used in clinical 
practice. The main risks of CGM are local irritation from the sensor or tape.  
Breach of confidentiality is a risk, although this is highly unlikely as data are used 
exclusively for research purposes and participants will be provided with information on 
how risks to confidentiality are minimized (see protection against risks for further 
details).  
Adequacy of Protection against Risks  
Recruitment and Informed Consent  
For both clinical sites (University of North Carolina, Stanford) we will invite eligible 
patients to participate in this study by emailing them an introductory letter that describes 
the study. These letters will be followed with telephone calls to answer questions and 
encourage participation.  
Research staff at the clinical sites will obtain written informed consent from participants. 
The study consent will explain the purpose of the study and measures taken to protect 
confidentiality (e.g., the data will not be linked with personal identifying information). A 
full informed consent protocol will be developed under the guidance of the Institutional 
Review Boards at each of the three clinical performance sites. Patients will be assured 
that participation is voluntary and that non-participation will not result in any 

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consequences to them. In addition, they will be informed that they may withdraw from 
the study at any time without consequences. Finally, participants will be informed that 
the data are used exclusively for research purposes, that identifying data will not be 
released by the investigators to their families or to any other individual or organization, 
and that any identifying information will be destroyed at the end of the project. 
Participants will be given adequate time prior to signing the informed consent document 
to ensure that they have an opportunity to ask and receive answers to any and all 
questions about study participation. 
In soliciting the cooperation of each young adult in our study, we will stress the data 
safeguards that will be in place to protect the confidentiality of the survey data. 
Minimizing the risk of disclosure requires careful data safeguards. Most important is the 
need to prevent the association of an individual’s name with sensitive information. We 
will keep participants’ names separate from their survey responses and store the link 
between names and study identification numbers in a password-protected file that is 
accessible only to authorized staff at the respective clinical sites.  
Participants will have opportunity to provide informed consent following the two-step 
recruitment process detailed above. For participants who agree to participate and 
schedule a baseline visit, the study consent form will be mailed or emailed to the 
participant prior to the scheduled baseline visit, so that the individual has ample time to 
review it on their own ahead of the visit. Participants will also be provided with 
instructions on how to use CDART, the data management system that we will employ 
to house participant data and house self-administered questionnaires. This email will 
also include a personalized link to a Qualtrics questionnaire, which provides 
participants the chance to read a consent form specific to completing baseline forms 
ahead of the in-person visit. If they choose to consent to completing these forms 
ahead of the visit, study staff will then email them their login information for CDART. 
These emails will include relevant visit reminders that have been previously reviewed 
during phone conversations with participants. Prior to the baseline measurement visit, 
participants will have a chance to complete several questionnaires in CDART, which 
will shorten the length of the in-person visit.  
 
At the time of the visit, study staff will review the full study consent in detail before 
standardized data collection begins. The study participant will be given as much time 
as needed to review the consent form and ask any questions prior to signing it. 
Participants will be informed that participation in the study is voluntary and they are 
free to withdraw their consent and discontinue participation in this research at any 
time. Study staff obtaining consent will utilize the tailored Consent Comprehension 
Checklist to guide a conversation with the participant that aims to ensure that she or 
he understands what she or he is consenting to and the nature of informed consent 
itself. 
 
COVID-19 PROVISIONS – VIRTUAL VISITS: 
Newly enrolled participants will be emailed the full consent form so that they may review it in 
detail. Then during a subsequent phone or Zoom call, the consent form will be reviewed 
verbally in detail by the Study Coordinator and participants will be given time to ask any 
questions and have these questions answered. Participants will be able to indicate their 

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consent using an electronic Qualtrics Survey in which they can indicate whether or not they 
agree to participate in the study as a whole as well as the stool kit collection and physical 
activity tracking opportunities. This consent process will include consent to complete online 
forms and thus will eliminate the use of the previous Qualtrics survey that allowed participants 
to complete online forms ahead of their in-person visits. 
Follow-up participants. These participants will be emailed a link to the revised consent 
addendum so that they may review it in detail. The study coordinator will discuss the changes 
to the study with already enrolled participants and go through the consent addendum in detail 
via a phone or Zoom call. They will be able to indicate their consent to participate in the 
revised virtual study online.  
 
Once participants have indicated their consent, they will be mailed their virtual measurement 
visit package and can begin all elements of the study visit.  
 
Following consent, participants may be involuntarily withdrawn from the study per the 
investigator’s discretion, if they develop a serious condition that would render 
participation unwise, including difficulties with glycemic control, and serious physical or 
psychiatric conditions. Females who become pregnant will also be withdrawn from 
study participation.     
 
Protections against Risk  
All institutions associated with this study are experienced with handling sensitive and 
confidential data. Certain routine administrative, personnel, physical security, 
information management, and computer system or network security practices are 
always in place given the policies and the requirements for safeguards consistent with 
the management of PHI at both clinical sites. All PHI will be used or disclosed in 
compliance with the Health Insurance Portability and Accountability Act (HIPAA). Paper 
forms will be kept in locked files when not in use. Participants will be assigned 
identification numbers in lieu of names on data management and data analysis files. A 
master list of identification numbers and names will be kept separate from all database 
files and will be maintained in a password-protected file that is accessible only to 
authorized staff at the respective clinical sites. Upon completion of the study, these files 
will be destroyed. No individual PHI will be used in reports or manuscripts. Data entered 
and stored on the microcomputer will be archived daily. The data collectors will follow a 
strict written protocol that describes study measures for protecting data privacy. Patients 
always have the right to refuse to participate or to refuse to answer any individual 
question they might find objectionable. 
Each site has a highly experienced endocrinologist as part of the local investigative 
team (UNC – Kirkman; Stanford – Maahs). To minimize the possibility of risks 
associated with the blood draw, experienced medical staff will obtain the blood samples. 
A local numbing medicine may be placed on the skin before the blood is drawn to 
decrease any pain. Participants who have a history of fainting or who develop 
symptoms of light-headedness will be placed in the supine position. The study 
physicians will review all laboratory findings for study participants in a timely fashion.  
Research staff will have guidance (“alert values”) for when to proactively contact the 
study physician for guidance.   
 

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Hemoglobin A1C 
The minimum amount of blood/plasma necessary to conduct these tests will be 
collected and the total amount collected will not exceed standard, weight-specific 
guidelines. Blood volumes will be approximately 22 ml at the baseline visit and 12 ml 
at the follow-up visits. Stored blood will be saved for 10 years after the end of the 
study. The following table describes the amount of blood required for the laboratory 
tests. 
 
The minimum amount of blood/plasma necessary to conduct these tests will be 
collected and the total amount collected will not exceed standard, weight-specific 
guidelines. Blood volumes will be approximately 22 ml at the baseline visit and 12 ml 
at the follow-up visits. Stored blood will be saved for 10 years after the end of the 
study. The following table describes the amount of blood required for the laboratory 
tests. 
MEASUREMENT 
Baseline 
Blood 
Draw 
Volume 
Remaining 
Visits 
 Blood Draw 
Volume 
Hemoglobin A1c 
2 ml 
2 ml 
Stored plasma 
10 ml 
10 ml 
Stored whole blood for DNA 
10 ml 
N/A 
Total maximum blood volume 
22 ml 
12 ml 
 
COVID-19 Provisions-Virtual Visits 
MEASUREMENT 
Baseline 
Blood 
Draw 
Volume 
Remaining 
Visits 
 Blood Draw 
Volume 
Hemoglobin A1c 
2 ml 
2 ml 
 
For the SMART pilot, the interventionists (Registered Dietitians) and study physicians 
will communicate regularly (verbally and in writing per protocol) regarding glucose 
control so that any changes in medical management can be made in a timely fashion, 
as it is understood that with weight loss, adjustments in medical management will be 
needed.   
Study personnel will be trained to identify the signs and symptoms of a blood glucose 
level that is low or high. They will also be trained to check the blood glucose level, 
using a glucometer. If low blood glucose occurs during a study visit (< 70 mg/dL), 
study personnel will be trained to administer 15 grams of an oral carbohydrate, and to 
repeat as needed every 15 minutes until the blood glucose level is > 70 mg/dL.111 If 
the blood glucose level is above 300 mg/dL during a study visit, study personnel will 
be trained to check for urinary ketones. In cases of low or high glucose levels (with or 
without the presence of ketones), additional medical interventions may sometimes be 

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needed. Local policies dictate these procedures, which may include a one-time 
adjustment in the dose of insulin taken and/or the administration of glucose gel, 
glucagon, or intravenous glucose. If participants experience hypoglycemia or 
hyperglycemia outside of study visits, they will be advised to treat these situations per 
their usual diabetes care plan. 
COVID-19 Virtual Visit Provisions: We are no longer asking participants to report their 
blood sugar or whether or not they have had anything to eat in the last 8 hours. The 
only fields of the ‘specimen collection form’ that we will complete are those that pertain 
to the HbA1c collection, that is, time and date of collection along with any problems the 
participant may have had.  
 
At each study visit and RD check-in call, hypoglycemia events will be reviewed with 
the participant. Participants will be asked to notify the study team within 48 hours of 
any severe hypoglycemic event (seizure, coma, or need for glucagon administration).   
Participants will be completing a CES-D form at all the measurement visits. Although 
the CES-D is not considered a diagnostic tool for the identification of clinical 
depression, it is designed to identify people who may be suffering from a depressed 
mood. Whenever a participant scores high (> 24) on the CES-D, study personnel will 
inform the participant that the CES-D score is “high” compared to what would be 
expected for most adults, indicating that the participant may be clinically depressed. If 
the participant is currently receiving mental health counseling or treatment, study 
personnel will recommend follow-up with his/her mental health provider. If the 
participant is not being treated by a mental health provider, study personnel will make 
a referral based on local guidelines and procedures.   
 
DXA scanning is performed by a certified radiology technologist, knowledgeable in the 
procedure and equipment. Female participants will undergo a urinalysis pregnancy 
test prior to each DXA scan to protect the unborn fetus from radiation exposure. 
COVID-19 VIRTUAL VISIT TRANSITION (4/2020) DXA discontinued. 
There may be unknown or unforeseen risks associated with study participation.  
 
13. Risk/Benefit Analysis 
Participation in this research study may help to improve glycemic control and weight in 
some participants. 
 
Potential Benefits of the Proposed Research to Human Subjects and Others  
The proposed research may lead to potential benefits for individuals with diabetes, 
including improved weight and improved diabetes control, and reduced risk of both 
short- and long-term complications. The risks to participants are reasonable in relation 
to the anticipated benefits to participants and others because: the risks are judged to 
be minimal and unlikely, safeguards against these risks are in place, and the potential 
benefits are important, both to individuals who participate in the study and to the 
broader population of young adults with T1D. 

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Importance of the Knowledge to be Gained  
This study should yield new information contributing to the self-management of 
diabetes, including both weight management and glycemic control, through the use of 
diet and related behavioral strategies to promote adherence. This knowledge may lead 
to better care for young adults with diabetes. The development of a feasible and 
effective novel intervention for young adults with T1D far outweighs potential risk of 
harm. 
14.  Data Safety & Monitoring:   
 
We will convene a 4-member Data and Safety Monitoring Board to meet twice yearly 
via video conference call. DSMB members will represent expertise in endocrinology, 
nutrition, health psychology and behavior change, and study design and statistical 
analysis relevant to SMART designs. Drs. Mayer-Davis, Maahs and Pratley will 
represent the ACT1ON consortium in interactions with the DSMB. The DSMB will 
review the final study protocol and any significant changes to the protocol over the 
course of the study especially as related to participant burden or safety. The DSMB 
will monitor and advise on study participant accrual and retention, progress and 
completeness for all standardized measurement visits and attendance at intervention 
sessions. Data quality will be reviewed and staff training and certification will be 
monitored. Adverse events will be monitored. A summary of the DSMB report will be 
sent to both the local site IRBs and NIDDK as part of the annual progress reports.  
Members of the DSMB have been identified and each individual listed below by area 
of scientific expertise (all with relevant expertise applied to T1D) has agreed to serve:  
 
Endocrinology: Irl Hirsch MD, University of Washington  
Nutrition: Sarah Couch PhD RD, University of Cincinnati  
Health Psychology and Behavior Change: Jessica Kichler, PhD, University of 
Cincinnati  
Study Design and Statistical Analysis: Ralph D’Agostino, PhD, Wake Forest University  
 
Data Monitoring  
Questionnaires will be administered to participants. Data will also be obtained via 
physical exam and biological specimen collection, as well as data collected based on 
structured interviewing of intervention acceptability. All aspects of data collection and 
data storage will be carefully monitored to ensure rapid detection of errors, 
inconsistencies or other problems. Data are reviewed systematically on a monthly 
basis throughout the data collection period so that data cleaning will happen close to 
“real time”. The data collectors will follow a strict written protocol that describes study 
measures and details for conducting measures accurately and in a manner that 
protects data privacy. They will explain to each participant that s/he has the right to 
refuse to participate or to refuse to answer any individual question that s/he finds 
objectionable and emphasize the importance of telling the truth. All institutions 
associated with this application are experienced in training data collection fieldwork 
personnel how to handle, store, and process sensitive and confidential data. Certain 
routine administrative, personnel, physical security, information management, and 

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computer system or network security practices are always in place. These practices 
include: building an audio-tape vault security, non-disclosure pledges, and 
account/keyword security on computer networks. In addition, we take multiple project-
specific steps to protect subjects from the risk of a breach in confidentiality. All data 
will be collected using study identification numbers. The list that links identification 
numbers to names will be kept in a password-protected file that is accessible only to 
authorized staff at the respective clinical sites. Only aggregate data that cannot be 
used to identify individuals will be included in any reports released to other agencies or 
for publication.  
Recruitment and retention will be monitored internally by the study via the study 
Recruitment, Retention, and Data Quality Committee, using the report templates 
established for the FLEX trial that show monthly participant recruitment and 
randomization accrual by site and overall. Reports also detail attendance at each of 
the intervention sessions and at each of the standardized measurement visits. Any 
participants permanently withdrawn from the study are documented, including reason 
for withdrawal. Reports also provide information on completeness of data collection as 
well as distribution of key variables (e.g., weight, height) for data quality checks. 
Internally, these reports will be reviewed monthly, and the DSMB will review the 
reports when they convene twice yearly.  
 
Adverse Events  
For purposes of monitoring and reporting adverse events, the following NIH definitions 
will be used:  
Adverse Event (AE): any unanticipated, untoward medical occurrence that may 
present itself during treatment or administration of an intervention, and which may or 
may not have a causal relationship with the treatment. Adverse events could arise 
from the study (e.g., breach of confidentiality) or could arise due to the population 
under study.  
Serious Adverse Event (SAE): Any medical occurrence that results in death; is life-
threatening; requires inpatient hospitalization or prolongation of existing 
hospitalizations; creates persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect.  
 
It is highly unlikely that participation in the SMART pilot intervention will cause an AE 
or SAE. Should an AE occur, however, the study coordinators will immediately report 
any AE’s connected to the study physician at the local site and to the study 
investigators, who will keep a log of AE’s and SAE’s. The log will also be used to 
provide information about AE’s in annual progress reports to participating IRBs and 
NIDDK. Any study participant experiencing hypo/hyperglycemia or an otherwise 
potentially expected symptom related to diabetes will be encouraged to consult their 
diabetes care provider or to go to the emergency room immediately as needed.  
  
For monitoring, the coordinators will report AEs to the study MPIs and the overall study 
project manager (Thomas) on a timely basis – 24-48 hours is typical for an SAE, 10-14 
days for a routine AE. Local IRB reporting requirements will be followed (rapid 

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reporting for SAEs only, routine AEs as part of the annual IRB renewal 
documentation).  
 
All AEs will be reviewed monthly by the study Recruitment, Retention and Data Quality 
committee, which also serves as the clinical oversight committee in this pilot project, to 
ensure completeness of documentation and study relatedness. AEs will be reviewed 
quarterly by the study Steering Committee.  
 
The following grading scale will be used by the Recruitment, Retention and Data 
Quality committee to adjudicate AE/SAEs. Consensus will be sought among all 
members and in the event of lack of consensus; this will be noted and reported to the 
DSMB. 
 
 
All AEs will be reviewed by the study Data and Safety Monitoring Board to determine if 
an AE is related to the research project. Our team will file a written report to the site 
IRBs in accordance with local IRB requirements, and to NIDDK. Outcomes for AE’s 
will be monitored by the DSMB and outcome information will be entered into a log for 
inclusion in reports to participating IRBs and NIDDK as required.  
 
Anticipated events relative to the population under study (e.g., low or high blood 
glucose) or relative to study activities (e.g., fainting associated with venipuncture) will 
be noted as potential risks on the informed consent form. The DSMB will also monitor 
the occurrence of these events. In addition, resource and referral listings for 
community services will also be provided on a routine basis as needed. Drs. Mayer-
Davis and Maahs will also work extensively with the staff at each of the clinics to 
ensure that if participants need to be referred, these situations are managed in a 
manner consistent with clinic preferences/policies.  
 
Should any other problems or concerns arise with the data collection or intervention 
program, the PI or local clinical PI will be available to address these. 
15.  Privacy & Confidentiality   
To protect the right of the participant’s privacy, the patients’ disease status will not be 
included on the mailing envelope or subject line of any recruitment materials or emails 

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for the study. In-person recruitment will occur in the diabetes clinics by study 
personnel. Study visits will occur in private settings.  
 
To minimize the risk of loss of confidentiality, all information related to study subjects 
will be confidential and kept in secure cabinets or password-protected computer files, 
in compliance with NIH and HIPAA requirements as detailed in NIH Notice OD-020 
issued December 30, 2004.   
 
Each participant will be assigned a unique study identification (ID) number. 
Participants will be identified on all study-related documents only by their study ID 
numbers. The roster containing the unique identifying number and direct participant 
identifiers will be kept in a local password-protected database on a secure network 
drive at the clinical sites. 
 
All hard copy data collection forms will be secured in a locked file cabinet or office.  
Data will be entered onto a secure Web-based data management system. Only the 
study coordinator and relevant research study staff will have access to this study 
database. Secure access will be assured by use of individual login codes and 
password protection. Entered data will be stored securely and accessed in accordance 
with current HIPAA standards, the HCFA’s Internet Security Policy, and other state 
and local requirements.  
 
All data interactions for the study by all users including participants, coaches, clinical 
staff, research staff, and investigators, are web-based communications between the 
given user’s web browser and the web server running the study website and/or data 
management software. All of these web-based communications are configured to use 
the standard HTTPS protocol with 128-bit encryption. This includes online forms 
submitted by participants as they are transferred to the servers at UNC.  
 
An online data management system utilizing CDART from the Collaborative Studies 
Coordinating Center will be developed for this SMART pilot. The system will include 
online data collection and tracking of participant randomization. CDART has robust 
security features including unique user logins with expiration dates and complex 
password requirements; storage of hashed passwords only; granular permissions based 
on user requirement; and encrypted data transmission. The secure server environment 
where the systems that host CDART reside is located within a hardened data center on 
the UNC campus, and is governed by standard UNC information security 
guidelines. Weekly vulnerability detection scans are performed by a third party vendor, 
which include full administrative credentials to perform maximum detection 
techniques. Real-time virus protection software is implemented, and weekly full system 
virus scans are performed. Daily backups of the data are made and stored in an off-site 
location. CDART is 21 FDA Part 11 compliant. 
For the purposes of tracking recruitment and scheduling, basic participant information, 
including first and last name, Study ID, and dates and other pertinent information 
regarding scheduled appointments (reminder calls, etc.) will be kept in a password-
protected Microsoft Access database stored securely at each clinical site. 

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The intervention does not require transmission of PHI by any cell phone. We recognize 
that participants may take the initiative to send PHI by cell phone. As is the case with 
all behavior intervention utilizing current technology, we will explain to participants that 
transmission of such information is not secure.   
 
Data will be obtained and stored based on structured interviewing of intervention 
acceptability, and audio-tapes of session delivery. All aspects of data collection and 
data storage will be carefully monitored to ensure rapid detection of errors, 
inconsistencies or other problems. The data collectors will follow a strict written 
protocol that describes study measures for protecting data privacy, explain to each 
participant that s/he has the right to refuse to participate or to refuse to answer any 
individual question that s/he finds objectionable, and emphasize the importance of 
telling the truth. All institutions associated with this study are experienced in training 
data collection fieldwork personnel how to handle, store, and process sensitive and 
confidential data. Certain routine administrative, personnel, physical security, 
information management, and computer system or network security practices are 
always in place. These practices include building an audio-tape vault security, non-
disclosure pledges, and account/keyword security on computer networks.   
 
In addition, we take multiple project-specific steps to protect subjects from the risk of a 
breach in confidentiality. All data will be collected using study ID numbers. Thus, no 
questionnaire will contain identifying information, and the roster containing the unique 
identifying number and direct participant identifiers will be kept in a local password-
protected database on a secure network drive at the clinical sites. Finally, only 
aggregate data that cannot be used to identify individuals will be included in any 
reports released to other agencies or for publication.

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16.  Study Timeline   
 
The study timeline for Phase 2 (SMART Trial) and Phase 3 (Efficacy Trial Development) is included below. 
 
 
May Jun Jul
Aug SeptOct Nov Dec Jan Feb Mar Apr May Jun Jul
Aug SeptOct Nov Dec Jan Feb Mar Apr May Jun Jul
Aug SeptOct Nov Dec Jan Feb Mar Apr May Jun Jul
Aug SeptOct Nov Dec Jan Feb Mar Apr
Phase 2, SMART Trial
Intervention Development
IRB Submission
Recruitment
Data collection/intervention
Analysis
Phase 3
Efficacy Trial Development
2017
2018
2019
2020
2021

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Appendix 1. 
PHYSICAL ACTIVITY STUDY PROTOCOL 
Background 
This protocol is designed specifically for the collection of physical activity data provided 
by participants enrolled in the ACT1ON DP3 SMART Pilot. 
Physical activity is an essential part of type 1 diabetes (T1D) management. Regular 
exercise has been shown to help individuals with T1D reduce HbA1c and improve lipid 
blood lipid profiles, body composition, and endothelial function1,2. People with T1D who 
exercise more frequently also tend to have lower total daily insulin needs and 
experience fewer diabetes related complications such as retinopathy, microalbuminuria, 
and diabetic ketoacidosis (DKA)3,4.  
It is currently recommended for individuals with T1D to participate in at least 150 
minutes of accumulated physical activity per week, with no more than two consecutive 
days without physical activity5,6. There are, however, distinct barriers to meeting 
physical activity guidelines among people with T1D, including exercise-related 
dysglycemia. Exercise, especially vigorous aerobic activity, increases the risk of 
hypoglycemia for at least 24 hours after7. Having to ingest additional carbohydrates 
(and thus calories) in response to hypoglycemia may create a feeling of futility around 
exercise that may prevent individuals with T1D from meeting recommended physical 
activity guidelines8.  
Research exploring the role of exercise in the management of T1D is needed. 
Specifically, the effects of varying exercise intensities and modalities on glycemic 
outcomes and weight management for people with T1D remains under-researched. The 
inclusion of additional physical activity data within the ACT1ON DP3 SMART Pilot study 
would allow for the elucidation of the effects of varying amounts and intensities of 
physical activity on its primary outcomes of weight management and glycemic control.  
Site Descriptions 
The two clinical sites include the 1) University of North Carolina at Chapel Hill (UNC-
CH) and 2) Division of Pediatric Endocrinology and Diabetes at Stanford University.  
Selection & Recruitment of Subjects 
Eligibility: 
  
Any participant in the SMART pilot willing to provide data regarding their physical 
activity will be invited to participate.  
Of the 42 participants at each site (84 total) that will be recruited, we expect that up to 
80 (40 at each site) will participate in the physical activity portion of the protocol. 

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Process of Obtaining Consent 
Participants will indicate whether or not they are willing to participate in the physical 
activity component of the study, including willingness to wear a Garmin Vivosmart 4 
Fitness Tracker and provide a session rate of perceived exertion (sRPE) rating with 
each bout of structured exercise during each 14-day data collection period. Consent to 
participate will be obtained remotely via phone at the time of the participant’s next 
regularly scheduled measurement visit following approval of this protocol. All 
participants currently enrolled are eligible to participate in this part of the study at each 
of their remaining measurement visits.  
Study Outcome Variables 
The Garmin Vivosmart 4 fitness tracker utilizes a built in Garmin Elevate™ Heart Rate 
monitor, altimeter, accelerometer, and Bluetooth® Smart and ANT+® technology to 
measure outcomes of interest, including heart rate (HR), step count, floors climbed, 
and energy expenditure (EE). The wearable device automatically syncs to the 
GarminConnect application.    
Session Rate of Perceived Exertion (sRPE) will be assessed by participants utilizing 
a validated sRPE scale. The scale will be made accessible to participants through a 
QR code printed on labels attached to a water bottle and keychain provided to the 
participants by the study site. If participants do not have access to a smartphone 
capable of utilizing a QR code, the link to the sRPE form will be provided through 
email. Session RPE has been shown to be a valid, reliable, and practical tool for 
monitoring training load. This method asks participants to assess the intensity of their 
workout with a single number rating between 0 – 10, with 0 being equivalent to 
complete rest and 10 being a maximal bout of exercise. Through incorporating both 
RPE and duration of exercise, this method can provide insight to the physical and 
psychological effort of exercise over the course of 14 days, as well as the total strain 
and monotony of training experienced by participants. It is recommended that 
participants wait at least 30 minutes following exercise to record their session RPE in 
order to prevent intensity of the end of their workout from affecting the overall rating of 
perceived exertion for the session.  
Objective Measures of Physical Activity Procedures 
Heart rate, step count, floors climbed and energy expenditure data will be gathered 
through the use of a wearable fitness tracker during a 14-day wear time consistent 
with the 14-day CGM wear time that is part of the current study protocol.  
a.) Research staff will provide participants with a Garmin Vivosmart 4 at each 
measurement visit and instruct participants on its use. For visits done remotely, 
the wearable device will be shipped to the participants. 
a. Research staff will: 
i. Instruct participants on how to use the Garmin Vivosmart 4 fitness 
tracker. 

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ii. Instruct participants on how to connect to the GarminConnect app 
and create a user profile.  
iii. Although the Garmin watch itself does not have GPS, the watch 
can use an antenna in a smartphone that can record GPS data for 
a walk, run, or bike activities. Participants will be informed in the 
information sheet and verbally by staff that they should not turn 
this feature on. We are not using GPS for any portion of 
this study. 
iv. Emphasize the importance of charging the Garmin Vivosmart 4 
each night to prevent data loss due to inadequate battery life.  
v. Instruct participants how to return the Garmin Vivosmart 4 fitness 
tracker following the completion of the 14-day data collection 
period. 
b.) Participants will ship the Garmin Vivosmart 4 fitness tracker back to the study 
site following the completion of the 14-day data collection period using prepaid 
materials provided to them by the study site.  
Session Rate of Perceived Exertion (sRPE) Data Collection 
Procedures 
a.) Following consent to participate, research staff will create an sRPE chart and 
corresponding QR Code for each participant. These will be stored in a secure 
folder in the ACT1ON Study staff site on Microsoft OneDrive. 
b.) The corresponding QR code will be printed on weatherproof labels which will 
then be applied to a water bottle and key chain to be shipped to participants 
along with the wearable device ahead of the timing of their next measurement 
visit. Participants will keep the water bottle and keychain as an additional 
incentive for participation in this part of the study. Additional QR-coded stickers 
will be provided to participants in case of loss or damage.  
c.) During the remote measurement visit, research staff will: 
a. Assist participants in the setup of the wearable device 
b. participants their preferred time of day for exercise. 
c. Schedule regular email or phone messages to remind participants to 
record their exercise session and perceived exertion.   
d. Instruct participants in how to use the QR code to access their sRPE 
chart.  
e. Instruct participants in how to use the sRPE scale to measure their 
exercise intensity utilizing the script provided in the appendix.   
f. Detail the information to be provided following each bout of structured 
exercise and to record their sRPE at least 30 minutes following exercise, 
but within 24 hours.  
Following a bout of structured exercise during the 14-day wear time, 
participants will scan the QR code to access their sRPE chart and record the 
time of day, duration, exercise modality, and their rate of perceived exertion for 

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the session (sRPE). These values should be recorded at least 30 minutes after 
exercise, but within 24 hours.  
Insulin Dosing  
For participants who are using insulin pumps, insulin use data will be downloaded from 
the participant’s insulin pump remotely.  
Materials and Technology 
The Garmin Vivosmart 4 is a waterproof fitness tracker worn around the wrist with built 
in accelerometer, altimeter and Garmin Elevate™ heart rate monitor. This fitness 
tracker has a touch interface and a battery life of up to seven days. It can automatically 
sync with the GarminConnect application through the use of Bluetooth® Smart and 
ANT+® technology. We will have 10 Garmin Vivosmart 4 fitness trackers at each study 
site, for a total of 20. The Garmin Vivosmart 4 will be provided to participants by mail 
prior to their next scheduled visit and returned following the 14-day wear time by mail 
to the study site with a prepaid shipping envelope.   
The GarminConnect application allows for the wireless syncing and storage of physical 
activity data and also provides participants with real-time feedback on their physical 
activity stats.  
Each participant will also be given a water bottle and a keychain, each with 
weatherproof labels attached containing the QR code corresponding to their sRPE 
chart to allow for quick and easy access to their assessment form.  
The website, www.qr-code-generator.com will be used to generate individual QR 
Codes needed to allow participants to access their sRPE assessment form.  
A secure platform, such as Microsoft OneDrive or REDCap, will be utilized for the 
secure storage of sRPE data from participants. 
 
 
 
 
 
 
 

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Study Timeline 
.
 
 
 
 

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Appendix 2. 
sRPE Familiarization Script 
Thank you for agreeing to participate in the physical activity component of our study! In 
addition to wearing a Garmin Vivosmart 4 activity tracker during this two-week period, if 
you decide to participate in structured exercise, we ask that you take the time to fill out a 
quick assessment form to provide us with a measure of the intensity of your workout.  
 
Assessment Form Details 
 
The assessment form asks you to record four things. These are the time of day you 
exercised, how long you exercised for, the type of exercise you participated in and 
then your rate of perceived exertion. For the rate of perceived exertion, we want you 
to answer the question “How hard was your workout?” To do this you will provide a 
rating of the intensity of your workout from 0 to 10, with 0 being equal to resting at home 
on your couch and ten being equal to the hardest workout you have ever done. 
 
Do you have any questions so far? (If yes: Go back over the assessment form) 
 
Accessing Assessment Form 
 
If no: Great! We ask that you fill out this form at least 30 minutes after your workout, but 
within 24 hours. You can access the assessment form through a QR code that we have 
printed on a sticker on your water bottle or keychain. You can use a QR code scanner 
or your smartphone camera to utilize the QR code. If you are unfamiliar with or unable 
to use QR codes, we are also happy to send you a link to the form over email or text.  
 
Do you have any questions about how to access the assessment form? (If yes: Review 
how to use QR codes or establish if the participant would prefer an email/text link). 
 
Email Reminders 
 
If no: Great! We will also send you a daily email reminder to fill out this form during this 
time. If you haven’t exercised that day, however, you do not need to worry about filling 
out the form for that day. Is there a time of day that you prefer to receive this reminder 
email? You might think about a time that would be within 24 hours of your favorite time 
to exercise. 
 
If They Have a Preferred Time: Ok, great! We can set up the email reminders to 
remind you around that time of day.   
 
If They Do Not Have a Preferred Time: Ok, we will just plan to remind you at about the 
same time every day.  
 
 
 

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Garmin Vivosmart 4 Physical Activity Tracker 
One physical activity device should be assigned per participant. Each physical activity device 
will be labeled and recorded in an excel document to track inventory.    
Charging the Garmin Device  
Site staff should charge the Garmin Vivosmart 4 prior to shipping. 
- 
Pinch sides of charging clip (1) to open arms on clip 
- 
Align clip with magnetic charging contacts (2) and release arms of clip 
- 
Plug USB cable into a power source to turn on device 
- 
Ensure fit is correct on magnetic charging contacts and watch is charging 
The device will turn on and say, “Hello!” (see photo below). 
      
 
- 
After initial charge, usually, best time to charge device is overnight (when participant is 
sleeping, can leave charger on night stand or next to bed) 
App and Device Setup 
Participant device accounts that require email address to complete sign up will use study-
generated email accounts:  
Format: ACT1ON-(3-digit site number)-(3-digit participant number at site)@gmail.com  
Example: ACT1ON-000-001@gmail.com  
Setting up Study ID: 
After informed consent form and all other applicable consenting documents have been signed, a 
participant ID number will need to be created by study team prior to performing any testing 
procedures for the study. 
The ACT1ON protocol uses the following format when assigning participant ID numbers:  
• 
Protocol designation prefix – ‘ACT1ON’ for this study 
• 
Site number (###) – site number (same for each protocol) – always 3 numbers 
o Stanford site number = 000 
o UNC site number = 111 
• 
Patient number at site (###) – always 3 numbers  
o Example (for Stanford): ACT1ON-000-001 

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o Example (for UNC): ACT1ON-000-001 
 
Each site will have prepared login credentials for 10 subjects.  
Garmin Connect App Download 
- 
The Garmin Vivosmart 4 uses the Garmin Connect app. The app is available for iOS on 
the App Store and Android on Google Play. See below for Garmin Connect App setup. 
Create Account for Garmin Connect 
- 
Each participant will have a Garmin Connect account to record his or her activity 
o Open Garmin Connect App 
o Press “Create account” 
o Allow participant to review legal terms and conditions 
o Enter participant ID in “name” field 
o Enter study email address in “email address” field 
o Enter assigned study password in “password” field 
o Bring physical activity watch in close range to participant’s smartphone so device 
can connect 
o Allow participant to follow on-screen tutorial on physical activity watch and app 
o When prompted, select preferred display orientation (portrait or landscape) 
o Select watch face that shows heart rate 
 
Watch face (above) shows: 
1) Current heart rate 
2) Resting heart rate zone 
Garmin Use 
- 
Double tap touchscreen to wake the device up 
- 
Note: screen turns off when not in use 
o Device is still active and recording data when screen is off 
- 
The device should be secured above the wrist bone and not move while running or 
exercising 
- 
Watch should be worn on non-dominant wrist 
 

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Log an Exercise  
The participant should log exercise through the Garmin physical activity wearable.  
Participant can record a timed activity, which can be saved and sent to their Garmin Connect 
account. 
 
- 
Double tap touchscreen to stop and resume activity timer 
- 
Tap to view additional screens which appear at top of touchscreen 
- 
After participant completes activity, double tap touch screen to stop timer 
- 
Select an option: 
 
Syncing Your Data with Garmin Connect Mobile App 
- 
Garmin device automatically syncs data with Garmin Connect Mobile app each time the 
app is opened 
- 
Garmin device periodically syncs data with Garmin Connect Mobile app automatically 
- 
Can also manually sync data at any time 
o Bring device near smartphone 
o Open Garmin Connect app 
o Press 
to view the menu 
o Select 
 
o Wait for data to sync 
o View current data in Garmin Connect app 
Preparing Garmin for Re-Assignment 

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- 
Garmin watch will be mailed back to clinic after every 2-week data collection period is 
complete (refer to timeline above) 
- 
Previous personal data on the Garmin device should be erased prior to assignment of 
the next participant  
o Press 
 to view Menu 
o Select 
 
o Select the following option: 
 
To reset all of device settings to factory default values and delete all user-
entered information and activity history, select Delete Data and Reset 
Settings 
o Press
 
o Select 
 
- 
Garmin Connect app should also be deleted from participant’s smartphone at the end of 
final study visit 
Other Notes 
- 
Garmin Vivosmart 4 should be worn on the same wrist at all times 
- 
Suggestions for optimal charge time include overnight since we are not collecting sleep 
data 
- 
Keep device on flat surface like a countertop when not in use 
- 
If patient prefers, can charge device ~30 mins daily when sitting (not preferred) 
- 
The device withstands pressure equivalent to a depth of 50 m and is waterproof 
- 
Can be worn for swimming and showering, but preferably not scuba diving or highspeed 
watersports 
- 
Clean device with a cloth dampened with mild detergent solution and wipe dry after 
watch is returned 
- 
Make sure device is completely dry before placing on wrist. Avoid chemical cleaners, 
solvents, and insect repellents that can damage the plastic components and finishes 
- 
Thoroughly rinse device with fresh water after exposure to chlorine, salt water, 
sunscreen, cosmetics, alcohol, or other harsh chemicals 
- 
Full manual for Garmin Vivosmart 4 provided here: 
https://www8.garmin.com/manuals/webhelp/vivosmart4/EN-US/vivosmart_4_OM_EN-
US.pdf