An Open-Label Pilot Intervention Trial to Prevent Diabetes in Prediabetic Adult Survivors of Childhood Cancer
Phase: PHASE2
Conditions: PreDiabetes, Adult Children
Sponsor: St. Jude Children's Research Hospital

PREDM
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
St. Jude
PREDM
Initial version, dated:  04-10-2020, (IRB Approved: 00-00-00)
Activation Date:  00-00-00
PREDM: AN OPEN-LABEL PILOT INTERVENTION TRIAL TO PREVENT DIABETES IN 
PREDIABETIC ADULT SURVIVORS OF CHILDHOOD CANCER
IND/IDE # (if applicable)
Principal Investigator
Stephanie B. Dixon, MD, MPH
Department of Oncology, Division of Cancer Survivorship
Collaborating Co-Investigators 
Gregory T. Armstrong, MD, MSCE
Department of Epidemiology and Cancer Control
Tara M. Brinkman, PhD
Department of Epidemiology ad Cancer Control
Wassim Chemaitilly, MD
Department of Pediatrics, Division of Endocrinology
Matthew J. Ehrhardt, MD, MS
Department of Oncology, Division of Cancer Survivorship
Timothy E. Folse, MD
Department of Oncology, Division of Cancer Survivorship
Thomas E. Merchant, DO, PhD
Department of Radiation Oncology
Daniel A. Mulrooney, MD, MS
Department of Oncology, Division of Cancer Survivorship
Sedigheh Mirzaei Salehabadi, PhD
Department of Biostatistics
Kirsten K. Ness, PhD
Department of Epidemiology and Cancer Control
DeoKumar Srivastava, PhD
Department of Biostatistics
Melissa M. Hudson, MD
Department of Oncology, Director, Division of Cancer Survivorship
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
Leslie L Robison, PhD
Chair, Department of Epidemiology and Cancer Control
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, Tennessee  38105-3678
Telephone:  (901) 595-3300
Contents of this document may not be extracted without permission from the Principal Investigator.
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
Protocol Summary
PREDM: An Open-Label Pilot Intervention Trial to Prevent Diabetes in Prediabetic 
Adult Survivors of Childhood Cancer
Principal Investigator: Stephanie Dixon, MD, MPH
IND Holder: St. Jude Children’s Research Hospital, # XXXX
Brief Overview: This is a first-in survivor, single-arm pilot study with the goal of 
establishing evidence of feasibility and safety of a combined pharmacologic (metformin) 
and lifestyle intervention (using an existing digital platform) to prevent diabetes in 
prediabetic adult survivors of childhood cancer. In addition, we will evaluate preliminary 
data for efficacy of the combined intervention to improve measures of glycemic control, 
insulin resistance, weight/anthropometric measures, physical activity and frailty. The 
metformin + lifestyle intervention will be administered for 24 weeks and measures of 
adherence, safety, glycemic control, insulin resistance and anthropometrics assessed. If 
successful, this pilot will provide the preliminary evidence needed for a phase 2, 
randomized controlled trial to establish efficacy. This proposal leverages the unique 
resource of the SJLIFE cohort of extensively phenotyped survivors available for 
longitudinal follow-up.
Intervention: 41 survivors age 18 to <45 years determined to have prediabetes based on 
American Diabetes Association diagnostic criteria will be enrolled and receive the 
combined metformin and lifestyle intervention (using a digitally delivered platform) for 6 
months.
Brief Outline of Treatment Plan: Eligible subjects who meet inclusion criteria will 
receive metformin extended release daily and be enrolled in the digital lifestyle 
intervention program. Following a 2-week run-in period at lower dose (500 mg/day) to 
minimize gastrointestinal side effects (diarrhea, nausea, flatulence, bloating), participants 
will be escalated to a maximum dose of 1000 mg/day. The digitally delivered lifestyle 
change program will include a core curriculum focused on diet quality, food types, 
exercise and behavioral strategies for goal setting, and self-monitoring. The intervention 
includes interaction with a lifestyle coach as well as a virtual peer group, hosted by a 
second group coach. Study end points will include treatment adherence will be assessed by 
telephone-based pill count at week 2, 4, 8, 16 and 20, and in-person assessment at 
subsequent clinic visits (12 and 24 weeks). Adherence to the lifestyle program will be 
monitored by completion logs from the digital platform as well as self-reported physical 
activity (NHANES-PAQ) and accelerometer data.  Safety will be assessed using the 
Global Rating of Side Effects Burden, which includes the Common Terminology Criteria 
for Adverse Events (CTCAE v5.0) grade. Glycemic control and insulin resistance will be 
assessed by change from baseline in fasting plasma glucose (FPG), hemoglobin A1c 
(HbA1c), insulin resistance using the homestatic model assessment (HOMA-IR) and 
insulin-like growth factor-binding protein 1 (IGF-BP1). We will also assess change from 
baseline in weight, body fat percentage, waist circumference, physical activity (self-report 
and accelerometer data) and frailty measures.
Study Design: Single-arm (combined metformin + digitally delivered lifestyle 
intervention), open-label pilot intervention trial to determine: 1) feasibility and safety 
using measures of treatment adherence, safety and adverse event reporting and 2) 
preliminary evidence for efficacy using measures of glycemic control, insulin resistance, 
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
PREDM: An Open-Label Pilot Intervention Trial to Prevent Diabetes in Prediabetic 
Adult Survivors of Childhood Cancer
weight/anthropometric measures, physical activity and frailty in adult survivors of 
childhood cancer who have prediabetes. The objective of this study is to provide initial 
evidence for feasibility, safety and efficacy in a pilot, open-label setting. If successful, 
these results will provide necessary preliminary data for a randomized, multi-arm phase 
2b trial of efficacy. 
Sample Size: We anticipate enrolling approximately 41 participants.
Data Management: The study team consisting of the study PI, study coordinator, 
protocol nurse, and the study statistician will be responsible for data management and 
monitoring, including implementation of stopping rules for feasibility and safety. 
Statistical analyses will be performed by the Department of Epidemiology and Cancer 
Control and the Biostatistics Department at St. Jude Children’s Research Hospital.
Human Subjects: The risk to subjects will be related to the toxicity of metformin 
extended release. Metformin is a biguanide class oral hypoglycemic agent that is FDA-
approved to improve glycemic control in adults and pediatric patients 10 years of age and 
older with type 2 diabetes mellitus. It has been widely utilized with safety and efficacy 
data in prediabetic adults, outside of it’s FDA-approved indication. The expected side 
effects of metformin are gastrointestinal symptoms (diarrhea, nausea, flatulence, bloating). 
Participants will be informed of this during informed consent discussion and adverse 
events will be monitored, reported and managed according to good medical practice. 
Commercially available metformin extended release will be purchased and supplied as 500 
mg tables at a dose of 500 mg on days 1-14, escalated to 1000 mg day 15 through study 
end (week 24).
Metformin extended release is associated with fewer gastrointestinal side effects, 
especially when the dose is titrated, as planned in our study. Metformin may cause lactic 
acidosis in extreme clinical scenarios including overdose and, therefore, patients with risk 
factors for lactic acidosis including severe chronic kidney disease, hepatic impairment or 
acute heart failure will be excluded.
The primary features of the lifestyle change program include a curriculum focused on diet 
and exercise goals using behavioral strategies and led by a lifestyle coach. Unique physical 
activity limitations of survivors, including frailty, may be a barrier to incorporating 
activity goals to meet the recommended 150 min/week, however, as no specific exercise or 
dietary restrictions are prescribed we do not anticipate adverse events related to the 
lifestyle component of the study.
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
1.0
OBJECTIVES…. .....................................................................................................................7
1.1 Primary Objective .......................................................................................................................7
1.2 Secondary Objectives..................................................................................................................7
1.3 Exploratory Objectives................................................................................................................7
2.0
BACKGROUND AND RATIONALE ....................................................................................8
2.1 Background .................................................................................................................................8
2.2 Rationale…................................................................................................................................10
3.0
PARTICIPANT ELIGIBILITY CRITERIA AND STUDY ENROLLMENT......................13
3.1 Inclusion Criteria.......................................................................................................................13
3.2 Exclusion Criteria......................................................................................................................13
3.3 Research Participant Recruitment and Screening .....................................................................17
3.4 Enrollment on Study at St. Jude................................................................................................18
3.5 Procedures for Identifying and Randomizing Research Participants........................................18
3.6 Compensation............................................................................................................................19
4.0
DESIGN AND METHODS ...................................................................................................19
4.1 Design and Study Overview......................................................................................................19
4.2 Definition and assessment of outcome measures......................................................................20
5.0
TREATMENT PLAN ............................................................................................................25
5.1 Treatment ……………………………………………………………………………………25
5.2 Dose Modifications ...................................................................................................................26
5.3 Definitions of Toxicity..............................................................................................................29
5.4 Concomitant Therapy................................................................................................................30
5.5 Supportive Care.........................................................................................................................31
6.0
DRUG INFORMATION........................................................................................................31
6.1 Drug Distribution ......................................................................................................................33
7.0
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS.......................................33
7.1 Screening Evaluations...............................................................................................................34
7.2 Evaluations During Therapy .....................................................................................................35
7.3 Response Evaluations................................................................................................................36
7.4 Off-Study Evaluations...............................................................................................................36
7.5 Long-Term Follow-up Evaluations...........................................................................................36
8.0
EVALUATION CRITERIA...................................................................................................36
8.1 Response Criteria ......................................................................................................................36
8.2 Toxicity Evaluation Criteria......................................................................................................36
8.3 Subject Compliance Monitoring ...............................................................................................37
9.0
OFF STUDY AND OFF THERAPY CRITERIA .................................................................37
9.1 Off study criteria .......................................................................................................................37
9.2 Off therapy criteria....................................................................................................................38
10.0 SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS ..............................38
10.1 Adverse Events (AEs).............................................................................................................38
10.2 Definitions...............................................................................................................................38
10.3 Handling of Adverse Events (AEs) and Deaths......................................................................39
10.4 Emergency Unblinding ...........................................................................................................40
11.0 DATA COLLECTION, STUDY MONITORING, AND   CONFIDENTIALITY...............40
11.1 Data Collection........................................................................................................................40
11.2 Study Monitoring ....................................................................................................................41
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
11.3 Confidentiality.........................................................................................................................43
12.0 STATISTICAL CONSIDERATIONS...................................................................................44
12.1 Anticipated Completion Dates ................................................................................................47
12.2 Summary of Primary and Secondary Objectives ....................................................................48
12.3   Stopping Rules ......................................................................................................................49
13.0 OBTAINING INFORMED CONSENT ................................................................................49
13.1 Informed Consent Prior to Research Interventions.................................................................49
13.2 Consent at Age of Majority.....................................................................................................49
13.3 Consent When English is Not the Primary Language.............................................................49
APPENDIX I: MATRIX FOR METFORMIN PILL COUNT.......................................................54
APPENDIX II: ……………………………………………………………………………………55
APPENDIX III: SCHEDULE OF RESEARCH EVALUATIONS................................................59
APPENDIX IV:DAST AND AUDIT QUESTIONNAIRES..........................................................60
APPENDIX V:……………… ........................................................................................................63
APPENDIX VI:BARRIERS TO MEDICATION ADHERENCE .................................................64
APPENDIX VII:DISALLOWED DRUGS ON STUDY................................................................66
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
1.0 OBJECTIVES
1.1 Primary Objective
   The primary aim of this proposal is to establish the feasibility and safety of a 24-
week combined metformin + intensive lifestyle intervention among adult 
survivors with prediabetes. 
   Primary endpoints of this trial will be adherence to 1) daily metformin 
administration, assessed by telephone-based pill counts (Appendix I), and 2) 
completion of required core-curriculum of the lifestyle change intervention. Safety 
will be assessed using the Global Rating of Side Effects Burden (Appendix II), 
which includes the Common Terminology Criteria for Adverse Events (CTCAE 
v5.0) grade. 
  Hypothesis: Metformin will be safe and well-tolerated among adult survivors of 
childhood cancer with prediabetes. Metformin can be successfully used in 
combination with a digitally delivered intensive lifestyle intervention.
1.2 Secondary Objectives
The secondary aim is to assess preliminary evidence for efficacy of the combined 
metformin + intensive lifestyle intervention on glycemic control and insulin 
resistance. Glycemic control will be measured by fasting plasma glucose (FPG) 
and hemoglobin A1c (HbA1c) and insulin resistance measured by the 
homeostatic model assessment (HOMA-IR) and IGF-binding protein 1 (IGF-
BP1; a measure of insulin sensitivity strongly correlated with euglycemic insulin 
clamp testing).1
Hypothesis: A combined metformin and lifestyle intervention will improve 
measures of glycemic control and insulin resistance among adult survivors of 
childhood cancer with prediabetes, comparing baseline to 12-week (interim) and 
24-week (study-end) timepoints.
 1.3 Exploratory Objectives
To assess preliminary evidence for efficacy of the combined metformin + 
intensive lifestyle intervention on weight, other anthropometric measures, blood 
pressure and lipid profile, physical activity (self-reported and as measured by 
accelerometer), frailty measures, and health-related quality of life (HRQOL). We 
will also assess diabetes development at future SJLIFE visits.
To assess measures of participation in the lifestyle change program as well as 
barriers to participation and medication adherence.
Hypothesis: A combined metformin and lifestyle intervention will improve 
measures of body composition (including weight loss among overweight or 
obese survivors) and physical activity among adult survivors of childhood cancer 
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
with prediabetes, comparing baseline to 12-week (interim) and 24-week (study-
end) timepoints. Survivors with higher participation/engagement will have 
improved efficacy endpoints.
2.0 BACKGROUND AND RATIONALE
2.1 Background
Childhood cancer survivors are at high risk for diabetes: Compared to siblings, 
adult survivors of childhood cancer have near twice the risk of diabetes.2,3 
Specific cancer treatment exposures such as corticosteroids, abdominal or 
pancreatic radiation therapy, cranial radiation therapy and total body irradiation 
(TBI) are known to increase risk for diabetes, likely through alterations in insulin 
resistance and/or pancreatic insulin producing capacity (Figure 1).2,3 Compared to 
siblings, survivors who received abdominal radiation experience a 3.5-fold 
increase in risk of diabetes and those who received TBI a near 12-fold increase in 
risk.2 Although no association between asparaginase and diabetes has yet been 
identified, it is plausible that direct pancreatic injury resulting from exposure to 
this agent or drug-induced pancreatitis (corticosteroids, asparaginase or novel 
agents) could lead to a reduced insulin producing capacity and increased diabetes 
risk. 
Survivors are at high risk for cardiac morbidity and mortality: Cardiac death is 
the leading non-cancer cause of late mortality in survivors of childhood cancer.4 
Survivors have a near 12-fold increase risk of cardiac death relative to similar 
age- and sex-matched US population.4 Among long-term survivors exposed to 
cardiotoxic therapy the occurrence of modifiable cardiovascular risk factors, 
including diabetes, portends a near-multiplicative increase in risk for major 
cardiac events.5 Thus, diabetes prevention could provide a significant risk 
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
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reduction impact on long-term cardiac morbidity and mortality in this high-risk 
population. 
Diabetes prevention and control reduces cardiovascular risk in the general 
population: In the general adult population, diabetes is a well-established 
cardiovascular risk factor. Among adults with diabetes, cardiovascular disease is 
the leading cause of death and occurs up to 15 years earlier than in non-diabetics.6 
Improvement in glucose control decreases this risk and for every 1% reduction in 
hemoglobin A1c (HbA1c) towards a value of <6% there is an estimated 11-16% 
decrease in cardiovascular events including stroke, myocardial infarction and 
heart failure.7 Additionally, adults with diabetes have a 60% increase in risk for 
all-cause mortality with an 80% increase in risk of death from vascular causes 
compared to those who do not have diabetes.8 The specific impact of improved 
glucose control and diabetes prevention on mortality and cardiac morbidity in 
adult survivors is unknown and preliminary data generated from this pilot study 
would be used to design a randomized, large-scale trial of efficacy for diabetes 
prevention in survivors.
 Diabetes prevention is effective in the general population: Prediabetes is defined 
as a fasting plasma glucose (FPG) of 100-125 mg/dl or hemoglobin A1c (HbA1c) 
5.7-6.4% in the absence of overt diabetes. In the general population it is estimated 
that without intervention, 4-10% of prediabetics will become diabetic over one 
year.9,10  Both pharmacologic therapy with metformin, a biguanide class oral 
hypoglycemic agent that reduces hepatic glucose production and impacts 
anaerobic glucose metabolism and uptake at the level of the intestine,11 and 
intensive lifestyle intervention used in the Diabetes Prevention Program (DPP) 
have each been established to prevent progression to diabetes among prediabetic 
adults in the general population.9,12 In this landmark trial, intensive lifestyle 
intervention included a 16-week core-curriculum led by a lifestyle coach and 
focused on diet, exercise and behavioral strategies targeting 7% weight loss and at 
least 150 minutes per week of moderate intensity physical activity (brisk walking 
or biking), and pharmacologic therapy was 850 mg metformin immediate release 
twice daily.13 At study completion, with an average follow-up time of 2.8 years, 
lifestyle intervention reduced the incidence of diabetes by 58% and metformin by 
31%, compared to placebo.12 However, in the youngest subset of participants (25-
44 years, the target age range for this application), metformin and lifestyle change 
had similar efficacy with the incidence of diabetes reduced by 44% in the 
metformin and 48% in the lifestyle group.12  Despite this, metformin is not 
commonly used in prediabetic adults. Less than 1% reported metformin use in the 
National Health and Nutrition Examination Survey (NHANES).14
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
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Whether treatment-related diabetes is preventable is unknown: Preliminary data 
from the St. Jude Lifetime Cohort (SJLIFE) suggests prediabetes prevalence in 
survivors is near twice that of similarly aged controls (Table 1). Still, it is 
unknown if interventions utilized in the general population are feasible or 
efficacious in this high-risk population. 
Prediabetes
Diabetes
Table 1. Prediabetes and 
Diabetes in SJLIFE 
Participants at Baseline 
by Age
N
N
%
N
%
Survivors
18-24 yrs
1012
172
17.0
26
  2.6
25-34 yrs
1465
412
28.1
71
  4.8
35-44 yrs
792
328
41.4
89
11.2
45-54 yrs
230
107
46.5
38
16.5
55-64 yrs
  30
  13
43.3
  5
16.7
Controls
18-24 yrs
  85 
   8
9.4
  1
  1.2
25-34 yrs
157
  23
14.6
  4
  2.5
35-44 yrs
136
  31
22.8
  9
  6.6
45-54 yrs
  53
  14
26.4
  7
13.2
55-64 yrs
  17
    5
29.4
  0
  0.0
2.2 Rationale
Type 2 diabetes has become an 
epidemic in the US, affecting 12% 
of the adult population.15 Among 
survivors, our data in the SJLIFE 
cohort, consistent with prior 
studies, demonstrates an increased 
prevalence of diabetes among 
adult survivors; specifically, 
among those in middle adulthood 
(35-64 years), 12.5% were 
diabetic (Table 1). In the original 
Diabetes Prevention Program 
(DPP) trial performed in the 
overweight, general adult 
population with prediabetes, 72% 
of participants randomized to the 
metformin arm took 80% of 
prescribed metformin dose.12 
Additionally, in the DPP, 74% of 
lifestyle participants met the 150 
min/week activity goal based on 
Table 2. Potentially Eligible Participants 
from SJLIFE Age 18-<45 Known to be 
Prediabetic (N=603)
Age at diagnosis, years
(median, IQR)
6.55
2.9-12.7
N
%
Age as of 12/1/2019
  18-24 years
  27
4.5
  25-34 years
237
39.3
  35-<45 years
339
56.2
Exposure Type
  Pancreatic Radiation
234
38.8
  Cranial Radiation
197
32.7
  Total Body Irradiation
  26
  4.3
  Corticosteroids
275
45.6
  Asparaginase
189
31.3
  Bone Marrow Transplant
  54
  9.0
Gender
  Male
385
63.8
  Female
218
36.2
Race
  White, Non-Hispanic
476
78.9
  Other
127
21.1
BMI Category (kg/m2)
  Underweight, <18.5
20
3.3
  Healthy weight, 18.5-24.9
142
23.6
  Overweight, 25.0-29.9
177
29.3
  Obese, ≥30.0
264
43.8
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
participant logs and 50% achieved the goal 7% weight loss at 24 weeks. The 7% 
weight loss goal was based on prior studies suggesting behavioral weight loss 
strategies are able to achieve a 5-10% weight loss in 6 month study periods and 
that risk of developing diabetes increases with increasing BMI, therefore any 
decrease in BMI would be anticipated to decrease diabetes risk.16 Unlike the 
DPP participants, some of the survivors in our study may have a BMI <25 kg/m2 
at study start, therefore we proposed a goal of 5% weight loss. Additionally, 74% 
of participants in the lifestyle arm of the DPP achieved the 150 minutes/wk 
activity goal at 24 weeks. For our feasibility aim, we chose to demonstrate 
adherence to the curriculum, not outcome based goals as over 25% of potentially 
eligible prediabetic survivors are not overweight (Table 2); therefore, although 
we will monitor change in weight, physical activity and diet, we have chosen 
adherence to the digitally-delivered curriculum to be defined as completion of at 
least 60% of core-curriculum during the 24 week study period. Finally, although 
72% of participants in the DPP were able to be adherent to metformin and at 
least 74% met either a physical activity or weight loss goal, we anticipate that 
adherence to the combined intervention will be more difficult to achieve. 
Therefore, we have chosen to consider this intervention feasible if at least 60% 
of survivors are adherent to at least 80% of metformin doses and at least 60% of 
the core curricula.
Because lifestyle change and metformin demonstrate similar efficacy in adults 
aged 25-44 in the general population (a similar age to our target survivor 
population),12 it is important to test both strategies in our pilot study. The 
etiology of prediabetes may differ in survivors due to prior therapy exposures 
and these interventions may work synergistically to improve glucose control and 
decrease insulin resistance. Each intervention is safe and tolerable in the general 
population, including those with heart failure and other chronic conditions.17 We 
plan to pilot a combined metformin and lifestyle intervention to prevent diabetes 
in young adult survivors of childhood cancer with prediabetes. This will provide 
feasibility data on each approach and identify if one or both are feasible in an 
efficient manner.  
The landmark DPP trial utilized a dose of metformin immediate release (IR) of 
850 mg twice daily.13 Metformin ER can be administered once daily and is 
associated with fewer gastrointestinal side effects,17,18 with evidence for at least 
equivalent glycemic control.19 Metformin may cause lactic acidosis in extreme 
clinical scenarios including overdose and, therefore, patients with risk factors for 
lactic acidosis including severe chronic kidney disease, hepatic impairment or 
acute heart failure are excluded.17,20 The incidence of lactic acidosis in patients 
using metformin for diabetes has been estimated at between 3 and 9 cases per 
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
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100,000 person years of administration.21-23 Given that most of these cases are in 
individuals with risk factors that will be excluded in our study, the potential risk 
of metformin associated lactic acidosis is extremely low. In many studies, 
including the landmark DPP trial, laboratory monitoring was performed no more 
frequently than every 3 months. Despite frequent gastrointestinal side-effects, 
most commonly diarrhea, metformin immediate release (IR) administered at 
doses up to 2.5 g/day was discontinued due to intolerable side effects in only 1.5-
5% of participants over multiple studies.18 Multiple studies have since 
demonstrated safety and efficacy of dosing up to and exceeding 1000 mg twice 
daily IR and 1000 mg daily ER in both diabetic and prediabetic 
populations.19,24,25 Therefore, we expect our metformin discontinuation rate to be 
<5%.
Approximately 25% of potentially eligible survivors with prediabetes have a 
BMI <25 kg/m2 (Table 2) and because eligibility criteria for entry into a DPP 
lifestyle change program includes a BMI of at least 25 kg/m2, a DPP lifestyle 
change program will not be utilized. The digitally delivered, lifestyle change 
program used in our study features a core curriculum administered over the 24 
week study period, similar to the set-up of the DPP. The focus is on dietary 
education and meal tracking, weight loss (for overweight and obese individuals) 
to a goal that can be tailored to each participant and physical activity through 
behavioral change using strategies based in cognitive behavioral therapy to 
promote self-efficacy. A lifestyle coach assigned to each participant by the 
digital lifestyle change platform virtually interacts with each participant and 
there is a second lifestyle coach from the digital lifestyle change platform that 
leads a peer group, both of these components are similar to the DPP digital 
programs. This program has demonstrated that the majority of regular users of 
the program achieve weight loss, with increased weight loss seen in individuals 
who demonstrate higher levels of engagement or adherence with self-monitoring 
in the application.26,27 Among overweight and obese participants another study 
demonstrated the digital lifestyle change program resulted in 7.5% mean weight 
loss as well as a 5.7 mg/dL decrease in fasting plasma glucose levels over the 
first 15 weeks of the program, weight loss at 1 year was 5% demonstrating 
maintenance.28  In a sub-analysis of DPP participants randomized to intensive 
lifestyle intervention, researchers identified that, for this group, weight loss was 
the primary predictor of decreased diabetes incidence and for every kilogram of 
weight loss the risk of diabetes was reduced by 16% after adjustment for dietary 
and activity changes.29 Prior studies of digitally delivered DPP lifestyle change 
programs have demonstrated an average weight loss of 5.0-6.5%,30,31 as well as a 
significant increase in exercise frequency and decrease in work absenteeism for 
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participants in the general population with prediabetes over the 16-course core 
curriculum.32 
Frailty is typically described in older adults and identifies individuals who are at 
risk for adverse health outcomes and early mortality.33,34 However, Ness et al. 
identified that the prevalence of frailty (7.9%) and prefrailty (22.2%), defined by 
the Fried criteria, among survivors in the SJLIFE cohort at a mean age of 33 
years was similar to the prevalence reported among adults over 65 years of 
age.33,34 Observational studies among older adults have demonstrated that 
metformin reduces all-cause mortality and frailty-related diseases, including 
reduced cancer and cardiovascular disease compared to both non-diabetes and 
diabetics using non-metformin regimens.35,36 These observations, as well as 
animal studies suggesting metformin has anti-aging effects, has led to research 
interest and there is at least one ongoing study of frailty prevention in prediabetic 
adults using metformin.37
3.0
PARTICIPANT ELIGIBILITY CRITERIA AND STUDY 
ENROLLMENT 
3.1 Inclusion Criteria 
We will recruit to enroll 41 survivors who are at least 18 but <45 years of age 
who participate in the St. Jude Lifetime Cohort Study (SJLIFE) and have been 
identified to have prediabetes defined as hemoglobin A1c (HbA1c) 5.7-6.4% or 
fasting plasma glucose (FPG) 100-125 mg/dl.
3.1.1   Participant in SJLIFE
3.1.2  ≥18 and <45 years of age
3.1.3  Prediabetic: fasting plasma glucose 100-125 mg/dL, hemoglobin A1c 5.7-  
6.4% (either or both criteria may be present)
According to institutional and NIH policy, the study will accession research 
participants regardless of sex and ethnic background.  Institutional 
experience confirms broad representation in this regard.
3.2 Exclusion Criteria 
3.2.1    Absence of treatment related diabetes risk. Survivors will be excluded if 
their cancer treatment required observation only, surgery alone not 
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involving the abdomen or brain, radiation alone not involving the chest 
(pancreatic risk), abdomen or brain (e.g. retinoblastoma treated with 
enucleation alone, melanoma of an extremity treated with excision alone, 
neuroblastoma in an infant requiring observation only)
3.2.2   Diabetes at baseline assessment: FPG ≥126 mg/dL, HbA1c ≥6.5% or 
previous diagnosis by a physician (except gestational diabetes that resolved 
post-partum)
3.2.3   BMI <19 kg/m2 
3.2.4  Current metformin use (including for any period  ≥30 days in the past 1yr)
3.2.5  Known allergy to metformin
3.2.6  Current use of other oral glucose lowering medications, non-insulin
injectable diabetes medications or insulin (Appendix)
3.2.7 Current participation in a lifestyle change program 
3.2.8 Chronic kidney disease ≥ stage IIIb (eGFR < 45 mL/min)
3.2.9 Severe cardiovascular disease or recent intervention (NYHA class ≥2 or heart 
failure hospitalization in the past 6mo, Aortic stenosis, Heart block  
including LBBB or 3rd degree AV block, SBP >180 or DBP >105 mmHg, 
myocardial infarction or coronary revascularization in the past 1 month)
3.2.10 Severe hepatic dysfunction: cirrhosis or AST/ALT >3 times upper limit of 
normal
3.2.11 Pulmonary disease with dependence on oxygen or daily use of 
bronchodilators
3.2.12 Weight loss >10% in the past 6 months
3.2.13 Bariatric surgery in the past 2 years
3.2.14 Pregnant, within 3 months post-partum, nursing, or planning to become 
pregnant
3.2.15 Anemia: hematocrit <36% in males or <33% in females
3.2.16 Ongoing alcohol or substance abuse using criteria from the AUDIT and 
DAST questionnaires (Appendix)
3.2.17 Diagnosis of schizophrenia or other psychotic disorder
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3.2.18 Vision impairment limiting ability to interface with the digital program
3.2.19 Unable to swallow medication
3.2.20 Non-English speaking
3.2.21 Cognitive impairment defined by IQ <80
3.2.22 Current active cancer or undergoing treatment for active cancer
Complete inclusion/exclusion criteria are listed in Table 3.
Table 3. Inclusion Criteria
Rationale
Participant in SJLIFE: ≥5 years from 
completion of therapy
Limits study to a population especially vulnerable due to young 
age at cancer therapy. Minimizes interference with cancer 
surveillance. Reflects eligibility for SJLIFE cohort participation.
≥18 and <45 years of age at study 
entry
≥18 years reflects eligibility of CDC-recognized lifestyle change 
programs. Prior studies suggest metformin and lifestyle change 
are equally efficacious in this age group. We expect a larger 
proportion of prediabetes in this group to be attributable to 
childhood cancer treatment and not only lifestyle and physiologic 
aging.
Prediabetic 
(FPG 100-125 mg/dl, HbA1c 5.7-
6.4%)
Targets subset of survivors at highest risk of developing diabetes.
Exclusion Criteria
Treated by:
1) observation alone or 2) surgical 
resection alone and resection did not 
include abdomen or brain or 3) 
radiation therapy alone and radiation 
field did not include chest (potential to 
pancreas), abdomen or brain
No known treatment related risk for diabetes.
Diabetes at baseline: FPG ≥126 
mg/dl or HbA1c ≥6.5% or previous 
diagnosis by a physician (except 
gestational diabetes, resolved post-
partum)
Requires additional medical management and monitoring which 
may include glucose lowering medications that would interfere 
with ability to conduct trial. 
BMI < 19 kg/m2
Concern that incidental weight loss using the lifestyle change 
program would be detrimental to underweight or near 
underweight survivors.
Current metformin use (including for 
any period of >30 days in the past 1 
year)
Limits assessment of current glycemia control measures and 
impact on glucose homeostasis.
Known allergy to metformin
Unable to tolerate intervention
Current use of other oral glucose 
lowering medications, non-insulin 
injectable diabetes medications or 
insulin
Limits assessment of current glycemia control measures and 
impact on glucose homeostasis. Limits inclusion of participants 
who are unclear about their prior diabetes diagnosis/current 
treatment or those on glucose lowering medications for 
indications other than diabetes.
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Includes: sulfonylureas, alpha-glucosidase inhibitors, dipeptidyl 
peptidase-4  (DPP-4) inhibitors, sodium-glucose transporter 
(SGLT) 2 inhibitors, thiazolidinediones, glucagon-like peptide-1 
(GLP-1) receptor agonists, meglitinides, amylinomimetics, 
insulins (Appendix)
Current participant in a lifestyle 
change program* (including for any 
period of >30 days in the past 3 
months)
Limits assessment of baseline weight and physical activity and 
impact of intervention on these measures and measures of 
change in glucose homeostasis. 
*Excludes participants of any CDC-recognized diabetes 
prevention program OR any lifestyle change program targeting 
weight loss and physical activity using behavioral 
therapy/psychology-based interventions (such as NOOM) but not 
traditional programs focused primarily on calories/points (such as 
Weight Watchers, myWW)
Renal dysfunction: ≥Stage IIIb chronic 
kidney disease (eGFR < 45mL/min)
Metformin may result in lactic acidosis if patient with renal 
insufficiency undergo unexpected surgery or imaging. 
Cardiovascular disease: NYHA class 
≥2 or heart failure hospitalization in 
the past 6mo, Aortic stenosis, Heart 
block (LBBB, 3rd degree AV block), 
SBP >180 or DBP >105 mmHg, 
Myocardial infarction or coronary 
revascularization in the past 1mo
Increases the risk of physical activity associated with lifestyle 
change program. Acute heart failure can increase theoretical risk 
for lactic acidosis.
Severe hepatic dysfunction: cirrhosis, 
AST/ALT >3 times upper limit of 
normal (ULN) 
Theoretically increases the risk for lactic acidosis.
Pulmonary disease with dependence 
on oxygen or daily use of 
bronchodilators
Increases the risk of physical activity associated with lifestyle 
change program.
Ongoing alcohol or substance abuse
Increases the risk of lactic acidosis. Interfere with ability to 
conduct trial. Scores on AUDIT >=13 in women and >=15 in men 
for alcohol abuse and DAST scores >=3 for substance abuse 
(Appendix)
Weight loss >10% in past 6 months or 
bariatric surgery within the past 2 
years
Interferes with ability to conduct trial, exception is postpartum 
weight loss.
Anemia: hematocrit <36% in males or 
<33% in females
Interferes with ability to adhere to intervention, potential increase 
of associated risk.
Pregnant, planning to become 
pregnant
Metformin is a category B drug; no identified risk in animal 
studies, absence of well-controlled human studies. However, 
pregnancy impacts glucose homeostasis.
Within 3 months post-partum or 
nursing
Weight loss and other physiologic changes immediately post-
partum and associated with increased energy demands during 
nursing would interfere with ability to assess changes in glycemic 
control and weight.
Diagnosis of schizophrenia or other 
psychotic disorder
May interfere with ability to adhere to medications and participate 
in digital lifestyle change platform.
Non-English speaking or literate
Unable to participate in the digital lifestyle change platform.
Vision impairment
Unable to fully participate in the digital lifestyle change platform.
Cognitive impairment defined as IQ < 
80
Unable to fully participate in the digital lifestyle change platform.
No access to electronic device 
compatible with the platform
Unable to participate in the digital diabetes prevention platform.
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Unable to swallow medication
Unable to receive metformin ER.
Current active cancer or undergoing 
treatment for active cancer
Potential for other medication interactions with metformin. 
Potential for current cancer or treatment to limit ability to 
participant in intervention.
3.3 Research Participant Recruitment and Screening
Participants for this study will be recruited from our NIH and institutionally-
supported St. Jude Lifetime Cohort Study (SJLIFE; U01 CA195547, M.M. 
Hudson, L.L. Robison, MPI).38 SJLIFE is a retrospective cohort with prospective 
follow-up and ongoing accrual that aims to facilitate prospective evaluation of 
health outcomes in aging adults surviving pediatric cancer.38 Eligibility criteria 
for participation in SJLIFE includes five-year survival following diagnosis of 
pediatric cancer treated or followed at St. Jude Children's Research Hospital 
(SJCRH) and now comprises over 5000 survivors diagnosed from the 1960s 
through 2000s who have completed comprehensive on-campus clinical 
assessments. 
We have identified 603 adult survivors <45 years old who were prediabetic at 
their last assessment (Table 2); however, as prediabetes prevalence increases 
with age and more survivors have aged in to the 18-24 group since last 
assessment, we anticipate an additional 200-300 potentially eligible participants 
based on a prevalence of prediabetes of 28% among those 18-<45 years in the 
SJLIFE cohort (Table 1). 
Potentially eligible survivors, based on age (18-<45 years), potential for cancer 
treatment related risk for diabetes, and prediabetes status at last assessment will 
be identified prior to campus visit for a scheduled, SJLIFE core assessment. 
After reviewing potential eligibility in a weekly meeting, survivors they will be 
contacted by the study team to explain the study, including potential benefits and 
risks and asked if they would be interested in participating. If they are interested 
they will be scheduled with study staff for a PREDM consent and screening visit. 
The potential participants will be consented to PREDM following their SJLIFE 
consent visit and once consented to PREDM, will have study specific IGF-BP1 
and lactate labs drawn at the same time as their SJLIFE core labs. Screening 
upon campus visit will be included in the typical SJLIFE core assessment 
including glycemia measure to assess if the participant meets all eligibility 
criteria, including being prediabetic by lab assessment (FPG 100-125 mg/dL or 
HbA1c 5.7-6.4%), neither FPG or HbA1c in the range for diabetes and not on 
any medications for diabetes or affecting glucose levels as detailed in the 
eligibility criteria. If all eligibility criteria are met (Table 3), they will be 
enrolled. We anticipate that 2/3 of survivors identified and consented will be 
eligible for study participation, therefore, in order to enroll 41 evaluable 
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survivors we will need to obtain baseline labs on a total of 60 SJLIFE 
participants. 
3.4 Enrollment on Study at St. Jude
Eligibility will be reviewed for completeness and correctness by the study team.  
A research participant-specific consent form will be released for participant  
signature.  
The Study Team will enter the Participant Eligibility checklist information into 
the central enrollment system and release the informed consent document.  The 
signed consent form will be scanned and sent to the CTO at 
protocoleligibilityoffice@stjude.org in order to complete enrollment.
To assist with enrollments and consent release, the CTO staff is available 
Monday through Friday. After hours, weekends, and holidays, the study team is 
referred to the CTO webpage for additional resources and instructions, Link:  
https://home.stjude.org/cto/Pages/default.aspx.
3.5 Procedures for Identifying and Randomizing Research Participants
Prior to initiating the study, the study team will be trained at SJCRH. The 
background to the study, study procedures, conditional enrollment and consent 
processes after determination of eligibility, user enrollment in the digital diabetes 
prevention platform by the study team, and plans to monitor intervention 
integrity and data quality will be included in this training workshop. 
Following completion of training, screening for potentially eligible research 
participants will begin with biweekly review of SJLIFE participants scheduled 
for core assessments at least 4 weeks from the planned SJLIFE visit. Potentially 
eligible participants will be confirmed during the weekly meeting with the PI 
(Dr. Dixon), co-investigator (Dr. Armstrong) and study team. The study team 
will contact potentially eligible subjects by phone at least 2 weeks prior to their 
scheduled on-campus assessment to screen for any obvious exclusion criteria 
(interim diagnosis of diabetes mellitus, chronic conditions or medications that 
would exclude participation detailed in Table 3, or pregnancy). If the research 
participant agrees, the study team will schedule the patient for a consent visit at 
their upcoming SJLIFE visit. Once consented they will have IGF-BP1 and lactate 
levels drawn with their SJLIFE labs. Study staff will provide them with an 
accelerometer and directions for use to provide 7 days of baseline physical 
activity data following their campus visit. Eligible subjects who meet inclusion 
criteria will receive metformin extended release 1000 mg daily (after an initial 
run-in period of 14 days at 500 mg daily to minimize gastrointestinal side-
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effects) and be enrolled in a digitally delivered lifestyle intervention program 
through an existing digital partner, after informed consent has been obtained.
3.6 Compensation
Participants will be compensated for their time and effort. They will receive 
$150 for completion of study visit 2 (week 12) and 3 (week 24). Study visit 
1/Screening Visit (Day 0) will occur at the time of a regularly scheduled SJLIFE 
Core visit and include the regular SJLIFE visit compensation.
4.0 DESIGN AND METHODS
4.1 Design and Study Overview
This is a single-arm, open-label intervention pilot trial (Figure 2) to assess the primary 
endpoints of: 1) feasibility and safety of a combined metformin + digitally delivered 
lifestyle change program, and 2) effects on glycemic control, insulin resistance, 
weight and anthropometric measures and physical activity in survivors of childhood 
cancer, aged 18-<45 years, who are prediabetic. The objective of this study is to 
provide feasibility data and initial evidence for efficacy in an efficient pilot, open 
label setting. If successful, these results will provide necessary preliminary data for a 
randomized, phase 2b trial of efficacy. In the general population, metformin and 
lifestyle change have each demonstrated efficacy to reduce the incidence of diabetes 
by 40-50% among prediabetic adults aged 25-44 years.12
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PREDM Study Schema 
Figure2.
StudySchema
PrediabeticAdult
Survivor of
ChildhoodCancer
EnrolledinSJLIFE
Age18-<45years
Consent
RegimenM +
LifestyleIntervention
MetforminER500mg/day
+
Digitallydeliveredlifestyle
changeprogram
Screening
1
2
4
8
12
16
20
24
Clinical and Lab Studies
Screening
2
4
8
12
16
20
24
Cancer treatment history
X
Historyandphysical
Xe
X
X
Anthropometricsa
Xe
X
X
Frailtymeasuresb
Xe
X
Fastingbloodworkc
Xe
X
X
Physical activityby7-dayaccelerometer data
X
X
X
Self-Administered Questionnaires
Demographic,medical &familyhistory
Xe
Xf
Xf
SF-36for HRQOL
Xe
X
X
DASTandAUDIT
X
X
Motivationtochange
X
Barrierstoparticipation
X
Treatment Management and AdherenceMonitoring
Lifestylechangeenrollment
X
MetforminER500mgtest dose
X
Studytabletsdispensed
X
X
X
X
X
X
X
Follow-upphonecall d
X
X
X
X
X
Symptomlog
X
X
X
X
X
X
X
X
Medicationadherencelog
X
X
X
X
X
X
X
Lifestylechangeadherencelog
X
X
X
X
X
X
X
Day90On-CampusEvaluation
Titrationto1000mg/day
Day180On-CampusEvaluation
Week1will bewhentheparticipant beginsmetformin500mg/dayandthelifestylechangeprogramandmayoccur upto28
daysafter screeningassessments. aAnthropometrics: BMI,bodyfat %,waist circumferencebFrailtymeasures: walkingspeed,
handgripstrength(bodyfat %) cFastingbloodwork: glucose, insulin,hemoglobinA1c,IGF-BP1,completemetabolicpanel
(CMP),lactate,cystatinc,completebloodcount,lipidpanel. dFollow-upphonecall: conduct pill count,confirmmedication
toleranceprior totitration,completesymptomlog, arrangemedicationrefill. eRepeat onlyif screening>30daysprior.
fLimitedinterimmedical historyincludingmedications.
AdherenceAssessment
AdherenceAssessment
AdherenceAssessment
AdherenceAssessment
*In the above schema, the 2 week visit will be conducted between +/- 4 days (between 10 
and 18 days) and all monthly assessments including phone calls, labs and on-campus visits 
at weeks 4, 8, 12, 16, 20 and 24 will occur +/- 7 days from the planned date.
4.2 Definition and assessment of outcome measures
4.2.1 Primary Outcomes of PREDM
Adherence for feasibility: A participant will be considered adherent to the 
combined intervention if they are 80% adherent to metformin ER and complete 
60% of the digitally-delivered core-curriculum. Metformin adherence will be 
monitored using virtual pill counts, the protocol will be adapted from Kalichman et 
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al.39 and available in Appendix I. Participants will also be asked to bring all 
dispensed medication to campus at week 12 and 24 visits to perform in person pill-
counts and any unused medication will be returned to pharmacy to be logged and 
discarded. Additionally, we will report on the proportion of days covered (PDC) 
where PDC= (number of days in period “covered”/number of days in period)*100% 
where “covered” refers to metformin being in the patients possession after a study 
visit or mail-out refill. Adherence to the digitally-delivered core curriculum will be 
assessed by completion of lessons on the app-based platform. 
Safety and Adverse Events: Assessment of side effects and adverse events 
assessed using the Global Rating of Side Effects Burden (Appendix II), which 
includes the Common Terminology Criteria for Adverse Events (CTCAE v5.0) 
grade. The CTCAE grading criteria, published by the National Cancer Institute 
(NCI) is the accepted standard classification and grading scale for adverse events in 
cancer therapy clinical trials. These criteria will be assessed by phone or in person 
at weeks 2, 4, 8, 12, 16, 20 and 24.   Additionally, study labs at week 12 and 24 
study visits will assess for any safety concerns (CMP, lactate, cystatin C, complete 
blood count (CBC)). Pregnancy testing will be performed for female participants at 
week 12 and 24 study visits and, arranged as needed, based on symptoms and 
menstrual history.
4.2.2 Secondary Outcomes of PREDM
Glycemia will be measured using FPG and HbA1c. All fasting labs will be 
performed after a minimum of an 8 hour overnight fast (water is the only liquid that 
may be consumed during this period). Measures for an individual participant at 
weeks 12 and 24 will be compared to baseline. If at any study visit a participant 
meets American Diabetes Association (ADA) criteria for diabetes,40 FPG is ≥126 
mg/dL or HbA1c is ≥6.5% and the two tests are discordant (FPG is ≥126 mg/dL but 
HbA1c is <6.5% or FPG is <126 mg/dL but HbA1c is ≥6.5%) then the test which 
was in the diabetic range will be repeated using a fresh blood sample. If both FPG 
and HbA1c meet criteria for diabetes, or the two separate tests are concordant (FPG 
≥126 mg/dL or HbA1c ≥6.5% on two occasions), the participant will be recorded as 
developing diabetes and be notified. They will be referred to their primary care 
provider for management and will come off-study.
Insulin resistance will be measured using the homeostatic method assessment for 
insulin resistance (HOMA-IR; fasting insulin (microU/L) x FPG (nmol/L)/22.5) and 
IGFBP-1 (a measure of insulin sensitivity strongly correlated with euglycemic 
insulin clamp testing).29 Measures for an individual participant at weeks 12 and 24 
will be compared to baseline. 
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4.2.3 Exploratory Outcomes of PREDM
Diabetes development over time
Although we anticipate few, if any, survivors will develop diabetes during the 24-
week trial period, we would like to follow over time. In order to do so, we will 
monitor PREDM participants at any SJLIFE core assessment or other return visit 
that includes a measurement of weight and fasting blood work (FPG and HbA1c) 
for development of diabetes. SJLIFE core assessments typically occur every 3-5 
years, however some participants return for specific studies sooner. We 
acknowledge that this will not capture all events in real time as some survivors may 
not seek medical care regularly and diabetes may remain undiagnosed.
Anthropometrics
Weight
BMI
Body fat % by skin calipers will be calculated from assessment of skinfold fat 
using the 3-site method from Jackson-Pollack for men41 (measured at chest, 
abdomen and thigh) and women42 (measured at triceps, suprailiac and thigh). 
This method has been found to be highly correlated with body fat percentage by 
dual-energy x-ray absorptiometry in childhood cancer survivors.43
Abdominal circumference (cm): measured at the midpoint between the lowest rib 
and the upper border of the iliac crest
Hip circumference (cm): measured at the level of the pubic symphysis and the 
greatest gluteal protuberance
Waist-to-Hip Ratio 
Physical activity and frailty measures
Self-reported physical activity reported using National Health and Nutrition 
Survey Physical Activity Questionnaire,44 administered as part of SJLIFE Core 
assessment on Day 0 (baseline) and then at study visits on week 12 and 24. 
Change from baseline for an individual participant will be assessed.
Physical activity: Physical activity will be monitored by accelerometer using an 
Actigraphy which will be  sent to participants following screening assessments  
before starting study drug and prior to, week 12 and 24 campus visits. The 
accelerometer will collect 7 consecutive days of physical activity data while the 
participant is in their home/routine setting. They will receive an accelerometer 
with written instructions, programmed to begin recording 12:01 a.m.. We have 
successfully used this method to collect physical activity data on over 2000 
members of the SJLIFE cohort in other studies (R01CA174851; R01CA132901); 
many participants will be familiar with this data collection strategy. Wearing 
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instructions are explained in writing and provided verbally over the phone. The 
device is programmed to detect and record magnitude of acceleration or “intensity” 
of movement. Data are stored in memory as “counts” per time interval. We will 
use a one minute time interval or “epoch.” An elastic belt with an adjustable 
Velcro closure and/or a belt clip will be provided. Participants will be instructed to 
wear the monitor at the right hip during waking hours. The device is removed for 
swimming and bathing. Accelerometer data will be converted into kilocalories. 
Males with <383 kcal per week and females with <270 kcal per week will be 
classified as having low activity.33 Change from baseline for an individual 
participant will be assessed.
Walking speed: Participants will be asked to walk as fast as possible for 50 feet. 
The time to complete the distance will be recorded in feet per seconds. This will 
be measured at day 0 (baseline) and then at study end (week 24). Change from 
baseline for an individual participant will be assessed. An abnormal walking 
speed will be defined by gender- and height- specific cut points for time to walk 
15 feet described by Fried in her aging cohort (Table 4).33
Hand grip strength: Hand grip strength in kilograms will be measured using a 
Jamar hand held dynamometer (Sammons Preston Rolyan, Nottinghamshire, 
UK). Participants will be seated with the shoulder at 0-10 and the elbow in 90 
degrees of flexion. The forearm will be positioned in neutral. Each participant 
will complete three trials, the average used for analysis.45,46 BMI specific cut 
points for strength, described by Fried in her aging cohort (Table 4),33 will be 
used to classify those with muscle weakness. 
Table 5. BMI-specific cut points for muscle weakness
Males
Females
BMI (kg/m2)
Cut-point (kg)
BMI (kg/m2)
Cut-point (kg)
≤24
≤29
≤23
≤17
24.1-26
≤30
23.1-26
≤17.3
26.1-28
≤30
26.1-29
≤18
>28
≤32
>29
≤21
Table 4.  Gender and height specific cut-points for walking speed
Males
Females
Height
Cut-point to walk 
15 feet
Height
Cut-point to walk 
15 feet
≤173 cm
≥7 seconds
≤159 cm
≥7 seconds
>173 cm
≥6seconds
>159 cm
≥6 seconds
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Exhaustion/fatigue: Self-reported exhaustion will be assessed by scoring the 
Vitality Subscale of the Medical Outcomes Survey Short Form-36 (SF-36), 
which is part of the SJLIFE Home Survey. The SF-36, Version 2,47 a widely 
used generic health profile appropriate for use with adults of all ages, has 
extensive age- and gender-specific norms for the US. The SF-36 provides 
subscale scores for 8 domains of health-related quality of life, including Vitality. 
Individuals with scores <40 on the Vitality subscale will be classified as having 
exhaustion/fatigue.
Low lean muscle mass: Determined using body fat % to calculate lean mass as 
(1-(body fat %/100))*total mass (kg). This value will then be used to determine 
the relative lean muscle mass: lean mass (kg)/height in meters squared. 
Individuals with a relative lean mass ≤ 1.5 standard deviations below age-, sex-, 
and race-specific values from the National Health and Nutrition Examination 
Study (NHANES) will be classified as low lean muscle mass.48 Of note, the 
NHANES study utilized calculations based on Dual x-ray absorptiometry and 
height.
Cardiovascular risk factors
Lipids: Total cholesterol, HDL, LDL, Triglycerides
Blood pressure
Health-related quality of life (HRQOL) 
Assessed by Medical Outcomes Short Form 36, SF-36
Participations/Engagement with lifestyle change application
We will also collect information from the app-based platform on user 
engagement/participation as proportion of days the app was accessed, time spent 
in the app, food-tracking, digital coach interaction, peer-to-peer interaction, 
activity logging and weight logging because engagement with a digitally-
delivered diabetes prevention program, such as lesson completions, have been 
demonstrated to predict success.30
Motivation to change 
Motivation to change will be assessed at screening visit using a 4 question 
survey (Appendix V)
Barriers to medication adherence and lifestyle change participation
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Barriers and facilitators to medication adherence will be assessed at 24-week 
visit using a modified version of the PETiT questionnaire (Appendix VI)
Barriers and facilitators to participation will be assessed at 24-week visit using a 
questionnaire developed from previously identified categories of barriers to 
participation in healthy behavior change (Appendix VI)
5.0 TREATMENT PLAN
5.1 Treatment
Eligible subjects who meet inclusion criteria will be enrolled on study at 
Screening/Day 0. Study assessments included in the SJLIFE Core visit and study 
specific laboratory assessments will be completed at the screening visit including 
body fat percentage using skin calipers, abdominal circumference, hip circumference, 
SF-36 vitality subscale, walking speed and hand grip strength.  Participants will be 
given a test dose of metformin ER (500 mg) and monitored for any adverse effects 
of medication for 1 hour in clinic by the study team. The dose will be administered 
after a meal or snack. At the study visit they will be dispensed the study drug and 
enrolled on the digital lifestyle 5.2 change program. A username will be selected by 
the study participant with the option to choose from a number of study team generated 
user names to provide anonymity for the study participant during group sessions.
On Day 1, participants will begin their digital lifestyle intervention using their smart-
phone application with their lifestyle coach and peer group. On the same day, they 
will also begin metformin ER 500 mg daily for 14 days, taken after the evening meal. 
The 14-day supply will include additional tablets to prevent days off medication 
while titration occurs. Day 1 will occur at least 7 days (to allow for baseline physical 
activity data collection) and up to 28 days after screening assessments and 
participants will be notified of the start date based on assignment to a lifestyle 
intervention group. 
On day 14, participants will be contacted by phone (+/- 4 days, day 10 to 18) and 
adherence assessed using virtual pill counts via phone calls, the protocol will be 
adapted from Kalichman et al.39, and symptoms assessed using the Global Rating of 
Side Effects Burden (Appendix II), which includes the CTCAE v5.0 grading of 
events. After this call, if there are no signs or symptoms of adverse events, metformin 
ER dose will be increased to 1000 mg daily and mailed to participant. 
At weeks 4, 8, 16 and 20 a phone-based pill count for adherence and adverse event 
symptom log will be completed and study medication dispensed. 
At week 12 (interim assessment) and 24 (study-end), the participant will return to St. 
Jude Children’s Research Hospital (SJCRH) for an in-person assessment to include 
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history and physical examination (weight, BMI, blood pressure, anthropometric 
measures, walking speed (week 24 only), hand-grip strength (week 24 only)), fasting 
blood work (FPG, HbA1c, insulin, IGFBP-1, CMP, CBC, lactate, cystatin C, lipid 
panel, pregnancy test if appropriate), adherence assessment by pill-count (all 
medication dispensed from past 12 weeks will be assessed to monitor for adherence 
over the prior 4 weeks and verify virtual assessments), NHANES-PAQ for self-
reported physical activity, SF-36 for HRQOL and frailty measure of exhaustion 
which uses the vitality subscale, and CTCAE for adverse event grading will be 
completed. Accelerometer will be mailed at least 10 days prior to the on campus visit 
for collection of physical activity data.  
The digital lifestyle change program will complete at week 24. We will collect data 
on lesson completion, self-reported weight, food logging, activity logging, 
participation with coach messages, participation with peer groups, dates and 
frequency of app access, and time spent in application.
The lifestyle change program includes dietary change with a goal to target 5% 
weight loss (among participants with a BMI ≥22 kg/m2) and at least 150 min/wk. 
moderate intensity physical activity (brisk walking, biking, swimming, etc.) using a 
digital, app-based platform that includes a lifestyle coach who helps facilitate a 
core-curriculum focused on diet, exercise and behavioral strategies for goal setting 
and self-monitoring. Weight loss in this pilot would be a goal for participants with 
BMI ≥22 kg/m2; however, dietary change, increased lean muscle mass and 
increased physical activity are desirable for all survivors. Participants will complete 
the remote, digitally-delivered core-curriculum, over 24 weeks with adherence 
measured by completion logs as well as monitoring of physical activity both by 
self-report (NHANES-PAQ) and accelerometer data. 
5.2 Dose Modifications
All patients will be assessed throughout the 24 weeks of the study with assessment 
at weeks 2, 4, 8, 12, 16, 20 and 24 time-points. If a severe adverse event occurs at 
any time, a formal review will occur.
It is the responsibility of the Principal Investigator to oversee the safety of the 
study. This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted below, as well as implementation of data and 
safety-monitoring. Medical monitoring will include a regular assessment of the 
number and type of serious adverse events.
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Renal dysfunction
Consideration to hold metformin should be made if a research participant’s serum 
creatinine and cystatin C indicates a decline in renal function to an eGFR < 
45mL/min due to possible increase in risk for lactic acidosis in the setting of severe 
renal impairment. Metformin peak and systemic exposure was 27% and 61% 
greater, respectively in mild renal impaired and 74% and 2.36-fold greater in 
moderate renal impaired patients as compared to healthy subjects. (from Highlights 
of prescribing information PDF)
Hepatic dysfunction
Consideration to hold metformin should be made if a research participant develops 
severe hepatic dysfunction (AST/ALT >3 times ULN, cirrhosis or other signs of 
synthetic dysfunction).
Lactic acidosis
Metformin will be held and best medical supportive care advised if lactic acidosis 
(serum lactate >4 mmol/L) or hyperlactatemia with elevation in lactate of 2 
mmol/L from baseline values. 
Gastrointestinal symptoms
Gastrointestinal AE including diarrhea, nausea, vomiting, flatulence and bloating 
are common with metformin. Diarrhea is the most common AE followed by nausea. 
If participants report CTCAE grade 2 diarrhea or nausea, consider reducing 
metformin ER to 500 mg daily (reassess titration of metformin to 1000 mg daily in 
14 days). If at any time a participant develops grade 2 vomiting or grade 3 diarrhea 
or nausea (requires hydration or hospitalization to treat or maintain nutrition), 
metformin should be temporarily held, and, if felt to be due to metformin (no 
alternative explanation such as gastroenteritis etc.) metformin should be descalated  
(to 500 mg daily if currently at 1000 mg daily) upon resolution of symptoms or 
discontinued if dose is at 500 mg daily. See Deescalation and Rechallenge below.
Imaging or surgical procedures utilizing iodinated contrast
Due to the possibility of iodinated contrast to impair renal function, participants will 
be advised to stop metformin the day prior to any imaging procedure requiring 
iodinated controls if eGFR at baseline is <60 mL/min or they have a history of 
stable heart failure or hepatic dysfunction that was not classified as severe. If 
intraarterial contrast is used, participants will be advised to stop metformin the day 
prior to procedure regardless of other organ system function. If procedure is 
uncomplicated and the does not require admission, the patient can resume 
metformin 48 hours after procedure completion, otherwise they will remain off 
metformin until their case is reviewed by the study team and they are contacted.
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Hospitalization
Due to the increased likelihood of acute onset renal dysfunction, need for imaging 
requiring iodinated contrast materials, and/or initiation of new medications, 
participants will be instructed to contact study staff with any hospitalization and 
that metformin should be discontinued during any hospitalization. Fortunately, as a 
large portion of the adult population admitted to US hospitals take metformin or 
other glucose reducing medications, it is common practice for physicians to review 
and often discontinue these medications at the time of hospitalization. 
Excessive alcohol intake
Participants will be ineligible if they report alcohol abuse. Alcohol abuse will be 
defined as a score ≥13 in women and ≥15 in men (Appendix). Alcohol potentiates 
the effect of metformin on lactate metabolism. Participants will be warned against 
excessive alcohol intake while receiving metformin. Consider discontinuation of 
metformin, during history if it becomes apparent that participants have increased 
alcohol intake during the study period. 
De-escalation and Rechallenge: If at any time during the study the participant is 
determined to require metformin to be held for reasons of toxicity or side effects 
(see those documented above) the following plan for de-escalation and rechallenge 
will be followed. If metformin is held for severe gastroinstestinal toxicity (see 
above) and the dose is at 1000 mg ER daily and toxicity felt to be likely or possibly 
due to metformin, the participant will have metformin held until symptom 
resolution or for a minimum of 3 days and will then be re-challenged with 500 mg 
metformin ER daily. If a participant develops severe gastrointestinal toxicity at 500 
mg metformin ER daily and it is felt to be likely or possibly due to metformin and 
metformin is held, they will not be rechallenged. If a participant develops moderate 
toxicity including gastrointestinal CTCAE grade 2 diarrhea or nausea, the 
participant will be encouraged to continue the current dose and symptoms will be 
closely monitored as the expectation is that they will develop tolerance to 
gastrointestinal side effects with continued, consistent dosing and symptoms will 
improve or resolve; however, if they require a dose de-escalation from 1000 mg, 
they will be taken to 500 mg. If after 2 weeks, they have no or mild gastrointestinal 
symptoms, they will be re-challenged at 1000 mg. If participants require de-
escalation of dosing x 2, they will remain at the highest tolerated dose of 500 mg. 
For this study, we will not use an intermediate dose of 750 mg metformin ER, 
however, this is a consideration for a future, large scale study if we find that 1000 
mg ER is not well tolerated in our population.
Missed doses: Participants will be asked to take a daily dose of metformin ER, as 
detailed above. The goal is to take this dose 
Monitoring for toxicity: Safety will be evaluated in this study through the 
monitoring of all serious and non-serious AEs, defined and graded according to 
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NCI CTCAE v5.0. Participants will be assessed for safety (including laboratory 
values) according to the specified study evaluations and time points beginning week 
1 and ending at the time of study completion (week 24). General safety assessments 
will include serial interval histories, physical examinations, and specific laboratory 
studies, including serum chemistries, lactate and blood counts. All adverse events 
and serious adverse events whether volunteered by the subject, discovered by study 
personnel during questioning, detected through physical examination, clinically 
significant laboratory test, or other means, will be recorded. Each recorded adverse 
event or serious adverse event will be described by its duration (i.e., start and end 
dates), severity, regulatory seriousness criteria suspected relationship to the 
investigational product(s), the event outcome, and any actions taken. All deaths 
should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself. Protocol specific data and 
adverse events will be documented in the medical record and entered into the SJCRH 
Trials Database.
The study team consisting of the study PI (Dixon), study coordinator, protocol 
nurse, and the study statistician (Srivastava) will be responsible for monitoring the 
data and safety of this study, including implementation of stopping rules (see 
section 12.2) for safety and feasibility. Any symptoms that occur while on study 
will be managed according to good medical practice. Participants will complete a 
symptom log at the time of each telephone-encounter with the study team (weeks 2, 
4, 8, 16 and 20) and during in-person assessments (weeks 12 and 24), which will be 
reviewed by the study team.
Decreased B12 serum was observed in approximately 7% of patients with 
previously normal levels prior to participation in clinical trials of 29-week duration 
with metformin HCl tablets.  However, this vitamin deficiency, can sometimes be a 
contributing factor in mild anemia, although typically rapidly reverse after stopping 
metformin. We will monitor participants’ blood levels for anemia and will 
determine if they will need to come off study and be referred to their primary 
physician.
5.3 Definitions of Toxicity
Gastrointestinal side effects including diarrhea and nausea  grade 3 or vomiting  
grade 2 would be unexpected with metformin and, if attributable to the study drug, 
would result in a decrease in dose or discontinuation of the drug.
Lactic acidosis with lactate >4 mmol/L will result in discontinuation of metformin. 
If lactic acidosis is determined to have resulted from an alternate cause, resumption 
of metformin may be considered after the acute event resolves.
We know metformin adherence can be associated with gastrointestinal symptoms, 
however, this rarely results in medication discontinuation in prior studies (~5%), 
therefore discontinuation of metformin in 10% or more of participants due to 
gastrointestinal symptoms will be considered unacceptable. Therefore, the trial will 
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be stopped if 5 or more among the first 20 survivors or 8 or more among the total 
41 discontinue metformin due to toxicity. These stopping rules are based on exact 
95% lower confidence bounds for the probability of failure. 
5.4 Concomitant Therapy
Drugs Affecting Glycemic Control:
A number of drugs are known to be associated with impaired glucose tolerance and 
may impact efficacy of metformin. Although risk of adverse events following 
concomitant administration has not been demonstrated in clinical trials, the impact 
of metformin on glucose control may be modified if these medications are initiated 
during the course of the study. These medications include: thiazides and other 
diuretics, calcium channel blockers, beta blockers, proton pump inhibitors, tyrosine 
kinase inhibitors, corticosteroids, thyroid products, phenothiazines, estrogens, oral 
contraceptives, phenytoin, nicotinic acid, sympathomimetics (including beta 
blockers), isoniazid and iodinated contrast materials. Although many anti-
hypertensive medications and HMG-CoA reductase inhibitors (statins) may 
potentiate the risk for diabetes, their coadministration is not a contraindication to 
trial initiation. Rather, new medications prescribed during the study that may impact 
blood glucose control must be carefully documented and evaluated prior to outcome 
reporting.49-51
Iodinated Contrast Materials:
Iodinated contrast materials are widely used for a variety of imaging procedures. 
However, they carry a risk for contrast induced nephropathy (CIN), which could 
significantly impair renal function. In this scenario, the risk of metformin 
accumulation, due to ineffective renal clearance, and subsequent lactic acidosis is 
increased. This is particularly relevant for individuals on metformin with baseline 
mild- to moderate- renal dysfunction.50 Therefore, metformin will be held on the 
day of any imaging procedure requiring iodinated contrast and will not be resumed 
for at least 48 hours after administration and after a serum creatinine level 
demonstrates an eGFR of at least 30 mL/min/m2. 
Drugs that Reduce Metformin Clearance including Cationic Drugs:
Caution should be used with coadministration of drugs that interfere with common 
renal tubular transport systems (organic cationic transporter-2, OCT-2, and 
multidrug and toxin extrusion, MATE, inhibitors) that are involved with renal 
elimination of metformin as there is a potential increase in risk for lactic acidosis 
due to increased exposure to metformin. However, this risk has not been 
demonstrated in clinical trials, and there will be no effort to exclude concurrent 
therapy with these drugs. These include cationic drugs eliminated by renal tubular 
secretion (amiloride, digoxin, morphine, procainamide, quinidine, quinine, 
ranitidine, triamterene, trimethoprim, vancomycin), which have a theoretical 
potential to compete with metformin for common transport systems. Risk increases 
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with higher doses of metformin (maximum dose of metformin ER is 2000 mg) or 
decreased renal function, however, the specific dosage level these effects may begin 
to be observed has not been determined or was not available. These risks are 
theoretical, however, in patients with renal dysfunction, consultation with a 
pharmacist regarding risk and need for reduced dosing of metformin will occur for 
any potentially eligible participants taking one of the following medications: 
Cimetidine, Ranitidine, Proton Pump Inhibitors (PPIs), Trimethoprim, Cephalexin, 
Dolutegravir, Pyrimethamine, Ranolazine, Vandetanib, Imatinib, Nilotinib, 
Gefitinib, Erlotinib, Atenolol, or other cationic drugs including but not limited to 
(amiloride, digoxin, morphine, procainamide, quinidine, quinine, triamterene, 
vancomyocin).50,51
Carbonic Anhydrase Inhibitors:
Caution should be used with concurrent use of topiramate, zonisamide, 
acetazolamide or dichlorphenamide as these medications often cause a decrease in 
serum bicarbonate and subsequent non-anion gap, hyperchloremic metabolic 
acidosis. Therefore, concomitant use may increase the risk for lactic acidosis. 
Consider increased monitoring if participant is using these agents and has low 
serum bicarbonate at baseline.52,53
Insulin Secretagogues or Insulin:
Co-administration of metformin with other agents used for diabetes control that 
lower blood glucose levels increases the risk for clinically significant 
hypoglycemia. Participants with diabetes at baseline are ineligible to participate and 
those who develop diabetes will be removed from the study. As a result, no 
participants should be co-administered other hypoglycemic agents used in diabetes 
management while enrolled on this protocol. Appendix contains disallowed drugs 
list and drugs that will be tracked on study.
5.5 Supportive Care
All participants will be advised regarding the risk of metformin use in the setting of 
new onset renal dysfunction, heart failure, liver failure, excessive alcohol use and at 
the time of studies utilizing iodinated contrast. Participants will be advised to 
contact the study team if they are hospitalized for any reason or if they are notified 
of new changes to their health status. However, these relative contraindications to 
metformin use are well known in the medical community and all participants should 
receive care as per best medical practice. As metformin is a commonly used 
medication for the treatment of diabetes and its prevention, and participants are not 
blinded to their receipt of metformin, they should notify any medical provider 
responsible for their care of their metformin use at the time of any routine or 
emergent healthcare encounter. 
6.0 DRUG INFORMATION 
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METFORMIN  (Brand Name™ D-Care DM2 [DSC]; Fortamet; Glucophage; 
Glucophage XR; Glumetza; Riomet; Riomet ER)
Source and Pharmacology: Metformin hydrochloride tablets, USP contain the 
antihyperglycemic agent Metformin, which is a biguanide, in the form of 
monohydrochloride. The chemical name of Metformin hydrochloride 
is N,Ndimethylimidodicarbonimidic diamide hydrochloride. Metformin 
hydrochloride, USP is a white to off-white crystalline compound with a molecular 
formula of C H N • HCl and a molecular weight of 165.63. Metformin 
hydrochloride is freely soluble in water, slightly 4 11 5 soluble in alcohol, 
practically insoluble in acetone and in methylene chloride. The pKa of Metformin is 
12.4. The pH of a 1% aqueous solution of Metformin hydrochloride is 6.68. 
Metformin hydrochloride tablets, USP contain 500 mg, 850 mg, or 1000 mg of 
Metformin hydrochloride, which is equivalent to 389.93 mg, 662.88 mg, 779.86 mg 
Metformin base, respectively. Each tablet contains the inactive ingredients 
povidone (K-30), povidone (K-90), pregelatinized starch, and magnesium stearate. 
In addition, the coating for the tablets contains artificial blackberry flavor, 
hypromellose, macrogol and titanium dioxide.
Metformin is an antihyperglycemic agent which improves glucose tolerance in 
patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma 
glucose. Metformin decreases hepatic glucose production, decreases intestinal 
absorption of glucose, and improves insulin sensitivity by increasing peripheral 
glucose uptake and utilization. With Metformin therapy, insulin secretion remains 
unchanged while fasting insulin levels and day-long plasma insulin response may 
decrease.
Formulation and Stability: Metformin is available as an oral immediate release 
solution (100mg/mL), an oral extended release suspension (100mg/mL), 500 mg, 
850 mg and 1000 mg immediate release tablets, and 500 mg and 750 mg extended 
release tablets.  The immediate release oral solution should be stored at 15oC to 
30oC (59oF to 86oF).  The extended release oral suspension should be stored at 20oC 
to 25oC (68oF to 77oF) with excursions permitted to 15oC to 30oC (59oF to 86oF).  
Any unused portion of the reconstituted extended release oral suspension should be 
discarded after 100 days.  Tablet formulations should be stored protected from light 
and moisture at 20oC to 25oC (68oF to 77oF) with excursions permitted to 15oC to 
30oC (59oF to 86oF). 
Supplier:   Commercially available
Toxicity: Toxicities include chest discomfort, flushing, palpitations, chills, 
dizziness, headache, taste disorder, diaphoresis, nail disease, skin rash, decreased 
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vitamin B12 serum concentrate, hypoglycemia, abdominal distention, abdominal 
distress, abdominal pain, abnormal stools, constipation, diarrhea, dyspepsia, 
flatulence, heartburn, nausea, nausea and vomiting, infection, myalgia, weakness, 
flu-like symptoms, rhinitis, upper respiratory tract infection, accidental injury.  Rare 
but important or life-threatening toxicities include hepatic injury (cholestatic, 
hepatocellular, and mixed), and lactic acidosis.
Dosage and Route of Administration: 500 mg dose/day to be taken orally, 
increased to 1000 mg dose/day at day 14 throuhg week 24. The dose should be 
taken immediately following the evening meal and at approximately the same time 
daily (i.e. immediately following dinner each night). If a dose is forgotten, it should 
be taken within 4-6 hours of the originally planned dose; however, if the next dose 
is due to be administered in <12 hours from the current time, the forgotten dose 
should not be taken (i.e. a forgotten dinner dose may be taken later in the evening 
before bed but should not be taken the following morning with breakfast and then 
again that evening with dinner). If a dose is missed and cannot be made up (it is 
past bedtime/midnight on the night of the missed dose) this dose will be skipped. 
Participants should not take 2 doses within the same calendar day and should avoid 
taking 2 doses within a 12 hour period (ie 10 pm on Friday evening and then 7 am 
on Saturday morning).
6.1 Drug Distribution
Metformin extended release will be ordered by the study team at 500 mg daily (a 
14 day supply) for each participant at the time of study enrollment and will be 
distributed to that participant by the St. Jude pharmacy during their time on 
campus. At the time of dose escalation (study day 14) and study visits conducted 
via phone (week 4, 8, 16 and 20), refills of metformin extended release 1000 mg 
daily (or reduced dose for gastrointestinal complications) will be dispensed in a 28 
day supply and mailed by the St. Jude pharmacy. On week 12, metformin extended 
release 1000 mg daily for 28 day supply will be dispensed during the study visit. 
To prevent missed doses during any delay of study visits or mailing, 7 additional 
doses will be dispensed with each refill. Participants will be asked to bring all 
study drug with them at the time of return visits (weeks 12 and 24). After pill 
count, any remaining metformin extended release will be returned to St. Jude 
Pharmacy for destruction.
7.0
 REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS
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7.1 Screening Evaluations
All entry/eligibility studies will be performed at the SJLIFE core visit including 
study-specific labs (lactate, IGFBP-1 level). Participants age 18-<45 years with 
prediabetes at last SJLIFE visit will be screened for potential eligibility by chart 
review performed by study team and potentially eligible participants will be 
contacted at least 2-3 weeks prior to their schedule SJLIFE core visit. If no 
exclusion criteria are identified at the PREDM consent visit and participants are 
willing, they will be consented. If eligibility is confirmed during SJLIFE visit based 
on examination and labs, the participant will be enrolled to receive study 
interventions. An accelerometer will be sent to them after their SJLIFE campus visit 
in order to monitor physical activity in their home environment for 7 days. If, due to 
split core visit or other reason, baseline data including labs have been performed 
>30 days participants will need to have studies repeated before starting on study 
drug/participating in digital lifestyle change program. 
Table 6. Screening Evaluations 
prior to starting 
study drug 
History and physical exam with 
height (cm), weight (kg), and VS 
including resting blood pressure
X
Anthropometrics including body fat 
percetaage using skin fold calipers, 
abdominal circumference, hip 
circumference
X
Laboratory Studies, performed 
fasting: CBC, CMP (includes 
fasting plasma glucose), 
hemoglobin A1c, insulin level, 
IGFBP-1, lactate/lactic acid level, 
cystatin C, lipid panel 
X
Walking speed
X
Hand grip strength
X
Accelerometer
X
*Pregnancy Test
X
HRQOL (SF-36) including Vitality 
subscale
X
NHANES-PAQ
X
Symptom Log: Global Rating of 
Side Effects Burden, includes 
CTCAE
X
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Motivation to change assessment
X
*The St. Jude IRB requires that a female patient of childbearing potential must have a negative pregnancy test as a condition of clinical research 
eligibility.
7.2 Evaluations During Therapy
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS
Table 7. Therapy 
Evaluations
Week 
2
+/- 4 days
Week 
4
+/- 7 days
Week 
8
+/- 7 days
Week 
12 
+/- 7 days
Week 
16
+/- 7 days
Week 
20
+/- 7 days
Week 
24/ Off 
Study
+/- 7 days
History including medications
X
X
Physical Exam (Ht, Wt, VS)
X
X
Anthropometrics: body fat %, 
abdominal circumference, hip 
circumference
X
X
Fasting blood work: CBC, 
CMP, HbA1c, insulin, 
IGFBP-1, lactate, cystatin C, 
lipid panel
X
X
Walking speed
X
Hand grip strength
X
Accelerometer (mailed prior 
to visit)
X
X
*Pregnancy Test
X
X
HRQOL (SF-36) 
X
X
NHANES-PAQ
X
X
Medication Adherence 
Assessment
X
X
X
X
X
X
X
Lifestyle Change Adherence 
Log
X
X
X
X
X
X
X
Symptom Log including 
CTCAE/Adverse Events
X
X
X
X
X
X
X
Barriers and facilitators to 
medication adherence and 
lifestyle change surveys
X
*The St. Jude IRB requires that a female patient of childbearing potential must have a negative pregnancy test as a condition of 
clinical research eligibility.
Obtain other studies as needed for good patient care. 
Fasting labs must be obtained after an overnight fast (minimum of 8 hours). For all 
labs obtained as part of SJLIFE core assessment (CBC, CMP, cystatin C, insulin 
level, hemoglobin A1c, lipid panel), no changes in collection will be specified for 
this study. For IGFBP-1 level, this should be collected as a minimum of 1 mL 
whole blood in a red top tube. For lactate/lactic acid level, this should be collected 
as a minimum of 1 mL in a light green top tube. The sample will be placed on ice 
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and is stable for 2 hours. Samples will be collected at St. Jude and performed on 
site. 
7.3 Response Evaluations
We will evaluate response at week 12, drawing fasting blood work including fasting 
glucose, HbA1c, IGFBP-1 and insulin, and measuring weight, anthropometrics, 
physical activity and HRQOL. 
7.4 Off-Study Evaluations
Similar to response evaluations, we will evaluate response at study completion 
(week 24) by drawing fasting blood work including fasting glucose, HbA1c, IGFBP-
1 and insulin, and measuring weight, anthropometrics, physical activity, HRQOL, 
walking speed and hand-grip strength. 
7.5 Long-Term Follow-up Evaluations
We will monitor participants of PreDM at subsequent SJLIFE core assessments or 
any assessment including fasting labs (FPG and HbA1c) and weight for the 
development of diabetes. We will record this data, including diabetes diagnosis, date 
of diagnosis (either at SJLIFE assessment or validated diagnosis by medical records 
or lab reports at an outside site), FPG, HbA1c and weight. We will follow these 
participants for a period of up to 6 years to ensure all participants will have had the 
opportunity to return for another SJLIFE core assessment.
8.0 EVALUATION CRITERIA
8.1 Response Criteria
N/A
8.2 Toxicity Evaluation Criteria
The Global Rating of Side Effects Burden which includes the CTCAE v 5.0 
grading of the National Cancer Institute will be utilized and can be found in 
Appendix II. Copies of the CTCAE versions can be downloaded from the CTEP 
home page (http://ctep.info.nih.gov) or from the St. Jude DocuShare home page.
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8.3 Subject Compliance Monitoring
Participant adherence to metformin will be monitored by virtual pill counts conducted 
using a web-based meeting by the study team on week 2, 4, 8, 15 and 20, the protocol 
will be adapted from Kalichman et al.39 In-person pill counts will be performed on 
weeks 12 and 24 to assess adherence for the prior 4 weeks and confirm virtual pill 
count assessments. Adherence to the lifestyle change program will primarily be 
assessed by review of the log of lesson completion at the time of study completion. 
We will also collect data on lesson completion, self-reported weight, food logging, 
activity logging, participation with coach messages, participation with peer groups, 
dates and frequency of app access, time spent in application.
9.0 OFF STUDY AND OFF THERAPY CRITERIA
9.1 Off study criteria

Death

Lost to follow-up

Request of the Participant

Discretion of the Study PI, such as the following: 

The researcher decides that continuing in the study would be harmful 

A treatment is needed that is not allowed on this study

The participant misses so many appointments that the data cannot be 
used in the study. Specifically, a participants data will not be evaluable 
for efficacy endpoints (secondary) if they are not assessed within 3 
weeks of the end of therapy time point (24 week visit) and will not be 
evaluable for interim efficacy if they are not assessed within 3 weeks of 
the interim campus visit time point (12 week visit). However, because 
the primary aim of the study is feasibility, participants will not be taken 
off study for non-adherence or missed appointments, of course, drug 
will not be dispensed (and therefore they will be non-adherent to the 
metformin intervention) until contacted and adherence and adverse 
events assessed by the study coordinator.

The participant develops diabetes requiring additional treatment (if 
FPG  126 mg/dl but < 140 mg/dL or HbA1c  6.5% but <7.0% and 
the patient’s PCP does not feel alternate therapy would benefit the 
patient they may remain on study as metformin + lifestyle change are 
typical first line diabetes management strategies)

New information is learned that a better treatment is available, or that 
the study is not in the participant’s best interest

Completion of week 24 evaluations
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9.2 Off therapy criteria

Development of unacceptable toxicity during treatment

Refusal of therapy

Discretion of the Study PI, such as the following: 

The researcher decides that continuing in the study would be harmful 

A treatment is needed that is not allowed on this study

The participant misses so many appointments that the data cannot be 
used in the study. Specifically, drug will not be dispensed unless the 
participant is contacted and adherence assessed within the timepoints 
detailed in the study schema; however, participants will remain enrolled 
in the lifestyle change program throughout the duration of the study.

The participant develops diabetes requiring additional treatment (if 
FPG  126 mg/dl but < 140 mg/dL or HbA1c  6.5% but <7.0% and 
the patient’s PCP does not feel alternate therapy would benefit the 
patient they may remain on study as metformin + lifestyle change are 
typical first line diabetes management strategies)

New information is learned that a better treatment is available, or that 
the study is not in the participant’s best interest

Completion of week 24 evaluations
10.0  SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS
10.1 Adverse Events (AEs)
Adverse events will be monitored from the time of first study intervention or 
treatment.  Participants will be instructed to report all AEs during the study and 
will be assessed for the occurrence of AEs throughout the study.  
10.2 Definitions
Adverse Event (AE): Any untoward medical occurrence associated in a study 
participant after the first treatment or intervention on study. Adverse Events will be 
graded by the NCI CTCAE version 5.0.
Serious Adverse Event (SAE): Any adverse event temporally associated with the 
subject’s participation in research that meets any of the following criteria:

results in death;

is life-threatening (places the subject at immediate risk of death from the 
event as it occurred);

requires inpatient hospitalization or prolongation of existing 
hospitalization;

results in a persistent or significant disability/incapacity;

results in a congenital anomaly/birth defect; or
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
any other adverse event that, based upon appropriate medical judgment, 
may jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the other outcomes listed in this definition.
10.3 Handling of Adverse Events (AEs) and Deaths
Recording of Adverse Events and Serious Adverse Events: Adverse events 
(AEs) will be evaluated and documented by the clinical staff and investigators 
through patient reports, phone-encounters and study visits. The study team will be 
responsible for reviewing documentation related to AEs and entering directly into 
the protocol specific database. The data to be recorded are 1) event description, 2) 
NCI CTCAE v5.0 code and grade, 3) onset date, 4) resolution date (or ongoing), 
4) action taken for event, 5) patient outcome, 6) relationship of AE to protocol 
treatment and/or interventions, 7) if AE was expected (ie GI intolerance with 
metformin) or unexpected, and 8) any comments felt pertinent to AE. 
Attribution of an adverse event
Not related – The lack of temporal relationship of the event to protocol treatment 
makes a causal  relationship not reasonably possible, or other drugs/medications 
(prescribed or taken outside of this study), therapeutic interventions or underlying 
conditions provide a sufficient explanation.
Unlikely related – The temporal relationship of the event to the protocol treatment 
makes a causal relationship reasonably unlikely, and other drugs/medications 
(prescribed or taken outside of this study), therapeutic interventions or underlying 
conditions may not provide sufficient explanation for the event observed.
Possibly related – The temporal relationship of the event to the protocol treatment 
makes a causal relationship reasonably possible, and the event is more likely 
explained by exposure to the study drug or interventions than by other 
drugs/medications, therapeutic interventions or underlying conditions. 
Reporting Adverse Events and Serious Adverse Events: The St. Jude PI, upon 
awareness of an event, will review adverse events to determine the seriousness of 
AEs (corrections will be made if applicable) and ensure that all SAEs and all 
Unanticipated Problems (UPs) are entered into the electronic submission system 
(iRIS) within 10 days. All AEs, serious or not, will be recorded in a log, 
spreadsheet, or report and submitted to the St. Jude IRB at the time of continuing 
review. The St. Jude Regulatory Affairs Office, upon receipt, reports SAEs on 
study to the FDA within mandated regulatory timelines per 21 CRF 312 or 812.
For the purpose of safety analyses, all AE’s that are classified as likely or possibly 
related will be considered treatment-related events. 
Reporting of Unanticipated Problems (UPs): The St. Jude PI will refer to St. 
Jude Human Research Protection Program (HRPP) Policy 01.720 for specifics on 
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the reporting of unanticipated problems to the St. Jude IRB. The St. Jude IRB 
reports UPs to BIMO as per 21 CFR 56.  The UP link follows: 
https://home.stjude.org/hrpp/Policies/01-720.pdf#search=unanticipated.
Deaths: All treatment related deaths and any unanticipated fatal or unanticipated 
life-threatening event judged by the study PI to be at least possibly due to the 
study treatment, will be reported to the FDA by telephone or fax as soon as 
possible but no later than seven calendar days after notification of the event and 
followed by a written safety report as complete as possible within eight additional 
days (ie. full report 15 calendar days total after notification of event).
Unanticipated non-fatal and non-life-threatening adverse events that occur in on-
study participants and that are considered due to or possibly due to the 
investigational agent, will be reported to the FDA by written safety report as soon 
as possible but no later than 15 calendar days of the notification of the occurrence 
of the event. Expected SAEs, even unexpected fatal SAEs, considered by the 
study PI to be not related to the study, will be reported to the FDA in the Annual 
Review Report along with non-serious AEs. All FDA correspondence and 
reporting will be conducted through the St. Jude Office of Regulatory Affairs.
Copies of the correspondence to the St Jude IRB, including SAE reports, are 
provided to the St Jude Regulatory Affairs office by the St. Jude study team. 
FDA-related correspondence and reporting will be conducted through the 
Regulatory Affairs office.
10.4 Emergency Unblinding 
N/A
11.0 DATA COLLECTION, STUDY MONITORING, AND   
CONFIDENTIALITY
11.1 Data Collection 
St. Jude Clinical Research Associates or the site Study Coordinator will be 
responsible for data collection. Data from the participant’s record will be entered 
directly into a secure study-specific database.  Instructions for data entry are outlined 
in the database.
Data management will be supervised by the Principal Investigator (PI). Protocol-
specific data and adverse events will be recorded in the electronic database within 2 
weeks following the completion of a study visit (either by phone or on campus). All 
questions will be directed to the PI or designee and will be reviewed at regularly 
scheduled working meetings.
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Regular summaries of toxicity and protocol events will be generated for the PI and 
the Department of Biostatistics to review.
The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each 
event for all subjects enrolled on the trial. All SAEs and protocol-defined events of 
special interest will be reported in an expedited fashion. Participants who have an 
ongoing study treatment−related adverse event upon study completion or at 
discontinuation from the study will be followed until the event has resolved to 
baseline grade, the event is assessed by the investigator as stable, new treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or until it has 
been determined that study treatment or participation is not the cause of the AE. All 
participants who receive any amount of study drug will be evaluable for toxicity. At 
each visit, a brief focused history will be obtained and any indication of treatment- 
related toxicity will be evaluated by appropriate examination and/or 
laboratory/radiographic studies. All events occurring during the conduct of a protocol 
and meeting the definition of a SAE must be reported to the IRB in accordance with 
their policies.
11.2 Study Monitoring
Moderate Risk 
An application for IND exemption is being prepared for submission for the use of 
metformin in this study. In the event that the IND exemption is granted, monitoring of 
this protocol is considered to be Moderate Risk. However, if an IND exemption is not 
granted and this becomes a St. Jude sponsored, investigator-initiated IND pilot study, 
monitoring for this protocol would be considered in the High Risk 3 category. The 
risks of the products are still being explored, although the study drug has been widely 
utilized with an acceptable safety profile in diabetic and prediabetic adults, including 
those with comorbid conditions. Both monitoring for Moderate Risk and HR-3 
studies are included below as the IND exemption has not yet been granted. 
If an IND exemption is obtained, this study is considered moderate risk for 
monitoring purposes. Protocol and regulatory compliance, including essential 
regulatory documentation, will be assessed as well as the accuracy and completeness 
of data points related to the primary study objective semi- annually. If the study 
design has strata, accrual will be tracked continuously.   The first two enrollees and 
then 10 % of participants will be monitored semi-annually.  
The PI and study team are responsible for protocol and regulatory compliance, and 
for data accuracy and completeness.  The study team will meet at appropriate 
intervals to review case histories or quality summaries on participants and retain 
copies of the minutes which are signed by the PI.
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Clinical Trials Operations (CTO) will verify informed consent documentation of and 
eligibility status for 50% of  trial participants within 5 days of enrollment. 
Additionally, A quality review will be performed by CTO personnel on 100% of St. 
Jude participants’ informed consent forms to assure completeness.
Overall study conduct, compliance with primary objectives, age of majority 
consenting, safety assessments and reporting, and the timeliness and accuracy of 
database entries are monitored routinely.  Study documents routinely monitored on 
selected participants include medical records, database entries, study worksheets, and 
case report forms.  Study documents are monitored for participant status, 
demographics, staging, subgroup assignment, treatments, investigational drug 
accountability, evaluations, responses, participant protocol status, off-study and off-
therapy criteria, and for all other specifics as detailed in a separate study-specific 
monitoring plan. The study-specific monitoring plan may be revised over time, to 
adapt monitoring frequency and/ or intensity to a changing environment when 
appropriate (for example:  new safety signals; positive history of compliance; all 
participants are in long term follow-up; or the enrollment period has ended).
The recording and reporting of Adverse Events, Serious Adverse Events (SAEs), and 
Unanticipated Problems (UPs) to include type, grade, attribution, duration, timeliness 
and appropriateness will be reviewed by the Monitor/ CRM. The CRM will generate 
a formal report which is shared with the Principal Investigator (PI), study team and 
the Internal Monitoring Committee (IMC).
Continuing reviews by the Institutional Review Board (IRB) and Scientific Review 
Committee (CT-SRC) will occur at least annually.  In addition, unanticipated 
problems are reviewed in a timely manner by the IRB.
High Risk 3 (HR-3) 
If an IND is required and obtained, this study is considered high risk (HR-3) for 
monitoring purposes. Protocol and regulatory compliance, including essential 
regulatory documentation, will be assessed as well as the accuracy and completeness 
of all data points relating to the primary and secondary objectives semi-annually.  If 
the study design has strata, accrual will be tracked continuously.  The first two 
enrollees will be monitored and 15 % of the study enrollees thereafter, semi-
annually.
The PI and study team are responsible for protocol and regulatory compliance, and 
for data accuracy and completeness.  The study team will meet at appropriate 
intervals to review case histories or quality summaries on participants and retain 
copies of the minutes which are signed by the PI.
Clinical Trials Operations (CTO) will verify informed consent documentation and 
eligibility status on 100% of St. Jude participants within 5 working days of enrollment 
completion.
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The Clinical Research Monitor (CRM) will perform a quality verification of select St. 
Jude participants during routine monitoring intervals (every 6 months). Overall study 
conduct, compliance with primary and secondary objectives, age of majority 
consenting, safety assessments and reporting, and the timeliness and accuracy of 
database entries are monitored routinely.
Study documents routinely monitored on selected participants include medical 
records, database entries, study worksheets, and case report forms.  Study documents 
are monitored for participant status, demographics, staging, subgroup assignment, 
treatments, investigational drug accountability, evaluations, responses, participant 
protocol status, off-study and off-therapy criteria, and for all other specifics as detailed 
in a separate study-specific monitoring plan. The study-specific monitoring plan may 
be revised over time, to adapt monitoring frequency and/ or intensity to a changing 
environment when appropriate (for example: new safety signals; positive history of 
compliance; all participants are in long term follow-up; or the enrollment period has 
ended).
The recording and reporting of Adverse Events, Serious Adverse Events (SAEs), and 
Unanticipated Problems (UPs) to include type, grade, attribution, duration, timeliness 
and appropriateness will be reviewed by the Monitor/ CRM. The CRM will generate 
a formal report which is shared with the Principal Investigator (PI), study team and 
the Internal Monitoring Committee (IMC).
Continuing reviews by the Institutional Review Board (IRB) and Clinical Trials- 
Scientific Review Committee (CT-SRC) will occur at least annually.  In addition, 
unanticipated problems are reviewed in a timely manner by the IRB.
11.3 Confidentiality
SJLife study numbers will be used in place of an identifier such as a medical record 
number. No research participant names will be recorded on the data collection forms. 
Information for this study will be collected during the evaluation at SJCRH, using 
physical measurements, lab assessments and standardized questionnaires in addition 
to by telephone or web-meeting encounters led by the study team. Information on 
cancer treatment has already been obtained from medical records abstracted as part of 
the SJLIFE study and will be linked to these new databases after participants have 
provided informed consent for this protocol. Data from the medical record abstraction, 
the physical and laboratory measurements and the questionnaires will be recorded by 
study personnel by participant identification number on optical recognition forms and 
downloaded daily into a dedicated study computer. All files will be password 
protected. Identifying information will be stored separately and the files linked by 
identification number.    Study related data from participation in the digital lifestyle 
change program will be transferred weekly. Any paper forms will be stored in a 
locked file cabinet. Study personnel will have access to data only on a need to know 
basis. Data will be evaluated without identifiers for safety monitoring, process 
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evaluation and outcomes analysis, and linked to the identifying information only if 
necessary for participant safety.
The medical records of study participants may be reviewed by the St. Jude IRB, FDA, 
clinical research monitors, auditors, etc.
12.0
STATISTICAL CONSIDERATIONS
We will test our primary hypothesis, that a combined pharmacologic and lifestyle 
intervention using metformin extended release and a digitally-delivered, lifestyle change 
intervention program will be feasible and safe by our primary endpoints: adherence and 
the number of CTCAE v5.0 grade 1-4 adverse events. We will test our secondary 
hypothesis that a combined metformin and lifestyle intervention will improve measures 
of glycemic control and insulin resistance in prediabetic survivors by our secondary end 
points: change at week 24 from baseline of glycemic control (FPG and HbA1c) and 
insulin resistance (HOMA-IR using fasting insulin and IGFBP-1 level). In addition, we 
will assess the hypothesis that a combined metformin and lifestyle intervention will 
improve anthropometric measures, physical activity, and quality of life by our 
exploratory end points: change at week 24 from baseline of anthropometric measures, 
physical activity (self-reported and measured through walking speed and accelerometer 
data), cardiovascular risk factors (lipids and blood pressure) and HRQOL. The analyses 
of the secondary and exploratory outcomes will demonstrate preliminary efficacy data to 
move this study forward to a larger randomized trial.
Analytic plan: 
Primary Objective - Establish the feasibility and safety of a combined metformin + 
intensive lifestyle intervention (using a digitally-delivered, lifestyle change program) 
among adult survivors with prediabetes.
Primary endpoints of this trial will be adherence to both the daily metformin 
administration, assessed by telephone-based (Appendix I) or in-person pill counts, and 
the lifestyle intervention, assessed by completion of required core-curriculum, and safety, 
assessed using the Global Rating of Side Effects Burden (Appendix II), which includes 
the Common Terminology Criteria for Adverse Events (CTCAE v5.0) grade. A single-
arm pilot study was chosen as it would establish the necessary safety and feasibility data 
of the combined intervention to then move forward to a larger randomized clinical trial 
of comparative efficacy of the combined intervention vs either metformin or lifestyle 
intervention.
For this study, adult survivors age 18-<45 years with prediabetes will be the target 
population. There are two components to feasibility assessment using combined 
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adherence to metformin and the lifestyle change program. Adherence will be assessed on 
day 14 for metformin titration and then every 4 weeks (weeks 4, 8, 12, 16, 20 and 24. 
Metformin adherence will be monitored using telephone-based pill counts, the protocol 
will be adapted from Kalichman et al.39 Adherence to the lifestyle change intervention 
will be assessed by completion of at least 60% of the educational lifestyle curriculum 
over the 24 week study period. Completion of each piece of educational content will be 
recorded within the digitally-delivered platform for each participant and then this data 
will be securely transferred and entered in the study specific database. A survivor would 
be considered to have met the combined adherence criteria if s/he takes 80% of the 
recommended drug and completes at least 60% of the digitally-delivered lifestyle change 
core curriculum. 
Sample size and power: Because metformin has been demonstrated to be safe and well-
tolerated in multiple population of adults with chronic health conditions,17,20 as well as 
in non-obese diabetic populations,54  and lifestyle change is the current recommended 
first line management for adults in the general population with prediabetes,55 we do not 
anticipate significant safety concerns. Therefore, the sample size justification is based on 
the combined adherence to metformin and the intensive lifestyle change curriculum. 
The study would be considered feasible if at least 60% of the survivors are adherent. 
However, adherence rates of less than 40% would be considered unacceptable. Note that, 
since survivors need to meet two criteria to be adherent, a slightly lower feasibility rate 
is acceptable. 
Simon's two-stage design (1988) is used to test the null hypothesis 
vs. 
H0:π =< 0.4  
H1
. This design has a type I error rate of 
 and power of 80%. 
:π ≥0.6
α = 0.05
In the first stage, 21 survivors will be accrued. If there are 9 or fewer among these 21 
who achieve at least 80% adherence to metformin and complete 60% of digital 
curriculum modules, the study will be stopped. Otherwise, 20 additional survivors will 
be accrued for a total of 41. The null hypothesis will be rejected if 22 or more survivors 
achieve at least 80% adherence to metformin and complete 60% of lifestyle change 
program among the total 41 survivors. This design yields a type I error rate of α=0.05 
and power of more than 80%.
Objective safety measures: The number of grade 1-4 toxicities (CTCAE v 5.0) will be 
tabulated. Any common gastrointestinal toxicity including diarrhea, nausea, flatulence, 
or bloating grade ≥3 or any other toxicity grade ≥2 will be considered abnormal. 
Discontinuation of metformin due to these side effects is rare and it is expected that less 
than 5% of the survivors will experience abnormal toxicity requiring medication 
discontinuation. Therefore, a rate of discontinuation >10% would be considered 
unacceptable. If among the first 20 survivors more than 5, and among 41 survivors, more 
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than 8 of them discontinue metformin due to toxicity, then the trial will be stopped. These 
stopping rules are based on the exact 95% lower confidence bounds for the probability 
of failure. 
Secondary and Exploratory Objectives:
Assess preliminary evidence for efficacy of the combined metformin + intensive 
lifestyle intervention on glycemic control and insulin resistance. Glycemic control will 
be measured by fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) and 
insulin resistance measured by the homeostatic model assessment (HOMA-IR: fasting 
insulin (microU/L) x FPG (nmol/L)/22.5) and IGFBP-1.
Detectable difference of mean for paired data:
Data from the landmark Diabetes Prevention Program (DPP) study in the general adult 
population demonstrated that at 6 months after randomization, the change in fasting 
plasma glucose in the placebo group was <1mg/dL increase while that in the metformin 
and lifestyle groups were 4-5 mg/dL decrease. While the change in HbA1c from 
baseline was approximately a 0.06% increase in the placebo group and a 0.04-0.08% 
decrease in the metformin and lifestyle groups.12 Based on preliminary date from 
prediabetic adults in the SJLIFE cohort, the mean and standard deviation of HbA1c%, 
FPG in mg/dL and HOMA-IR are known (Table 6). Based on sample size 41 with 80% 
power, standard deviation of the difference and additional assumptions of  i) variability 
of  hemoglobin A1c, fasting plasma glucose and HOMA-IR considered to be the same 
at the baseline and the 6-month follow-up at the end-of-study visit and  ii) there is at 
least a 0.5 correlation between values at the baseline and the follow-up, this study 
would be powered to detect an approximately 4 mg/dL change in FPG, 0.2% change in 
HbA1c and 2 unit change in HOMA-IR. Detectable differences for key secondary 
outcomes are provided in the Table 6. 
Table 8. Detectable differences for glycemia and insulin resistance
 
Mean (SD) at baseline
Detectable difference of mean 
for paired data
HbA1c, %
5.59 (0.34)
0.15
Fasting plasma glucose, mg/dL
101.74 (8.62)
3.92
HOMA-IR
4.92 (4.41)
2.00
The measurements of glycemic control and insulin resistance will be collected at 
baseline, week 12 and week 24. The primary focus will be the change in these measures 
from baseline to study end (week 24). The measurements at baseline and 24 weeks are 
denoted by Y1 and Y2, respectively, then Di = (Y2i – Y1i) for i=1,2,…,n denotes the 
differences for n survivors. We will test whether the mean difference is different from 0 
(i.e. test the hypothesis H0:μD=0 vs. H1:μD0), where D denotes the population mean of 
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the differences. For each outcome measure (FPG, HbA1c, HOMA-IR, IGFBP-1), we will 
obtain the difference Di for i=1,2, …,41 and then we will assess if the mean differences 
are significantly different from 0 using a one-sample t-test. We will also conduct analyses 
to determine whether the effect of the combined intervention is noticeable at week 12. In 
a similar manner, as discussed above, we will take the differences between week 12 and 
baseline observations. 
In addition, since we will have observations at three time points, we will also use a 
Generalized Estimating Equations (GEE) approach to assess the pattern of change over 
time using PROC GENMOD in SAS 9.4 and using compound symmetry as the working 
covariance structure to account for correlation among repeated observations.
The exploratory outcomes of weight, body fat %, cholesterol and triglyceride measures, 
systolic blood pressure (SBP), diastolic blood pressure (DBP), physical activity 
(NHANES-PAQ score, measured activity by accelerometer data and walking speed) 
and HRQOL will also be assessed at baseline, week 12 and week 24 and, in the case of 
frailty measures (walking speed, hand grip strength, lean muscle mass, exhaustion and 
low activity) at baseline and week 24. Similar to the secondary outcomes above, the 
mean difference from baseline to week 24 (and then week 12) in the outcome measures 
will be assessed using a one sample t-test to determine if the mean difference for each 
outcome is significantly different from 0. 
12.1 Anticipated Completion Dates
Anticipated Primary Completion Date: December 2022 
Anticipated Study Completion Date December 2022  
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12.2 Summary of Primary and Secondary Objectives
Objective 
#
Objective 
Type
Analysis 
#
Resp 
Party
Stat
Safety
Analysis Measure
Analysis Title 
Data 
Collection 
Time Frame
# of 
Participants
1.0
P
1
 
SBD
DK, 
SMS
N
Combined metformin and lifestyle 
adherence, proportion of metformin 
pills taken and proportion of lifestyle 
curriculum completed
Assess adherence to combined 
metformin and lifestyle change 
intervention
Weeks 2, 4, 8, 
12, 16, 20, 
and 24
41
1.0
P
2
SBD
DK, 
SMS
Y
Safety of combined intervention, 
CTCAE graded adverse events
Assess safety of combined 
intervention 
41
2.0
S
1
SBD
DK, 
SMS
N
Glycemic control (FPG, HbA1c), 
change in FPG, HbA1c from 
baseline
Effect of intervention on 
glycemic control
Baseline, 
weeks 12, 24
41
2.0
S
2
SBD
DK, 
SMS
N
Insulin resistance (HOMA-IR, IGF-
BP1), change in HOMA-IR, IGF-
BP1 from baseline
Effect of intervention on insulin 
resistance
Baseline, 
weeks 12, 24
41
3.0
S
1
SBD, 
KN
DK, 
SMS
N
Anthropometrics, change in weight, 
BMI, body fat % and waist-to-hip 
ratio from baseline
Effect of intervention on weight 
and other anthropometric 
measures
Baseline, 
weeks 12, 24
41
3.0
S
2
SBD, 
KN
DK, 
SMS
N
Physical activity, change in self-
reported and accelerometer measures 
of physical activity from baseline
Effect of intervention on 
physical activity
Baseline, 
weeks 12, 24
41
3.0
S
3
SBD
DK, 
SMS
N
Blood pressure, change in SBP and 
DBP from baseline
Effect of intervention on blood 
pressure
Baseline, 
weeks 12, 24
41
3.0
S
4
SBD
DK, 
SMS
N
Lipid profile, change in lipid profile 
from baseline
Effect of intervention on lipid 
profile
Baseline, 
weeks 12, 24
41
3.0
S
5
SBD, 
KN
DK, 
SMS
N
Frailty, change in frailty measures 
from baseline
Effect of intervention on 
measures of frailty
Baseline, 
week 24
41
3.0
S
6
SBD
DK, 
SMS
N
Health-related quality of life, change 
in HRQOL by survey from baseline
Effect of intervention on 
HRQOL
Baseline, 
weeks 12, 24
41
3.0
S
7
SBD
DK, 
SMS
N
Future diabetes (GPG, HbA1c), 
proportion of participants who 
develop diabetes
Effect of intervention on 
diabetes long-term
All return 
SJLIFE core 
visits through 
6 years
41
3.0
S
8
SBD, 
TB
DK, 
SMS
N
Participation in lifestyle program and 
barriers to participation and 
metformin adherence
Assess lifestyle program 
participation (logging, days 
accessed, etc) and relationship 
to efficacy, assess barriers to 
adherence and participation
Baseline, 
week 24
41
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12.3   Stopping Rules
This ad hoc stopping rule is designed based on unacceptable toxicity of metformin. A 
rate of discontinuation of metformin >10% would be considered unacceptable. If 
among first 20 survivors more than 5, and among 41 survivors, more than 8 of them 
discontinue (stop taking for 7 or more days without intent to resume) metformin due to 
toxicity, then the trial will be stopped. These stopping rules are based on the exact 95% 
lower confidence bounds for the probability of failure. 
13.0 OBTAINING INFORMED CONSENT
13.1 Informed Consent Prior to Research Interventions 
Informed consent will be obtained prior to all study related observations, 
evaluations and interventions.
13.2 Consent at Age of Majority
N/A; Participants must be 18 years or older to enroll on the study.
13.3 Consent When English is Not the Primary Language
Due to current limitations of the digital lifestyle change platform, participants who 
are unable to participate in English will not be eligible for this study.
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compared to immediate release formula on glycemic control and glycemic variability in 
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Crowley MJ, Diamantidis CJ, McDuffie JR, et al: Clinical outcomes of metformin 
use in populations with chronic kidney disease, congestive heart failure, or chronic liver 
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Moin T, Schmittdiel JA, Flory JH, et al: Review of metformin use for type 2 
diabetes prevention. Am J Prev Med 55:565-574, 2018
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Jacobs S, Radnitz C, Hildebrandt T: Adherence as a predictor of weight loss in a 
commonly used smartphone application. Obes Res Clin Pract 11:206-214, 2017
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using a smartphone application in those with overweight and obesity. Sci Rep 6:34563, 
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Toro-Ramos T, Lee DH, Kim Y, et al: Effectiveness of a Smartphone Application 
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29.
Hamman RF, Wing RR, Edelstein SL, et al: Effect of weight loss with lifestyle 
intervention on risk of diabetes. Diabetes Care 29:2102-7, 2006
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Sepah SC, Jiang L, Peters AL: Translating the Diabetes Prevention Program into 
an Online Social Network: Validation against CDC Standards. The Diabetes Educator 
40:435-443, 2014
31.
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Program (Transform) for Adults With Prediabetes: Secondary Analysis. JMIR diabetes 
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phenotype. J Gerontol A Biol Sci Med Sci 56:M146-56, 2001
34.
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35.
Campbell JM, Bellman SM, Stephenson MD, et al: Metformin reduces all-cause 
mortality and diseases of ageing independent of its effect on diabetes control: A systematic 
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36.
Wang CP, Lorenzo C, Habib SL, et al: Differential effects of metformin on age 
related comorbidities in older men with type 2 diabetes. J Diabetes Complications 31:679-
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37.
Espinoza SE, Jiwani R, Wang J, et al: Review of Interventions for the Frailty 
Syndrome and the Role of Metformin as a Potential Pharmacologic Agent for Frailty 
Prevention. Clin Ther 41:376-386, 2019
38.
Hudson MM, Ness KK, Nolan VG, et al: Prospective medical assessment of adults 
surviving childhood cancer: study design, cohort characteristics, and feasibility of the St. 
Jude Lifetime Cohort study. Pediatr Blood Cancer 56:825-36, 2011
39.
Kalichman SC, Amaral CM, Cherry C, et al: Monitoring medication adherence by 
unannounced pill counts conducted by telephone: reliability and criterion-related validity. 
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Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes 
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Jackson AS, Pollock ML, Ward A: Generalized equations for predicting body 
density of women. Med Sci Sports Exerc 12:175-81, 1980
43.
Karlage RE, Wilson CL, Zhang N, et al: Validity of anthropometric measurements 
for characterizing obesity among adult survivors of childhood cancer: A report from the St. 
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National Health and Nutrition Examination Survey. 2007-2008 Data Documentation, 
Codebook, and Frequencies. Physical Activity (PAQ_E), 2009
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Mathiowetz V, Kashman N, Volland G, et al: Grip and pinch strength: normative 
data for adults. Arch Phys Med Rehabil 66:69-74, 1985
46.
Mathiowetz V, Weber K, Volland G, et al: Reliability and validity of grip and 
pinch strength evaluations. J Hand Surg Am 9:222-6, 1984
47.
Ware JE, Jr., Sherbourne CD: The MOS 36-item short-form health survey (SF-36). 
I. Conceptual framework and item selection. Med Care 30:473-83, 1992
48.
Kelly TL, Wilson KE, Heymsfield SB: Dual energy X-Ray absorptiometry body 
composition reference values from NHANES. PLoS One 4:e7038, 2009
49.
Eleftheriadou I, Tsioufis C, Tsiachris D, et al: Choice of antihypertensive 
treatment in subjects with pre-diabetes. Is there a dream after the navigator. Curr Vasc 
Pharmacol 9:715-22, 2011
50.
Pakkir Maideen NM, Jumale A, Balasubramaniam R: Drug Interactions of 
Metformin Involving Drug Transporter Proteins. Advanced pharmaceutical bulletin 7:501-
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51.
Triplitt C: Drug Interactions of Medications Commonly Used in Diabetes. 
Diabetes Spectrum 19:202-211, 2006
52.
Zaidi FH, Kinnear PE: Acetazolamide, alternate carbonic anhydrase inhibitors and 
hypoglycaemic agents: comparing enzymatic with diuresis induced metabolic acidosis 
following intraocular surgery in diabetes. The British journal of ophthalmology 88:714-
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53.
Ismail IS: The Role of Carbonic Anhydrase in Hepatic Glucose Production. Curr 
Diabetes Rev 14:108-112, 2018
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54.
Ong CR, Molyneaux LM, Constantino MI, et al: Long-Term Efficacy of 
Metformin Therapy in Nonobese Individuals With Type 2 Diabetes. Diabetes Care 
29:2361-2364, 2006
55.
American Diabetes A: Prevention or Delay of Type 2 Diabetes: Standards of 
Medical Care in Diabetes-2019. Diabetes Care 42:S29-S33, 2019
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APPENDIX I: MATRIX FOR METFORMIN PILL COUNT
Drug and 
Dose
Number 
of doses 
per day
Pills 
taken 
per 
dose
Previous 
number 
of pills 
counted
Pills 
dispensed 
since 
previous 
count
Total 
pills 
counted
Stop 
date
Start 
date
Metformin ER
500 mg
1
Metformin ER
500 mg
1
Metformin ER
500 mg
1
Metformin ER
500 mg
1
Metformin ER
500 mg
1
Metformin ER
500 mg
1
Metformin ER
500 mg
1
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APPENDIX II:
Adverse Event Monitoring Log
Global Rating of Side Effects Burden
MRN:  ___________  Name: ____________________     Date:  __________Timepoint: _____________
Completed By: _________________________                                             
Answer Yes or No if you have experienced any of these symptoms since the last time we spoke.  We last 
spoke on (insert day) and it has been about (insert how many days since last symptom questionnaire). 
Answer “Yes” only if a symptom developed after starting the study drug or worsened while on the study 
drug.   For any side effect marked “yes”, complete the side effect detail on later pages. 
Symptom
Present - Yes or 
No
Drug dose (mg)
CTCAE Score (1-
5)
Muscle pain
Y___   No___
Leg cramp
Y___   No___
Muscle weakness
Y___   No___
Joint pain
Y___   No___
Headache
Y___   No___
Abdominal pain
Y___   No___
Diarrhea
Y___   No___
Nausea
Y___   No___
Other stomach problems
Y___   No___
Attention/concentration problem
Y___   No___
Memory problem
Y___   No___
Sleep change/problem
Y___   No___
Depression
Y___   No___
Fatigue/Lack of energy
Y___   No___
Dizziness
Y___   No___
Irritability
Y___   No___
Change in sexual function
Y___   No___
Rash / skin problems
Y___   No___
Extremity swelling
Y___   No___
Numbness/tingling/burning
Y___   No___
Urinary dysfunction
Y___   No___
Any other
Y___ No___
List other:
Y___ No___
Y___ No___
Y___ No___
Y___ No___
Y___ No___
Y___ No___
Physician Reviewed by: _________________________    Review Date: __________________________
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Collect details for all reported symptoms.  Only collect side effects that occurred since the last contact with the 
participant.  Check all relevant boxes.
Symptom 1:_________________________________
Details:
a.
Choose the response that best describes the frequency of the side effect of the metformin you have taken in 
the past (time interval since last monitoring) weeks.  Do not rate side effects if you believe they are due to 
treatments that you are taking for other medical conditions.
No side 
effects
10% of the 
time
25%
50% of the 
time
75%
90%
All the time
b.
Choose the response that best describes the intensity of the side effects that you believe are due to the 
metformin you have taken within the last (study interval) weeks.  Rate the intensity of the side effect:
No side effect
Trivial
Mild
Moderate
Marked
Severe
Intolerable
c.
Choose the response that best describes the degree to which this side effect has interfered with your day to 
day functions.
No
impairment
Minimal
impairment
Mild 
impairment
Moderate 
impairment
Marked 
impairment
Severe 
impairment
Unable to 
function due 
to side 
effects
d.
Did you receive treatment for the side effect, details: ___________________________________
e.
Did you go to the doctor or hospital for the side effect, details:____________________________
f.
Is this side effect related to treatment:
Definitely 
Related
Possibly 
Related
Not
Related
g.
Is this a serious adverse event?  Yes                   No
h.
Is this expected or unexpected?   Expected    Unexpected
CTCAE Grade: ______________________
Symptom 2:_________________________________
Details:
a.
Choose the response that best describes the frequency of the side effect of the metformin you have taken in 
the past (time interval since last monitoring) weeks.  Do not rate side effects if you believe they are due to 
treatments that you are taking for other medical conditions.
No side 
effects
10% of the 
time
25%
50% of the 
time
75%
90%
All the time
b.
Choose the response that best describes the intensity of the side effects that you believe are due to the 
metformin you have taken within the last (study interval) weeks.  Rate the intensity of the side effect:
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No side effect
Trivial
Mild
Moderate
Marked
Severe
Intolerable
c.
Choose the response that best describes the degree to which this side effect has interfered with your day to 
day functions.
No
impairment
Minimal
impairment
Mild 
impairment
Moderate 
impairment
Marked 
impairment
Severe 
impairment
Unable to 
function due 
to side 
effects
d.
Did you receive treatment for the side effect, details: ___________________________________
e.
Did you go to the doctor or hospital for the side effect, details:____________________________
f.
Is this side effect related to treatment:
Definitely 
Related
Possibly 
Related
Not
Related
g.
Is this a serious adverse event?  Yes                   No
h.
Is this expected or unexpected?   Expected    Unexpected
CTCAE Grade: ______________________
Symptom 3:_________________________________
Details:
a.
Choose the response that best describes the frequency of the side effect of the metformin you have taken in 
the past (time interval since last monitoring) weeks.  Do not rate side effects if you believe they are due to 
treatments that you are taking for other medical conditions.
No side 
effects
10% of the 
time
25%
50% of the 
time
75%
90%
All the time
b.
Choose the response that best describes the intensity of the side effects that you believe are due to the 
metformin you have taken within the last (study interval) weeks.  Rate the intensity of the side effect:
No side effect
Trivial
Mild
Moderate
Marked
Severe
Intolerable
c.
Choose the response that best describes the degree to which this side effect has interfered with your day to 
day functions.
No
impairment
Minimal
impairment
Mild 
impairment
Moderate 
impairment
Marked 
impairment
Severe 
impairment
Unable to 
function due 
to side 
effects
d.
Did you receive treatment for the side effect, details: ___________________________________
e.
Did you go to the doctor or hospital for the side effect, details:____________________________
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IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
f.
Is this side effect related to treatment:
Definitely 
Related
Possibly 
Related
Not
Related
g.
Is this a serious adverse event?  Yes                   No
h.
Is this expected or unexpected?   Expected    Unexpected
CTCAE Grade: ______________________
Symptom 4:_________________________________
Details:
a.
Choose the response that best describes the frequency of the side effect of the metformin you have taken in 
the past (time interval since last monitoring) weeks.  Do not rate side effects if you believe they are due to 
treatments that you are taking for other medical conditions.
No side 
effects
10% of the 
time
25%
50% of the 
time
75%
90%
All the time
b.
Choose the response that best describes the intensity of the side effects that you believe are due to the 
metformin you have taken within the last (study interval) weeks.  Rate the intensity of the side effect:
No side effect
Trivial
Mild
Moderate
Marked
Severe
Intolerable
c.
Choose the response that best describes the degree to which this side effect has interfered with your day to 
day functions.
No
impairment
Minimal
impairment
Mild 
impairment
Moderate 
impairment
Marked 
impairment
Severe 
impairment
Unable to 
function due 
to side 
effects
d.
Did you receive treatment for the side effect, details: ___________________________________
e.
Did you go to the doctor or hospital for the side effect, details:____________________________
f.
Is this side effect related to treatment:
Definitely 
Related
Possibly 
Related
Not
Related
g.
Is this a serious adverse event?  Yes                   No
h.
Is this expected or unexpected?   Expected    Unexpected
CTCAE Grade: ______________________
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
APPENDIX III: SCHEDULE OF RESEARCH EVALUATIONS
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS
STUDIES TO BE 
OBTAINED
Pre-
Study*
Week 
2
+/- 4 
days
Week 
4
+/- 7 
days
Week 
8
+/- 7 
days
Week 
12
+/- 7 
days
Week 
16
+/- 7 
days
Week 
20
+/- 7 
days
Week 
24
+/- 7 
days
History including 
medications
X
X
X
Physical Exam (Ht, 
Wt, VS)
X
X
X
Anthropometrics: body 
fat %, abdominal 
circumference, waist-
to-hip ratio
X
X
X
Fasting blood work: 
CBC, CMP, HbA1c, 
insulin, IGFBP-1, 
lactate, cystatin C, 
lipid panel
X
X
X
Walking speed and 
hand grip strength
X
X
Accelerometer (mailed 
prior to visit)
X
X
X
*Pregnancy Test
X
X
X
HRQOL (SF-36) 
X
X
X
NHANES-PAQ
X
X
X
Medication Adherence 
Assessment
X
X
X
X
X
X
X
Lifestyle Change 
Adherence Log
X
X
X
X
X
X
X
Symptom Log 
including 
CTCAE/Adverse 
Events
X
X
X
X
X
X
X
X
Motivation to change
X
Barriers to medication 
adherence and lifestyle 
change participation
X
* Pre-study evaluations may be completed up to 30 days prior to enrollment.
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
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IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
APPENDIX IV:DAST AND AUDIT QUESTIONNAIRES
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
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IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

PREDM
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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

PREDM
Page 62
Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

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Page 63
Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
APPENDIX V:
    Motivation to Change
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
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IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
APPENDIX VI:BARRIERS TO MEDICATION ADHERENCE
Please answer the following questions based on your feelings about the study drug over the past 
week. 
Often
Sometimes
Never
1.
I forget to take my medication
2.
I am often too busy to take my medication
3.
My medication is helping me
4.
I dislike my current medication
5
Friends and family believe that my current 
medication is good for me
6.
Taking medication is unpleasant
7.
Taking my medication interferes with my 
planned meal times
8.
I feel that the good things about taking 
medication outweigh the bad
Questions 1, 3, 4, 5, 6 and 8 were taken from the Personal Evaluations of Transitions in Treatment (PETiT) 
questionnaire developed by Voruganti and Awad in 2002.
Please answer the following questions based on your feelings about changing diet and physical 
activity and the digital lifestyle change program, referred to as “the app”. 
Strongly 
Disagree
Disagree
Neutral
Agree
Strongly 
Agree
1.
Healthy food options cost too much 
2.
It is too hard or time consuming to eat 
healthy
3.
I don’t have time for physical activity 
4.
I don’t have access to exercise equipment 
or safe, outdoor spaces for walking
5
Persistent side effects of my cancer 
treatment (neuropathy, pain, etc) limit my 
physical activity
6.
I have more motivation to make healthy 
changes because I am a cancer survivor
7.
I often (3 or more days per week) forgot 
to read the daily lessons in the app
8.
It was too time consuming to log meals
9.
It was too complicated to log meals
10.
It was too time consuming to log physical 
activity
11.
It was too complicated to log physical 
activity
12.
I often (3 or more days per week) forgot 
to log meals
13.
I often (3 or more days per week) forgot 
to log physical activity
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
14.
I forgot to log my weight
15.
I don’t have access to a scale
16.
The tools in the app didn’t work for me
17.
I liked having a health coach in the app
18.
I liked having a peer group in the app
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

PREDM
Page 66
Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
APPENDIX VII:DISALLOWED DRUGS ON STUDY
Anti-hyperglycemic or diabetes medications
Insulins
(not allowed on study):
Regular insulin
Insulin aspart
Insulin Glulisine
Insulin lispro
Insulin isophane
Insulin degludec
Insulin detemir
Insulin glargine
Amylinomimetic drug
(not allowed on study):
Pramlintide
Alpha-glucosidase inhibitors
(not allowed on study):
Acarbose
Miglitol
Dopamine agonist
(not allowed on study):
Bromocriptine
Dipeptidyl peptidase-4 (DPP-4) inhibitors
(not allowed on study):
Alogliptin
Linagliptin
Saxagliptin
Sitagliptin
Glucagon-like peptide-1 (GLP-1) receptor 
agonists
(not allowed on study):
Albiglutide
Dulaglutide
Exenatide
Exenatide extended-release
Liraglutide
Semaglutide
Meglitinides
(not allowed on study):
Nateglinide
Repaglinide
Sodium-glucose transporter (SGLT) 2 
inhibitors
(not allowed on study):
Dapagliflozin
Canafliglozin
Empagliflozin
Ertugliflozin
Sulfonylureas
(not allowed on study):
Glimepiride
Gliclazide
Glipizide
Glyburide
Chlorpropamide
Tolazamide
Tolbutamide
Thiazolidinediones
(not allowed on study):
Rosiglitazone
Pioglitazone
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
Monitored/Recorded Drugs on Study
Drugs Affecting Glycemic Control
Thiazide diuretics
(will be tracked on study):
Chlorothiazide
Chlorthalidone
Hydrochlorothiazide
Indapamide
Metolazone
Calcium channel blockers
(will be tracked on study):
Amlodipine
Diltiazem
Felodipine
Isradipine
Nicardipine
Nifedipine
Nisoldipine
Verapamil
Beta-blockers
(will be tracked on study):
Acebutolol
Atenolol
Bisoprolol
Carvedilol
Esmolol
Labetalol
Metoprolol
Nadolol
Nebivolol
Penbutolol
Pindolol
Propranolol
Sotalol
Timolol
Proton pump inhibitors (PPIs)
(will be tracked on study):
Esomeprazole
Dexlansoprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
Oral corticosteroids
(will be tracked on study):
Cortisone
Dexamethasone
Hydrocortisone
Methylprednisone
Methylprednisolone
Prednisone
Prednisolone
Thyroid replacement hormone
(will be tracked on study):
Levothyroxine sodium
Liothyronine sodium
Liotrix
Oral estrogens and oral contraceptives
(will be tracked on study):
Estrogen and/or progesterone containing 
oral medications
HMG-coA reductase inhibitors
(will be tracked on study):
Atorvastatin
Fluvastatin
Lovastatin
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
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IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020

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Initial version, dated: 04-10-20                                                                            IRB approval date: 00-00-00 
Protocol document date: 10-12-2020
Drugs with Potential to Reduce Metformin 
Clearance
Cationic drugs eliminated by renal tubular 
secretion (OCT-2 and MATE inhibitors)
(will be tracked on study and consultation 
with pharmacy regarding need to dose 
adjustment if eGFR <90 ml/min/m2):
Amiloride
Atenolol
Cephalexin
Cimetidine
Digoxin
Dolutegravir
Erlotinib
Gefitinib
Imatinib
Morphine
Nilotinib
Procainamide
Proton pump inhibitors (PPIs)
Pyrimethamine
Quinidine
Quinine
Ranitidine
Ranolazine
Triamterene
Trimethoprim
Vancomycin
Vandetanib
Other Drugs with Theoretical Increase in 
Risk for Lactic Acidosis
Carbonic Anhydrase Inhibitors
(will be tracked on study):
Topiramate
Zonisamide
Acetazolamide
Dichlorphenamide
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IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020
St. Jude Children's Research Hospital
IRB NUMBER: 20-0550
IRB APPROVAL DATE: 11/10/2020