Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission
Phase: NA
Conditions: Type 2 Diabetes, Obesity
Sponsor: Wake Forest University Health Sciences

Official Title:  Data-Assisted Approach for High Intensity Weight Loss for Diabetes Remission
NCT04663061
IRB Approval Date:  09/11/2022

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
1
Data-Assisted Approach for High Intensity Medical 
Weight Loss for Diabetes Remission 
National Clinical Trial (NCT) Identified Number: NCT04663061 
Principal Investigator: Jamy Ard 
Sponsor: Wake Forest School of Medicine 
Funded by: Savvy Sherpa, LLC 
Version Number: v.1.1 
12 October 2020 
Table of Contents 
Statement of Compliance .............................................................................................................................................. 3 
Investigator's Signature ............................................................................................................................................. 3 
1 Protocol Summary ...................................................................................................................................................... 5 
1.1 Synopsis ............................................................................................................................................................... 5 
1.2 Schema ................................................................................................................................................................ 6 
1.3 Schedule of Activities ........................................................................................................................................... 8 
2.1 Study Rationale .................................................................................................................................................... 9 
2.2 Background .......................................................................................................................................................... 9 
2.3 Risk/Benefit Assessment.................................................................................................................................... 10 
2.3.1 Known Potential Risks ................................................................................................................................. 10 
2.3.2 Known Potential Benefits ........................................................................................................................... 11 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................................... 11 
3 Objectives and Endpoints ......................................................................................................................................... 12 
4 Study Design ............................................................................................................................................................. 14 
4.1 Overall Design .................................................................................................................................................... 14 
4.2 Scientific Rationale for Study Design ................................................................................................................. 14 
4.3 Justification for Intervention ............................................................................................................................. 14 
4.4 End-of-Study Definition ..................................................................................................................................... 15 
5 Study Population ...................................................................................................................................................... 16 
5.1 Inclusion Criteria ................................................................................................................................................ 16 
5.2 Exclusion Criteria ............................................................................................................................................... 16 
5.3 Lifestyle Considerations ..................................................................................................................................... 17 
5.4 Screen Failures ................................................................................................................................................... 17 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 17 
6 Study Intervention(s) or Experimental Manipulation(s) ........................................................................................... 18 
6.1 Study Intervention(s) or Experimental Manipulation(s) Administration ........................................................... 18 
6.1.1 Study Intervention or Experimental Manipulation Description ................................................................. 18 
Active intervention .................................................................................................................................................. 18 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
2
Control Intervention: ............................................................................................................................................... 20 
6.1.2 Administration and/or Dosing ....................................................................... Error! Bookmark not defined. 
6.2 Fidelity ............................................................................................................................................................... 20 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING ............................................................................................ 20 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 21 
6.4 Study Intervention/Experimental Manipulation Adherence ............................................................................. 21 
6.5 Concomitant Therapy ........................................................................................................................................ 21 
6.5.1 Rescue Therapy ........................................................................................................................................... 21 
7 Study Intervention/Experimental Manipulation Discontinuation and Participant Discontinuation/Withdrawal .... 23 
7.1 Discontinuation of Study Intervention/Experimental Manipulation ................................................................. 23 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 23 
7.3 Lost to Follow-Up ............................................................................................................................................... 24 
8 Study Assessments and Procedures ......................................................................................................................... 25 
8.1 Endpoint and Other Non-Safety Assessments ................................................................................................... 25 
8.2 Safety Assessments ............................................................................................................................................ 27 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 28 
8.4 Unanticipated Problems .................................................................................................................................... 28 
8.4.1Definition of Unanticipated Problems ......................................................................................................... 28 
8.4.2Unanticipated Problems Reporting ............................................................................................................. 28 
9 Statistical Considerations ......................................................................................................................................... 30 
9.1 Statistical Hypotheses ........................................................................................................................................ 30 
9.2 Sample Size Determination................................................................................................................................ 30 
9.3 Populations for Analyses ................................................................................................................................... 30 
9.4 Statistical Analyses............................................................................................................................................. 31 
9.4.1 General Approach ....................................................................................................................................... 31 
10 Supporting Documentation and Operational Considerations ................................................................................ 32 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 32 
10.1.1 Informed Consent Process ........................................................................................................................ 32 
10.1.2 Confidentiality and Privacy ....................................................................................................................... 32 
10.1.3 Future Use of Stored Specimens and Data ............................................................................................... 32 
10.1.5 Key Roles and Study Governance ............................................................................................................. 33 
10.1.5 Safety Oversight ........................................................................................................................................ 33 
10.1.6 Clinical Monitoring .................................................................................................................................... 33 
10.2 Additional Considerations ............................................................................................................................... 33 
10.3 Abbreviations and Special Terms ..................................................................................................................... 33 
10.4 Protocol Amendment History .......................................................................................................................... 34 
11 References .............................................................................................................................................................. 36 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
3
STATEMENT OF COMPLIANCE 
1. The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
o 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
OR 
2. The trial will be conducted in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and 
the [specify NIH Institute or Center (IC) [ Terms and Conditions of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the funding agency and documented approval from the 
Institutional Review Board (IRB), and the Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) sponsor, if applicable, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed Human Subjects Protection and ICH GCP Training. 
For either option above, the following paragraph would be included: 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. 
All changes to the consent form(s) will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
INVESTIGATOR'S SIGNATURE 
Principal Investigator or Clinical Site Investigator: 
Signed: 
  
Date: 
  
Name*:  
Jamy D. Ard, MD 
Title*:  
Principal Investigator 
 
 
Investigator Contact Information: 
Affiliation*:  Wake Forest School of Medicine 
Address:  
1 Medical Center Boulevard, Winston Salem, NC 27157 
Telephone:   336-716-9837 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
4
Email: 
 jard@wakehealth.edu 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
5
1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
Data-Assisted Approach for High Intensity Medical Weight Loss 
for Diabetes Remission 
Grant Number: 
IRB00067950  
We will study the efficacy of a high intensity medical weight loss 
intervention paired with a digital platform to create weight loss 
and induce remission of T2DM compared to a diabetes self-
management education intervention. The digital platform 
provides the capability to tailor the treatment plan, provide 
automated support, and alert providers when a participant may 
need more support from the clinical team. If shown to be 
efficacious, this research could be highly impactful, causing us to 
rethink our approach to care for those with T2DM and shift the 
paradigm for millions of individuals in the US. Furthermore, this 
approach will demonstrate the feasibility of helping people 
engage in metabolic treatment strategies in a way that is 
scalable leveraging digital and mobile solutions that extend the 
patient-provider relationship, shift care from episodic 
approaches to more of an on-going model that extends into the 
life of the patient, while also integrated within the healthcare 
system workflows. 
Objectives*: 
Primary Objective: Test the effectiveness of the combined 
interventions (data-assisted approach for high 
intensity medical weight loss) for weight loss in 
a group of adults with recently diagnosed type 
2 diabetes compared to standard of care 
diabetes self-management education. 
Secondary 
Objectives: 
Demonstrate the feasibility of pairing a high 
intensity medical weight loss treatment for 
diabetes remission with a digital platform that 
integrates remote monitoring, patient self-
report, and care pathways into a data-assisted 
and personalized treatment program. 
Endpoints*: 
Primary Endpoint: Change in body weight (kg) from baseline 
to 12 months 
Secondary 
Endpoints: 
Hemoglobin A1c (%) change from baseline 
at 3, 6, 9, 12 months 
  
Diabetes remission at 12 months, including 
partial remission (HbA1c of 5.7-6.4% 
without the use of anti-diabetes 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
6
medications) and complete remission 
(HbA1c of 5.7-6.4% without the use of anti-
diabetes medications) 
  
Continuous glucose monitoring 
outcomes. CGM related outcomes that we 
will assess at baseline and 12 months 
include time in range, episodes of 
hypoglycemia, glucose variability, and 
average glucose. 
Study Population: 
Participants will be individuals 18 and older who have T2DM 
diagnosed within the past 6 years with a BMI of 27-50 kg/m2. 
Participants must have an HbA1c between 6.5-11.9%. Sample 
size will be 30 participants per treatment group. 
Phase* or Stage: 
Phase 4 
Description of 
Sites/Facilities Enrolling 
Participants: 
Wake Forest Baptist Health Weight Management Center (WMC) 
Wake Forest Baptist Health Diabetes Center (DC) 
Description of Study 
Intervention/Experimental 
Manipulation: 
Participants randomized to the HIWL treatment group will be 
placed on a meal replacement-based weight loss protocol. Our 
active intervention will be delivered with the aid of a technology 
platform that will automate portions of the intervention and 
assist clinicians in tailoring treatment and responding to 
participant needs in a “just-in-time” manner that we frame as a 
“data-assisted approach.”  
Study Duration*: 
15 months 
Participant Duration: 
12 months 
 
 
1.2 SCHEMA 
  
  

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
7
 
 
 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
8
 
1.3 SCHEDULE OF ACTIVITIES 
Study activity 
T<-
4 
T -
4 
T 
-
2 
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 28 32 36 40 44 48 52 
Phone screen 
x 
  
                                                                  
Consent 
  
x                                                                   
Screen visit (SV) 1 
  
x                                                                   
History and physical exam 
  
x                                                                   
Medication review 
  
x                                                                   
Past medical history 
  
x                                                                   
Electrocardiogram 
 
x             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Center for Epidemiologic Studies 
Depression Revised Scale  
 
x             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SV2 
  
  
x                                                                  
EuroQOL-5D 
  
  
x                                                 x             x 
Diabetes Distress Scale  
  
  
x                                                 x             x 
Binge Eating Scale 
  
  
x                                                 x             x 
Yale Food Addiction Scale 
  
  
x                                                                 
Dietary intake assessment1 
  
  
x                         x                       x             x 
Physical activity assessment2  
  
  
x                         x                       x             x 
Adverse events 
  
  
x                          x                        x              x 
Randomization 
  
  
  x                                                               
Treatment orientation 
  
  
  x                                                               
Lifestyle counseling (Experimental 
groups) 
  
  
  x x x x x  After this point, lifestyle counseling will be based on treatment 
response and guided by data-assisted intervention strategy. 
Continuous glucose monitoring 
  
  
x                         x                       x             x 
Body weight 
 
x x x           
 
x  
 
 
 
 
 
 
 
 
 
 
x  
 
x  
 
 
x 
Height 
 
x             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
 
x x x           
 
x  
 
 
 
 
 
 
 
 
 
 
x  
 
x  
 
 
x 
Pulse 
 
x x x           
 
x  
 
 
 
 
 
 
 
 
 
 
x  
 
x  
 
 
x 
Waist circumference 
 
x x            
 
x  
 
 
 
 
 
 
 
 
 
 
x  
 
x  
 
 
x 
Clinical labs (CMP) 
  
  
      x   x   x   x   x   x                        x      x        x 
HbA1c 
  
  
x                         x                       x     x       x 
Insulin, lipids, C-peptide 
  
  
x                                                 x             x 
CBC, CMP 
  
  
x                                                                 
Study closeout visit 
  
  
                                                                x 
1- ASA24 self-administered 24 hour dietary recall 
2- Pedometer-https://www.yamax.co.uk/yamax-pedometers/ 
 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
9
2 Introduction 
2.1 STUDY RATIONALE 
We will study the efficacy of a high intensity medical weight loss intervention paired with a digital 
platform to create weight loss and induce remission of T2DM compared to a diabetes self-management 
education intervention. The digital platform provides the capability to tailor the treatment plan, provide 
automated support, and alert providers when a participant may need more support from the clinical 
team. If shown to be efficacious, this research could be highly impactful, causing us to rethink our 
approach to care for those with T2DM and shift the paradigm for millions of individuals in the US. 
Furthermore, this approach will demonstrate the feasibility of helping people engage in metabolic 
treatment strategies in a way that is scalable leveraging digital and mobile solutions that extend the 
patient-provider relationship, shift care from episodic approaches to more of an on-going model that 
extends into the life of the patient, while also integrated within the healthcare system workflows. 
 
 
2.2 BACKGROUND 
Largely as a consequence of increasing obesity rates, diabetes prevalence is growing and is predicted 
to continue to grow in the US. Obesity rates in the U.S. have increased dramatically in the past 3 
decades.1 The increasing rates of obesity have been linked with a higher rate of diseases, including type 
2 diabetes mellitus (T2DM).2 The association between excessive weight gain and T2DM has been well 
established, and it is suspected that much of the increased prevalence of T2DM is being driven largely by 
excessive weight gain. 3 It is expected that the prevalence of T2DM could increase from most recent 
levels in 2015 of 12.2% of US adults aged 18 and older to 25-33% by 2050.4  
The consequence of a high burden of diabetes is costly for our society. T2DM affects a number of 
organ systems, which results in significant morbidity and mortality and increased health care costs. The 
American Diabetes Association estimates that approximately 16% of CVD deaths are attributable to 
diabetes. 5,6 It is estimated that approximately 55% of deaths due to renal failure are attributable to 
diabetes.7 As a result of the effect of diabetes on CVD risk, renal function, and other organ systems, 
diabetes accounted for approximately 246,000 deaths in the U.S.7  In 2012, the estimated cost of 
diabetes was $245 billion in the US, where an individual with diabetes had an average medical 
expenditure of $13,700 annually—2.3 times higher than those without diabetes.7 
Prevention of T2DM is an important strategy to combat the growing threat that T2DM poses; 
however, once someone develops T2DM, our options are limited. Our current strategies to deal with 
diabetes primarily include prevention strategies or, once developed, glycemic and risk factor control. 
The well-known Diabetes Prevention Program has shown that weight losses of 7% of body weight can 
lead to over 50% reduction in the incidence of T2DM in people with known impaired fasting glucose or 
glucose intolerance. 8-10 While prevention is important, some will develop diabetes despite lifestyle 
changes, and many others may not have access to or do not avail themselves of preventive treatments. 
Once a person develops T2DM in our current health care system, the focus is primarily on learning how 
to live with and manage the disease using education, diabetes medications, and lifestyle changes. 11,12 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
10
Even when T2DM is well controlled, significant risks and negative impacts associated with living with 
T2DM still remain. A recent systematic review showed that there was a 30% relative risk increase for 
severe hypoglycemia when attempting to achieve intensive glycemic control without any significant 
improvements in risk for all-cause and cardiovascular mortality. 13 In 5 years, the ACCORD trial reported 
19% more deaths in the intensive glucose-management group than in the standard glucose-
management group. 14 Recent reports have identified increased risk of all-cause mortality with 
intensification of T2DM treatment when adding insulin to metformin, raising questions about risks 
associated with insulin therapy. 15 Additionally, the impact of T2DM on quality of life can be significant. 
Norris et al pooled data from 118 studies that assessed health related quality of life in persons with 
T2DM, finding that all 8 component scores of the Short Form-36 were lower than comparable U.S. 
population norms. 16 
We know that diabetes remission can be achieved with significant weight loss in the right patient 
populations. The landmark DiRECT trial demonstrated that long-term remission of T2DM can be 
achieved with the use of a total meal replacement diet and achievement of >10% weight loss.17 After 1 
year of treatment, those in the intervention group had a mean weight loss of 10% compared to no 
weight loss for the control group. The rate of diabetes remission, defined as an hemoglobin A1c of 
<6.4% was 46% in the treatment group compared to 4% in the control arm. Remission was achieved in 
86% of participants who lost at least 15 kg. At 2 years of follow up, the intervention group maintained a 
lower body weight (-5.4 kg [95% CI, -6.9 to -4]) and HbA1c (-0.44% [-0.76 to -0.13]); the rate of diabetes 
remission at 2 years was 36% for the intervention group compared to 3% for the control group (aOR 
25·82, 8·25 to 80·84; p<0·0001).18 Participants in this trial were 20-65 years old, had T2DM for <6 years, 
BMI 27-45 kg/m2, and were not on insulin.17 
 
 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
There is some minor discomfort and risk of mild bruising during venipuncture.  
A breech of participant confidentiality is an additional risk for each participant. 
The participants in this study may also be subject to fluctuations in their blood glucose levels as a result 
of restricting calories and modifying the types of foods they are consuming. This could lead to 
symptomatic hypoglycemia. 
Discomfort associated with venipuncture is rapidly reversible.  Bruises from venipuncture will heal in 
several days.  Hypoglycemia is reversible with appropriate therapy. 
The continuous glucose monitor will be worn throughout the study for those in the High Intensity 
Weight Loss Group plus Continuous Glucose Monitoring group and by everyone else during study visits 
at baseline and weeks 12, 24, and end of study. Use of the continuous glucose monitor could be 
associated with some skin irritation from the adhesive or the filament that is under the skin. Some 
people will notice some discomfort with use of the monitor. 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
11
2.3.2 KNOWN POTENTIAL BENEFITS 
The benefits to participants of participating in the study are that persons may lose weight or changes in 
body composition may occur. Additionally, many may see improvements in the control of their blood 
glucose values and lower overall risk of heart disease, heart attacks or stroke. If the study hypotheses 
are correct, the treatments could make a difference for a lot of people living with diabetes. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
The risks to participants in this study are not largely different from what might be experienced in the 
course of diabetes care and weight loss treatment in the general community, but the potential benefits 
may be significant especially if persons are able lower their blood glucose levels to the point that they 
normalize and do not require medication to control their blood glucose. 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
12
3 OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE MECHANISMS 
OF ACTION 
Primary 
Test the effectiveness 
of the combined 
interventions (data-
assisted approach for 
high intensity medical 
weight loss) for weight 
loss in a group of adults 
with recently diagnosed 
type 2 diabetes 
compared to standard 
of care diabetes self-
management 
education. 
Change in body weight 
(kg) from baseline to 12 
months  
Body weight is primary 
target for medical 
weight loss 
interventions 
  
Secondary 
Demonstrate the 
feasibility of pairing a 
high intensity medical 
weight loss treatment 
for diabetes remission 
with a digital platform 
that integrates remote 
monitoring, patient 
self-report, and care 
pathways into a data-
assisted and 
personalized treatment 
program. 
Hemoglobin A1c (%) 
change from baseline at 3, 
6, 9, 12 months; Diabetes 
remission at 12 months, 
including partial remission 
(HbA1c of 5.7-6.4% 
without the use of anti-
diabetes medications) and 
complete remission 
(HbA1c of 5.7-6.4% 
without the use of anti-
diabetes medications); 
As a result of weight 
change, we expect to 
see changes in glycemic 
control.  
Reductions in fat mass due 
to energy restriction, 
leading to less insulin 
requirements and greater 
use of fat stores to make 
up the energy deficit.  
Tertiary/Exploratory 
Demonstrate the 
impact of including 
CGM as part of the 
remote monitoring 
system with the data-
assisted approach for 
high intensity medical 
weight loss treatment. 
Patient satisfaction with 
CGM; length of time to 
achieve A1c goals; study 
retention 
CGM provides 
immediate feedback to 
patients about glycemic 
control. We expect this 
to improve behavioral 
reactions and future 
choices in a shorter 
term. 
Feedback loops with 
relevant data and clear 
actions leading to more 
decisive improvements in 
biomarkers. 
Compare estimated 
healthcare 
expenditures and 
EuroQOL-5; healthcare 
utilization from self-report 
Intensive weight loss 
intervention involves 
cost and time. However, 
Weight reduction could 
decrease healthcare 
utilization by resolving 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
13
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE MECHANISMS 
OF ACTION 
utilization between the 
active treatment 
groups and the control 
intervention 
and review of medical 
records 
we might expect cost 
savings due to reduction 
in weight and improved 
glycemic control. 
obesity related 
complications and 
decreasing need for 
medications and other 
healthcare. 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
14
4 STUDY DESIGN 
4.1 OVERALL DESIGN 
This project will determine if a data-assisted, high intensity medical weight loss intervention (HIWL) will 
lead to significant weight loss and diabetes remission in individuals with a BMI 27-50 kg/m2 with T2DM 
of less than 6 years as compared to a diabetes self-management education intervention 
(DSME).  Complete diabetes remission is considered to be achieved when the patient is not taking any 
anti-diabetes medication for at least 12 months, and the HbA1c is < 5.7%. Partial remission is achieved 
when the patient is not taking any anti-diabetes medication and has an HbA1c of 5.7-6.4% for at least 12 
months. Using a randomized controlled study design, we will randomly assign 90 participants to HIWL, 
HIWL + CGM, or DSME. Participants assigned to HIWL will receive a high intensity behavioral weight loss 
intervention delivered using a digital patient engagement platform. Participants will be prescribed a low 
calorie dietary plan and a recommended physical activity program designed to produce 15-20% weight 
loss over 12 months. Those assigned to HIWL + CGM will receive the same intervention as HIWL; in 
addition we will provide them with CGM to use as part of their remote monitoring on a daily basis. 
Those assigned to DSME will participate in a comprehensive diabetes education program designed to 
provide education and skills for optimal diabetes management plus lifestyle modification counseling to 
produce 5% weight loss over the same timeframe. The primary outcome of weight loss will be assessed 
at 12 months.  
 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
We will use a randomized controlled trial design to compare the two interventions. This provides the 
best study design to assign causality and a direct link to our secondary objectives of improved glycemic 
control.  
 
 
4.3 JUSTIFICATION FOR INTERVENTION 
From a patient-centered perspective, reducing the burden of disease (e.g., medication dosage, diabetes 
self-monitoring, and diabetes distress) has a direct impact on the individual. From a health system 
perspective, if those with T2DM cost approximately $7,700 more annually to care for than those without 
T2DM 7, inducing remission saves $23,100 over 3 years. Based on data from the DiRECT trial, the 
absolute risk reduction (ARR) at 2 years is 33%; therefore, the number needed to treat (NNT) to achieve 
one remission is 3 (1 ÷ ARR). Comparatively, the well-accepted Diabetes Prevention Program had an 
overall absolute risk reduction of 14.3% compared to placebo, with a NNT of 7.19 Even if the ARR is 
adjusted based on modifying the population of patients included in such an intervention (e.g., including 
people on insulin), an ARR of 20% is still superior to the Diabetes Prevention Program. 
  

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
15
To make this type of intervention accessible, we need to demonstrate a model of delivery that is 
scalable and sustainable. Our application addresses this specific challenge. The Wake Forest Baptist 
Health Weight Management Center (WMC) has the expertise and infrastructure to deliver total meal 
replacement diets designed to achieve higher percentages of weight loss. We have demonstrated 
previously that our mean weight loss achieved in all-comers is higher than that reported in the DiRECT 
trial. We have also reported improvements in glycemic control and diabetes remission rates. Our intent 
with this proposal is to pair our proven treatment programs with a digital platform designed to provide a 
tailored treatment experience that is scalable and sustainable. 
  
Our proposed strategy is to use a combination of software applications, remote monitoring, patient self-
reporting tools, and defined care algorithms to create a data-assisted high intensity medical weight loss 
treatment strategy for diabetes remission. We believe this approach can be effective in engaging 
patients with the lifestyle and behavior change needed to achieve the treatment goals. By using the 
digital platform, we can leverage computer automation to expand the reach of individual providers, 
tailor and personalize treatment immediately based on real-time data flows, and provide assistance in a 
“just-in-time” fashion that creates efficiency that allows for greater scale of implementation. The shorter 
latency time between patient need and provider support means that patients will likely stay engaged 
longer and more consistently to achieve better outcomes. We can also integrate this system with the 
electronic health record (EHR) providing the patient’s care team a clear view of the actions and resulting 
impacts of the intervention. 
 
 
4.4 END-OF-STUDY DEFINITION 
This study will be carried out to completion, defined as 12 months of follow up for all enrolled 
participants. 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
16
5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Age 18+ 
Phone 
Type 2 diabetes mellitus by A1c +/- medication ≤ 6 
years 
Phone 
BMI 27-50 kg/m2 
Phone; SV 1 
Able to participate in intervention 
Phone 
Has a mobile phone with text messaging 
Phone  
 
 
5.2 EXCLUSION CRITERIA 
Poorly controlled depression (CES-D >16) 
Phone; SV 1 
Recent hospitalization for psychosis or bipolar 
disorder 
Phone 
Poorly controlled blood pressure (>159/99) 
SV 1 
Prior surgical procedure for weight control  
Phone 
Unable to make changes to their diet 
Phone 
Unable to exercise (walk for at least 6 minutes and 
perform simple strength and stretch exercise tests) 
Phone 
Use of weight loss medications in previous 3 months Phone 
Recent self-reported weight change (+/- 15lbs) 
Phone 
Current use of oral corticosteroids more than 
5days/month 
Phone 
Cardiovascular disease event within the past 6 
months 
Phone 
Severe pulmonary disease requiring supplemental 
oxygen 
Phone 
Renal failure (end stage renal disease) 
Phone 
History of non-skin cancer in the past 5 years 
Phone 
Major liver dysfunction within the last 2 years 
Phone 
Recently quit smoking less than 6 months prior 
Phone 
Inability to attend visits and adhere to study 
protocols 
Phone 
Pregnancy or currently lactating 
Phone 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
17
5.3 LIFESTYLE CONSIDERATIONS 
During the study, participants will be asked to: 
• 
Refrain from receiving outside treatment for obesity, including other treatment plans, medications, or 
pursuing surgery 
• 
Avoid pregnancy 
  
Anyone who engages in either will have their study participation closed out. 
 
 
5.4 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently assigned to the study intervention or entered in the study. Individuals who do not meet 
the criteria for participation in this trial (screen failure) because of meeting one or more exclusion 
criteria that are likely to change over time may be rescreened. Examples include the successful 
treatment of a previous affective disorder, and the lifting of physical activity restrictions previously in 
place. Rescreened participants will be assigned the same participant number as for the initial screening. 
 
In the case that a participant fails screening due to indications of suicidal ideation (as noted on the 
CESD-R), the research team will implement an Immediate Action Protocol to address the safety of the 
participant and ensure appropriate care. The study clinician will be notified and assess the immediate 
safety of the participant. If the participant is thought to be at high risk for self-harm, an immediate 
referral to psychiatric care will be initiated. Transportation to the appropriate facility will be arranged. If 
the participant is not suspected to be high risk and can contract for safety, follow up with psychiatric 
care will be arranged.  
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
Potential volunteers for this study will be recruited from the greater Winston-Salem, NC metro area. 
This is a primary catchment area for Wake Forest Baptist Health, and remains a reliable source of 
participants for clinical trials conducted by members of this research team. Both Drs. Ard (obesity 
medicine) and Aloi (endocrinology) have clinical programs in the WFBH system that can serve as a 
source of patients. Patients in these clinics who meet potential eligibility criteria to enroll will be invited 
to screen for the study. We will also screen medical records using i2b2 and the CTSI to identify potential 
participants who meet eligibility criteria. Individuals who are identified in the medical record screen will 
be invited to screen for the study via direct mail. In the direct mail invitation, participants will be able to 
complete a brief survey to indicate interest in screening for the study. One of the study team members 
will follow up with the potential volunteer by phone to complete a phone screen. If the potential 
participant passes the phone screen and is interested in proceeding, he/she will be invited to an in-
person screening. 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
18
6 STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
6.1 STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
ACTIVE INTERVENTION 
High intensity medical weight loss: Participants randomized to the HIWL treatment group will be placed 
on a meal replacement-based weight loss protocol. Dr. Ard will oversee the medical management team 
and implementation of this protocol at the Weight Management Center. He serves as the medical 
director for medical weight management and has over 13 years of experience treating a wide range of 
patients with a low calorie meal replacement protocol. Participants will consume a minimum of 80 
grams of protein daily in 4-5 servings of meal replacement. Minimum caloric intake will be 960 kcal/day 
with adjustments to intake made based on BMI and activity levels, holding the percent of calories from 
protein constant at 35%. The meal plan provides 100% of daily recommended needs for micronutrients. 
Meal replacements will be supplied at no cost to the participant at weekly clinic visits. Meal 
replacements are in the form of shakes, soups, and meal bars. Participants will begin to incorporate food 
into their routine beginning at week 13 with guidance from a dietitian. From weeks 13-24, caloric 
prescriptions will be between 1100 to 1600 kcal/day, using a combination of meal replacements and 
food, for continued weight loss. Beyond week 25, caloric intake will be individually tailored to achieve 
continued gradual weight loss or maintenance of body weight based on individual weight loss goals. 
Minimum caloric intake during this third treatment segment will be 1200 kcal/day. Participants will be 
seen by a study team clinician weekly for the first 4 weeks of the treatment plan. This weekly follow up 
will allow the medical weight loss team the opportunity to assess early treatment response, assess for 
side effects, and adjust medications to avoid hypoglycemia, hypotension, and/or dehydration. The first 
month of treatment is also critical to identify potential non-responders and alter their treatment plan 
early on. Research suggests that treatment non-response in the first 4-12 weeks is associated with poor 
weight loss outcomes. 20,21 Beyond this first month of scripted intervention, the team will use 
information from the digital platform (described below) to dictate the type and intensity of follow up. 
Key factors that will influence the treatment plan are treatment response including pace of weight loss 
and changes in glycemic control; engagement in key behaviors including self-monitoring and physical 
activity; and complexity of the participant’s medical regimen including use of insulin, anti-hypertensives, 
or other medications that we adjust during weight loss. 
Digital platform: Our active intervention will be delivered with the aid of a technology platform that will 
automate portions of the intervention and assist clinicians in tailoring treatment and responding to 
participant needs in a “just-in-time” manner that we frame as a “data-assisted approach.” Consumer-
centric healthcare models enabled by technology are a new frontier in healthcare. Rising healthcare 
costs, consumer adoption of smart-phones, and a shift toward value-based payment models designed to 
produce better health outcomes all contribute to this trend. Our partner technology provider is Carium. 
Carium’s software product is a HIPAA compliant, cloud-based, flexible platform, accessible via mobile 
and web applications, that allows patients and providers to co-create personalized care plans that are 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
19
informed by data and enable continuous collaboration during the course of everyday life. Through just-
in-time encouragement and information, automatic medication reminders, and secure communication 
with care providers, the application supports patients in achieving their health goals, maximizing 
medication adherence, and achieving optimal health outcomes. This approach moves our current 
treatment pathways from generalized protocols that try to anticipate patient needs based on average 
responses to customized treatment plans that amplify the reach and impact of the current provider 
team. This makes the proposed intervention highly scalable and sustainable in a value-based care world. 
The platform has been deployed in a variety of healthcare settings, including primary care practices, 
care management programs, and community centers. In addition to the software component, the 
Carium team provides expertise in clinical practice transformation, patient engagement, behavior 
change science, and the latest technology. Core capabilities of Carium’s offer include integration with 
remote monitoring devices such as activity trackers (Apple HealthKit, FitBit, Google Fit, etc.), 
glucometers (Omron, Dexcomm, Contour, etc.), blood pressure cuffs (Omron, etc.), scales (FitBit, 
Omron, BodyTrace, etc.); surveys, interviews, and self-assessments; secure messaging (one-to-one and 
groups) (Figure 2); photo and text journaling; content management and sharing; data-driven reminders, 
rules, and alerts to enable habit-engineering and behavior change; automation for patient experience 
and care team efficiency; dashboards and reports on engagement, patient progress, outcomes, 
population health; and seamless integration into clinical EMR workflows. 
Body weight: To further enhance intervention engagement and self-monitoring, participants in the HIWL 
group will also receive a Bluetooth-connected body weight scale. The scale and Carium digital 
intervention will link electronically; the scales will transmit weight data automatically in a secure fashion 
to participants’ accounts, allowing the participant and his or her providers to view the weight data in 
real time. We will instruct participants to weigh themselves daily throughout the course of the study. 
Continuous glucose monitoring: Thirty participants will receive the HIWL intervention as outlined above 
and also receive a supply of continuous glucose monitors to use throughout the trial. The CMG we 
provide will give the patient instant feedback on blood glucose levels and be readable using a mobile 
phone device or an associated CGM reader (For details of the CGM device, see 8.1 ENDPOINT AND 
OTHER NON-SAFETY ASSESSMENTS) . The data from the CGM will be integrated into the Carium app and 
used to help guide the patient’s actions based on defined care pathways. 
Development and refinement of care pathways: We will work with the Carium development team to 
expand and tailor the standard care pathway for the treatment objectives of this proposal—weight 
reduction and improved glycemic control. The focus of the care pathway will be on supporting lifestyle 
change, minimizing risk of adverse events, and providing actionable data to predict higher risk of 
disengagement. We will build key modules that enable automated guidance based on stage of 
treatment and anticipated difficulties/challenges that are most likely at a given stage. This process will 
use participant response to brief surveys and queries to determine which content needs to be delivered 
and when clinical support (i.e., someone from the clinic team) should be engaged. This will result in 
provision of content and support when it is most appropriate and in an efficient manner. For example, 
through this process we can develop content that anticipates GI related side effects of a MR-based diet 
(e.g., constipation) and provide participants with educational content on how to prevent it in the first 1-
2 weeks of treatment. Surveys would be timed to go out when our clinical experience suggests 
symptoms of constipation might develop. If a survey response indicates that current constipation 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
20
prevention measures are ineffective, a team member can engage the participant in a chat session to 
provide support to resolve the issue before it becomes more distressing and resource intensive (e.g., 
requiring a call to the center with multiple workflows and provider types engaged to deal with a 
preventable/predictable side effect). Content can be programmed based on participant characteristics 
(e.g., on insulin versus only on metformin) so that information can be targeted and highly relevant to 
the individual user. The pathway will also have key outcome indicators that will roll up into a clinical 
dashboard shared by the provider team. The indicators will help providers allocate time and attention to 
those who would benefit most based on pre-set cut points. Over time, we will adjust the cut points 
based on treatment outcomes to improve the sensitivity and specificity of each indicator. 
  
CONTROL INTERVENTION: 
Diabetes self-management education (DSME): The DSME intervention will be administered and 
delivered at the WFBH Diabetes Center, located next to the Weight Management Center. The diabetes 
education program is accredited by the American Diabetes Association in recognition of meeting 
national standards for diabetes self-management education. The goal of the program is to provide 
participants with information to make informed decisions about how to best integrate diabetes 
management strategies into their daily lives. Assessment, planning, implementation, and evaluation are 
the basic components of the diabetes education process. The DSME will be delivered by qualified 
personnel in group and individual settings. The DSME will be provided over the course of 12 months. 
Participants will have a variety of learning objectives that are part of the core Comprehensive Diabetes 
Education Program provided by the WFBH Diabetes and Endocrinology Center. Participants will attend 
an initial group class or individual appointment in the first month, followed by at least quarterly 
individual appointments through the next 11 months. Additional appointments may be recommended 
by the diabetes educator. Participants will be prescribed a weight reducing diet that is 500-750 kcal 
below estimated total energy expenditure using the Mifflin-St. Jeor equation.22 The dietary plan will 
focus on carb counting and healthy diet quality, allowing up to 45 g carbs per meal for women and 60 g 
carbs per meal for men. Similar to the HIWL intervention, the physical activity prescription will be a goal 
of 180 minutes of moderate intensity activity per week, using a combination of resistance training and 
aerobic exercise. However, the DSME group will not have exercise training sessions, but we will provide 
written and oral instructions on strategies in the group and individual counseling sessions to meet the 
exercise goals. 
 
 
 
6.2 FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
  
Fidelity to treatment impacts reliability and validity of study findings. To ensure consistency of 
intervention content and delivery, we will use standardized treatment protocols and procedures. A 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
21
comprehensive Manual of Operations and Procedures will be developed in the start-up period and 
distributed to all personnel. Written procedures will exist for assessments, treatment delivery, and 
monitoring of treatment delivery. Study personnel will be thoroughly trained in the interventions and 
given corrective feedback in practice sessions. Even among highly trained interventionists, there is a 
potential for slight deviations from treatment protocol to occur over time, commonly referred to as 
“intervention drift.” In order to protect against this, regular “booster” training sessions will be 
conducted. Treatment fidelity will be monitored also by live supervision. The Interventionist will be 
observed regularly by one of the investigators during group and individual sessions. Live supervision 
corrects for procedural and intervention drift and enhances adherence to the protocol. 
 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Participants will be randomized using a web-based protocol for treatment assignment. Once participants 
are screened as eligible to participate, the study coordinator will submit the participant's study number 
for treatment assignment via the study web portal. Randomization will be done in blocks of 10, stratified 
by sex. 
 
 
6.4 STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
For participants in the HIWL or HIWL + CGM interventions, participation and engagement will be 
monitored through the Carium platform on a regular basis. At the end of each week of participation, a 
summary assessment of participant engagement levels will be generated from the platform. Individuals 
who show unexplained drop offs in participation levels will have follow up outreach to assess key factors 
that might be affecting engagement. 
  
For participants in the control intervention, participation and engagement will be monitored during 
participation in the group-based DSME. There will be a regular review of food diaries and tailored 
information provided to the participants to help guide plan implementation. Participants who are 
showing signs of lower or decreased engagement will be engaged by the study team to see what can be 
done to maintain/improve engagement. 
 
 
6.5 CONCOMITANT THERAPY 
  
6.5.1 RESCUE THERAPY 
  
Medication adjustment: For participants in the data-assisted HIWL arms, the medical weight loss team 
will make medication adjustments at the beginning of the intervention, at any subsequent clinic visit or 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
22
encounter where the participant reports symptoms of hypoglycemia with corresponding low blood 
glucose readings, or at quarterly assessments of HbA1c. For participants in the DSME intervention, Dr. 
Aloi with meet weekly with the diabetes education interventionist to review participant blood glucose 
logs and make adjustments in medication dosing. Participants will be asked to self-monitor BG values at 
least twice daily (fasting and pre-dinner meal), not including additional measures if they are 
experiencing signs/symptoms of hypoglycemia. At each clinic visit, we will review the average values and 
ascertain episodes of hypoglycemia, defined as glucose levels less than 70 mg/dL. If the participant 
reports an episode of severe hypoglycemia (hypoglycemia resulting in a loss of consciousness or inability 
to self-treat) or symptomatic hypoglycemia on multiple occasions to a non-clinical staff member, one of 
the study clinicians will be notified to make adjustments in medications within 24 hours per the protocol 
(Table 4).Medication can be discontinued if the lowest dose available is being prescribed and the 
average BG ≤ 140 or HbA1c < 6.5%. Once total insulin dose is below 20 units daily with adequate control, 
the participant will be transitioned to an oral medication regimen (i.e., non-insulin). 
  
  
 
 
Table 4. Medication Dose Adjustment Plan 
  
  
Event 
Action 
Follow up Desired outcome 
Initiating weight loss intervention 
Reduce meds by up to 50% 
and/or discontinue all oral 
hypoglycemic 
1 week 
No hypoglycemic events and 
average BG less than or equal to 
baseline A1c 
One episode of severe 
hypoglycemia or symptomatic 
hypoglycemia 2 times or more per 
week 
Reduce meds by 50-100% 1 week 
No hypoglycemic events 
14-day average BG < 126 
Reduce meds by 25-50% 
2 weeks 
Average BG ≤ 140 
14-day average BG > 140 in absence 
of hypoglycemia 
Increase meds by 25% 
2 weeks 
Average BG ≤ 140 and no 
hypoglycemia 
HbA1c > 7% at quarterly 
assessment 
Increase meds by 25% or 
add new class 
2 weeks 
Average BG ≤ 154 and no 
hypoglycemia 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
23
7 STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
When a subject discontinues from HIWL, HIWL + CGM,  or Control groups, but not from the study, 
remaining study procedures will be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods for 
determining the need to discontinue 
• 
If the participant is due to complete assessments within 2 weeks of being discontinued from the 
study intervention, those assessments will be administered at the time of discontinuation; if the 
next scheduled assessments are more than 2 weeks from the discontinuation date, the 
discontinued participant will wait for the next scheduled assessment. Thereafter, the participant 
will be included in all future scheduled assessments, even though not participating in the 
intervention. 
 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
• 
Initiation of a disqualifying weight loss treatment (e.g., bariatric surgery)  
• 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
• 
Any event or medical condition or situation occurs such that continued collection of follow-up study data 
would not be in the best interest of the participant or might require an additional treatment that would 
confound the interpretation of the study 
• 
The participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation (e.g., becomes pregnant) 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Study 
Discontinuation Case Report Form (CRF). Subjects who sign the informed consent form and are 
randomized but do not receive the study intervention may be replaced.  Subjects who sign the informed 
consent form, and are randomized and receive the study intervention, and subsequently withdraw, or 
are discontinued from the study, will not be replaced. 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
24
7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive scheduled 
visits and study staff are unable to contact the participant after at least 3 attempts. 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant, reschedule the missed visit within 5 business days, 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter 
to the participant’s last known mailing address or local equivalent methods). These contact attempts will 
be documented in the participant’s study file. 
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
25
8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
All measures will be assessed at baseline and every 3 months thereafter (unless a different schedule is 
specified below). The primary outcome (change in body weight) will be assessed as weight at 12 months 
– weight at baseline. 
Weight: Weight and height will be measured in light indoor clothes without shoes using standard 
procedures. Weight measurements will be taken to the nearest 0.1kg by a high-quality digital scale. 
Scales will be calibrated annually by the Bureau of Weights and Standards and quarterly by trained study 
personnel using standard weights. Height will be measured using a standard wall-mounted stadiometer. 
Study personnel will be trained and certified to follow measurement procedures according to study 
protocol. Percent weight loss will be calculated based on baseline weight obtained at the first in-person 
screening visit. 
Glycemic control: Serum HbA1c measurements will be drawn quarterly on all participants. Assessment of 
glycemic control will be done in the context of anti-diabetes medication usage. Documentation of 
medications will be obtained electronically from all available sources (e.g., EHR, pharmacy) and by 
physical review of medicines using the “brown bag” method. Participants will be requested to bring all 
of their medication to the clinic for review. Research assistants will reconcile medication regimens from 
the electronic record and those presented by the patient. Medicines will be described as any 
prescription or non-prescription substance they take on a regular basis including tablets, liquids, 
inhalers, creams and ointments. Continuous glucose monitoring (CGM) with sub-dermal sensors will be 
used as a secondary measure of glycemic control for all participants. CGM provides information beyond 
what traditional finger stick blood glucose testing affords. CGM provides measurements of interstitial 
blood glucose (BG) at 1- 15 minute intervals and correlates well with capillary blood glucose 
measurements. Collection of continuous glucose values allows immediate recognition of current BG and 
prediction of trajectory of BG; preventing hypoglycemia. We will utilize the FreeStyle Libre, which is one 
of the most frequently used CGM in the world as a result of both its accuracy and simplicity of use. 
Sensors are placed on the upper arm using a painless spring loaded injector. BG recordings are available 
within an hour and the device will record BG every 15 minute minutes without a need for calibrations 
for 2 weeks. CGM related outcomes that we will assess at baseline and 12 months include time in range, 
episodes of hypoglycemia, glucose variability, and average glucose. For individuals in the HIWL + CGM 
arm of the trial, data from the CGM they are using in the intervention will be used for these outcomes. 
Diabetes remission: Diabetes remission status will be assessed at 12 months as a secondary outcome for 
this study. At the time of assessment, if the participant has achieved an HbA1c of 5.7-6.4% without the 
use of anti-diabetes medications, the participant will be classified as being in partial remission. If the 
participant has achieved an HbA1c of <5.7% without any medications, the participant will be classified as 
being in complete remission. The sum of these two outcomes will comprise the outcome of any 
remission (partial + complete). 
Demographics: Demographic information including sex, race/ethnicity, and date of birth (age) will be 
captured at the first screening visit during verification of eligibility. Medical history including date of 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
26
diabetes diagnosis (duration of diabetes) and co-morbid conditions will be captured by interview and 
verification from the medical record when available. 
Dietary intake: To assess dietary intake, we will use NCI’s automated, self-administered 24-hour dietary 
recall, the Automated Self-Administered 24-hour (ASA24 ®) dietary assessment tool (version: ASA24-
2018). The ASA24-2018 will be completed on three, non-consecutive days (including one weekend day) 
at baseline (pre-randomization), and again at months 3, 6, and 12. The ASA24-2018 is available for use 
on computers and mobile devices. At the baseline visit, participants will complete one ASA24 assisted by 
a research staff member. They will then be asked to complete a second and third ASA24 during run-in, 
on their own, as a part of the baseline assessment. During office visits at each relevant follow-up time 
point (3, 6 and 12 months), participants will again complete the ASA24. Following each of these visits, a 
staff member will contact participants within six days (on a randomly selected day) to inform them to 
complete 2 additional dietary recalls and will offer to conduct the recall over the phone if needed (the 
ASA24 performs equally well as a self- or interviewer- administered questionnaire).23,24 Follow-up 
reminder calls will be made to encourage completion of the recalls if not completed within 24-hours 
following a contact. Using the ASA24 data from each time point (baseline, 3, 6, and 12 months), specific 
outcomes of interest will include: total daily energy intake (kcal; averaged across 3 days), 
macronutrient composition of diet (%Carbohydrate/Fat/Protein; averaged across 3 days), number of 
eating episodes per day, and Healthy Eating Index (HEI)-2015 score (a validated summary measure of 
dietary quality, rated on a 100-point scale, 25,26 which is sensitive to change with dietary 
intervention26,27, and can be calculated using publicly-available SAS code from the ASA24 website). 
Physical activity: We will use pedometers to assess objective physical activity (PA) – operationalized as 
daily step counts – at baseline, 3, 6, and 12 months. Although accelerometry is the gold standard for 
objective PA measurement,28 pedometers have 99.8% step count accuracy, particularly when worn at 
the hip.29,30 For our study, participants will be fitted with a pedometer and asked to wear it for all 
waking hours (except while bathing or water activities) over their right hip for 7 consecutive days at each 
relevant time point in follow-up. At the end of the 7th day, participants will open the unit, record the 
final step count, and return the pedometer to WFSOM via a pre-stamped mail envelope. Self-report: In 
order to compare our results with the extant literature that has used self-reported PA outcomes, we will 
also include the short form of the IPAC, a self-report instrument with good reliability (Spearman’s 
rho=0.8) and criterion validity comparable to other self-report instruments.31 
Diabetes medication class/dose: All medications will be assessed quarterly as previously described. 
Variables of interest include medication name, total dose, and class of medication at baseline and 
longitudinal changes during the trial follow up. 
Healthcare utilization and quality of life: To capture differences in quality of life associated with the 
intervention arm, we will use EuroQol’s EQ-5D-5L instrument as the quality measure 32. This instrument 
takes responses to five questions on mobility, self-care, ability to perform usual activities, pain, and 
anxiety/depression to produce a validated quality score (0 to 1). This instrument will be administered at 
baseline and at the end of the study (12 months). We anticipate no patient deaths during the study 
period; as such, we will treat the difference in the quality score at the end of the study period and at 
baseline as the change in the quality of life year (QALY). For instance, if the quality score is 0.4 at 
baseline and 0.6 at the study-end, the change in the quality of life will be 0.2 QALYs. 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
27
Cost data: There will be two cost categories: intervention costs and healthcare utilization costs. 
Intervention costs will cover the costs incurred in the implementation of the intervention. This will 
include, for the HIWL arm, the provider visits (in-person and telemedicine) associated with the 
intervention will be assessed in terms of the insurance reimbursement ($). For intervention services and 
resources not reimbursed by insurance (meals, software installation, staff time), we will use the micro-
costing approach to aggregate the costs. As insurance reimbursement for the same service may vary by 
insurer, we will use Medicare fee-for-service reimbursement as the standardized rate so as to limit 
confounding arising from differences in insurer composition across intervention arms (ResDAC 2020).  
Patient out-of-pocket costs will also be included (e.g., insurance co-payments and deductibles). We will 
not include any costs relating to the research administration (e.g., staff time for data collection and 
analysis). For the HIWL+ CGM arm, we will include the cost of continuous glucose monitoring. 
Healthcare utilization costs will include healthcare services used during the study period but are not part 
of the interventions: hospitalizations, emergency department visits, outpatient visits, and prescription 
medications. Costs of these services will be assessed at Medicare rates. We will refer to the sum of the 
intervention and healthcare utilization costs as the total costs. Note that an intervention may lead to 
higher intervention costs compared to the control arm; however, If an intervention results in higher 
rates of diabetes remission, then healthcare utilization may be lower for the intervention cohort, 
compared to the control arm. The total cost captures the net change of the higher intervention and 
lower utilization costs. 
 
Cost-effectiveness Outcomes: Our main outcome for cost-effectiveness analysis will be diabetes 
remission. We will compare the relative costs of achieving one additional remission using alternative 
interventions. As secondary outcomes, we will also examine the cost-effectiveness of (a) one percentage 
unit reduction in A1c and (b) one additional QALY. 
 
 
8.2 SAFETY ASSESSMENTS 
The primary safety assessment will be monitoring of blood glucose and frequency of hypoglycemia. All 
participants in the HIWL only and the control group will receive a blue tooth-connected digital 
glucometer. The participants will be instructed to monitor blood glucose at least twice daily, including 
once fasting and once 4-hours postprandial. Participants will also be instructed to monitor blood glucose 
if they feel symptoms of hypoglycemia. The study physicians will adjust medications as noted previously 
based on self-monitored blood glucose and reported episodes of hypoglycemia. For individuals in the 
HIWL + CGM arms, the monitoring of blood glucose will be continuous. 
  
Participants in the active intervention arm will also have safety monitoring as part of their treatment 
protocol while initiating weight loss with the HIWL dietary strategy. Dr. Ard will be responsible for 
reviewing the chemistry panels that will be obtained at weeks 2, 4, 6, 8, 12,  and 16. He will adjust the 
treatment plan including making adjustments in the dietary prescription or concomitant medications to 
resolve any abnormalities. 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
28
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Participants will be queried for side effects and specific adverse events (AE) at each in-person study visit 
using a standardized questionnaire. Blinded staff will enter data directly into our centralized study 
database. Should an AE be detected using this process, or by spontaneous report between visits, or if an 
AE is detected using physical or laboratory examination, a determination of relatedness to study 
intervention will be made by the study physician. Serious adverse events (SAE) will be reviewed by the 
study physician and reported to the IRB per local policy. We will examine the total number of AEs and 
SAEs at 12 months by study group, as well as several subcategories of events.  
 
 
8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human 
Research Protections (OHRP). OHRP considers unanticipated problems involving risks to participants or 
others to include, in general, any incident, experience, or outcome that meets all of the following 
criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved 
research protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• 
Related or possibly related to participation in the research ("possibly related" means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in 
the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
  
8.4.2 UNANTICIPATED PROBLEMS REPORTING 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI's name, and the IRB project number 
• 
A detailed description of the event, incident, experience, or outcome 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
29
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the study sponsor/funding 
agency within 10 days of the investigator becoming aware of the event 
• 
Any other UP will be reported to the IRB and to the study sponsor/funding agency within 15 days of the 
investigator becoming aware of the problem 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
30
9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
1.    Test the effectiveness of the combined interventions (data-assisted approach for high intensity 
medical weight loss) for weight loss in a group of adults with recently diagnosed type 2 diabetes 
compared to standard of care diabetes self-management education. 
H1- The data-assisted approach for HIWL (with or without CGM) will lead to 12% greater weight loss 
compared to the standard of care DSME. 
2. Assess the impact of the data-assisted approach for high intensity medical weight loss on glycemic 
control outcomes including hemoglobin A1c and diabetes remission rates compared to diabetes 
self-management education. 
H2a- The data-assisted approach for HIWL (with or without CGM) will lead to greater reduction in 
HbA1c compared to DSME. 
H2b- The data-assisted approach for HIWL (with or without CGM) will lead to a greater proportion of 
participants achieving diabetes remission (HbA1c < 6.5%) compared to DSME. 
3.  Explore impacts of adding CGM to the HIWL intervention on time to achieve A1c goals and 
participant satisfaction. 
H3a- The HIWL + CGM approach will achieve A1c goals in a shorter timeframe than HIWL alone. 
H3b- Participant satisfaction will be equivalent between the HIWL and HIWL + CGM approaches. 
4. Explore differences in healthcare utilization between the treatment groups. 
H4- The HIWL groups will have lower healthcare utilization compared to standard of care DSME. 
  
 
 
9.2 SAMPLE SIZE DETERMINATION 
Power Considerations: Power was estimated assuming a longitudinal framework based on linear mixed 
models allowing for attrition. The estimated change in weight for the active intervention is 15% at 12 
months. The estimated change in weight for the DSME intervention is 3% at 12 months. We anticipate 
10% of the study population will be lost to follow up; however, we estimated power based on lost to 
follow up rates of up to 20%. Using a pooled standard deviation of 6.8% for percent weight loss, we will 
have > 95% power to detect our hypothesized difference at 12 months with 30 participants per arm. 
 
 
9.3 POPULATIONS FOR ANALYSES 
All participants who are randomized and receive the intervention will be included in the analysis 
population (intent to treat). 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
31
9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
Analyses: In general, two types of analyses will be performed: 1) those aimed at estimation of the 
difference between intervention groups for outcomes like percent change in body weight and HbA1c, 
and 2) those aimed at estimating differences in the proportion of participants achieving remission by 
treatment arm. We will analyze the data based on intention to treat principles. Analysis of covariance 
will be used to estimate the effect of the intervention on 12-month continuous measures including body 
weight percent change and HbA1c.  The model to be used will include the following covariates: the 
baseline value of the outcome, gender, and age (to control for possible imbalance due to the small 
number of participants randomized).  95% confidence intervals will be generated for the intervention 
effect on these and other outcomes. The proportion of remission between two groups will be compared 
using a two-sided chi-square test and summarized using an odds ratio (OR) and confidence intervals (CI). 
The primary outcome will be percent change in initial body weight. Secondary outcomes include change 
in HbA1c and diabetes status (remission will be indicated by a dichotomous yes or no). 
Cost-Effectiveness Analysis:  The most commonly used measure of cost-effectiveness is the incremental 
cost-effectiveness ratio (ICER), defined as the ratio of between incremental costs (difference in total 
costs between intervention and control arms) and incremental diabetes remission (difference in the 
number of patients with remission in the intervention and control arms) 33. This measure is meaningful 
in contexts where an intervention increases total costs (since the denominator is expected to be 
positive, with higher diabetes remission in the intervention arm relative to the control arm). However, in 
our context where total costs include both intervention and non-intervention healthcare utilization, 
total costs for the intervention arm may be lower (e.g., if diabetes remission is accompanied by fewer 
emergency department visits or fewer medications). In this situation, we will report two measures: a) 
the average additional intervention cost for each additional diabetes remission achieved; and b) the 
average reduction in healthcare utilization cost for each additional diabetes remission achieved. For the 
secondary outcome of A1c reduction, we will similarly estimate the average cost of achieving one 
percentage point reduction in A1c and one additional QALY for each arm (Laiteerapong et al. . We will 
obtain 95% confidence interval of each estimate based on bootstrap resampling (Briggs et al. 1999). We 
will perform a variety of sensitivity analyses, including alternative healthcare reimbursement rates (e.g., 
10 percent higher than Medicare rates). 
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
32
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
Written informed consent will be obtained from all participants during the baseline study visit.  
10.1.1.1 CONSENT PROCEDURES AND DOCUMENTATION 
 A trained staff member or investigator will give an overview of the study, describe the intervention 
components and data collection requirements, and encourage potential participants to ask questions. 
All potential participants will be informed of the study design and interventions, the risks and benefits of 
participation, their rights and responsibilities as research participants, and alternatives to participation. 
They will also be informed that participation is voluntary and that they can withdraw from the study if 
their initial or on-going experience makes it oppressive, burdensome, or otherwise uncomfortable. 
Potential participants will be asked to read the informed consent form and to ask questions. The form 
will be written in simple, easy-to-understand language. As a part of the consent process, study staff will 
be required to review all key aspects of the study verbally and will be provided with a structured 
checklist for this purpose. A copy of the signed and dated consent form will be given to participants, and 
the original document will be placed in the participants’ individual study files, which will be stored in a 
secure location at the clinical site.  
10.1.2 CONFIDENTIALITY AND PRIVACY 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy and 
confidentiality, only a unique study identifier will appear on the data collection form.  Any collected 
patient identifying information corresponding to the unique study identifier will be maintained on a 
linkage file, store separately from the data.  The linkage file will be kept secure, with access limited to 
designated study personnel.  Following data collection subject identifying information will be destroyed 
by deleting any data files three years after study closure, consistent with data validation and study 
design, producing an anonymous analytical data set.  Data access will be limited to study staff.  Data and 
records will be kept locked and secured, with any computer data password protected.  No reference to 
any individual participant will appear in reports, presentations, or publications that may arise from the 
study. 
 
 
10.1.3 FUTURE USE OF STORED SPECIMENS AND DATA 
 Participants who provide consent for storage of blood samples will have a sample of blood stored with a 
unique identifier that will not include any identifiable information. The unique identifier will be a 
randomly assigned number and only the principal investigator will have access to the code that links the 
unique identifier to the study participant. In the case that future researchers need to know more details 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
33
about the study participants’ health, only those participants who consented to being contacted in the 
future for inclusion in additional research will be contacted. 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator  
Medical Monitor  
 Study coordinator 
Maintenance of regulatory documents; 
reporting to IRB 
 Investigator team 
Review of data, outcomes, and safety 
events 
Biostatistician 
Analysis 
  
  
  
  
  
10.1.5 SAFETY OVERSIGHT 
 The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study staff. 
 
10.1.6 CLINICAL MONITORING 
 The clinical care teams for each treatment group will be responsible for monitoring the clinical health of 
the participants as it pertains to the conduct of this protocol. 
 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
AE 
Adverse Event 
ANCOVA Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
34
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator's Brochure 
ICH 
International Council on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
35
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
36
11 REFERENCES 
 
 
1. 
Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United 
States, 2011-2012. JAMA : the journal of the American Medical Association. 2014;311(8):806-
814. 
2. 
Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS Guideline for the Management of 
Overweight and Obesity in Adults: A Report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2013. 
3. 
Eckel RH, Kahn SE, Ferrannini E, et al. Obesity and type 2 diabetes: what can be unified and what 
needs to be individualized? Diabetes care. 2011;34(6):1424-1430. 
4. 
Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden 
of diabetes in the US adult population: dynamic modeling of incidence, mortality, and 
prediabetes prevalence. Population health metrics. 2010;8:29. 
5. 
Economic costs of diabetes in the U.S. In 2007. Diabetes care. 2008;31(3):596-615. 
6. 
Carnethon MR, Biggs ML, Barzilay J, et al. Diabetes and coronary heart disease as risk factors for 
mortality in older adults. The American journal of medicine. 2010;123(6):556 e551-559. 
7. 
Economic costs of diabetes in the U.S. in 2012. Diabetes care. 2013;36(4):1033-1046. 
8. 
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes 
with lifestyle intervention or metformin. The New England journal of medicine. 2002;346(6):393-
403. 
9. 
Aguiar EJ, Morgan PJ, Collins CE, Plotnikoff RC, Callister R. Efficacy of interventions that include 
diet, aerobic and resistance training components for type 2 diabetes prevention: a systematic 
review with meta-analysis. The international journal of behavioral nutrition and physical activity. 
2014;11:2. 
10. 
Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in 
lifestyle among subjects with impaired glucose tolerance. The New England journal of medicine. 
2001;344(18):1343-1350. 
11. 
American Diabetes A. 4. Foundations of Care: Education, Nutrition, Physical Activity, Smoking 
Cessation, Psychosocial Care, and Immunization. Diabetes care. 2015;38(Supplement 1):S20-S30. 
12. 
American Diabetes A. 7. Approaches to Glycemic Treatment. Diabetes care. 
2015;38(Supplement 1):S41-S48. 
13. 
Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting 
conventional glycaemic control for type 2 diabetes mellitus. The Cochrane database of 
systematic reviews. 2013;11:CD008143. 
14. 
Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 
diabetes. The New England journal of medicine. 2008;358(24):2545-2559. 
15. 
Roumie CL, Greevy RA, Grijalva CG, et al. Association between intensification of metformin 
treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among 
patients with diabetes. JAMA : the journal of the American Medical Association. 
2014;311(22):2288-2296. 
16. 
Norris SL, McNally TK, Zhang X, et al. Published norms underestimate the health-related quality 
of life among persons with type 2 diabetes. Journal of clinical epidemiology. 2011;64(4):358-365. 
17. 
Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 
2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet (London, England). 2017. 

Data-Assisted Approach for High Intensity Medical Weight Loss for Diabetes Remission 
Version 1.3
Protocol  
01 January 2021
37
18. 
Lean MEJ, Leslie WS, Barnes AC, et al. Durability of a primary care-led weight-management 
intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-
randomised trial. Lancet Diabetes Endocrinol. 2019;7(5):344-355. 
19. 
Sussman JB, Kent DM, Nelson JP, Hayward RA. Improving diabetes prevention with benefit 
based tailored treatment: risk based reanalysis of Diabetes Prevention Program. Bmj. 
2015;350:h454. 
20. 
Unick JL, Hogan PE, Neiberg RH, et al. Evaluation of early weight loss thresholds for identifying 
nonresponders to an intensive lifestyle intervention. Obesity. 2014;22(7):1608-1616. 
21. 
Unick JL, Pellegrini CA, Demos KE, Dorfman L. Initial Weight Loss Response as an Indicator for 
Providing Early Rescue Efforts to Improve Long-term Treatment Outcomes. Curr Diab Rep. 
2017;17(9):69. 
22. 
Mifflin MD, St Jeor ST, Hill LA, Scott BJ, Daugherty SA, Koh YO. A new predictive equation for 
resting energy expenditure in healthy individuals. The American journal of clinical nutrition. 
1990;51(2):241-247. 
23. 
Thompson FE, Dixit-Joshi S, Potischman N, et al. Comparison of Interviewer-Administered and 
Automated Self-Administered 24-Hour Dietary Recalls in 3 Diverse Integrated Health Systems. 
American journal of epidemiology. 2015;181(12):970-978. 
24. 
Kirkpatrick SI, Subar AF, Douglass D, et al. Performance of the Automated Self-Administered 24-
hour Recall relative to a measure of true intakes and to an interviewer-administered 24-h recall. 
Am J Clin Nutr. 2014;100(1):233-240. 
25. 
Guenther PM, Reedy J, Krebs-Smith SM. Development of the Healthy Eating Index-2005. J Am 
Diet Assoc. 2008;108(11):1896-1901. 
26. 
Guenther PM, Kirkpatrick SI, Reedy J, et al. The Healthy Eating Index-2010 is a valid and reliable 
measure of diet quality according to the 2010 Dietary Guidelines for Americans. J Nutr. 
2014;144(3):399-407. 
27. 
Ptomey LT, Willis EA, Goetz JR, et al. Portion-controlled meals provide increases in diet quality 
during weight loss and maintenance. J Hum Nutr Diet. 2016;29(2):209-216. 
28. 
Troiano RP, McClain JJ, Brychta RJ, Chen KY. Evolution of accelerometer methods for physical 
activity research. Br J Sports Med. 2014;48(13):1019-1023. 
29. 
Wallmann-Sperlich B, Froboese I, Reed JL, Mathes S, Sperlich B. How accurate are Omron X-HJ-
304-E and Yamax SW-700/701 pedometers at different speeds and various inclinations? J Sports 
Med Phys Fitness. 2015;55(1-2):113-117. 
30. 
Cruz J, Brooks D, Marques A. Accuracy of piezoelectric pedometer and accelerometer step 
counts. J Sports Med Phys Fitness. 2017;57(4):426-433. 
31. 
Craig CL, Marshall AL, Sjostrom M, et al. International physical activity questionnaire: 12-country 
reliability and validity. Medicine and science in sports and exercise. 2003;35(8):1381-1395. 
32. 
van Reenen M, Janssen B. EQ-5D-5L User guide. Basic information on how to use the EQ-5D-5L 
instrument. Version 2.1, April 2015. In: Rotterdam, the Netherlands: EuroQol Research 
Foundation; 2015. 
33. 
Drummond MF, Sculpher MJ, Claxton K, Stoddart GL, Torrance GW. Methods for the economic 
evaluation of health care programmes. Oxford university press; 2015.