Conditions: Breast Cancer Prostate Cancer Lung Cancer Colon Cancer Melanoma of Skin Endometrial Cancer Liver Cancer Pancreatic Cancer Rectal Cancer Kidney Cancer Other Solid Malignant Tumors
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 121
Healthy volunteers: no

Brief summary:
This is a prospective, single-center randomized trial with three arms, and an allocation ratio of 1:1:1. The study design is an efficacy study to evaluate the effect of metformin and coach-directed behavioral weight loss versus self-directed weight loss on insulin-like growth factor (IGF)-1 and IGF-1 to THE IGFBP-III ratio blood levels after 6 and 12 months of intervention. The coach-directed Behavioral Weight Loss arm is a web-based remote delivery and communication system that promotes healthy behavioral changes. The Metformin arm is a pharmaceutical intervention of oral metformin. This is a secondary prevention study for men and women who have survived solid malignant tumors

Detailed description:

Arms:
arm 1: In this group, the study staff will meet with you once at the beginning of the study to give you written information about weight management. arm 2: The Remote Lifestyle Coaching intervention is based on the Call Center Directed intervention to help you loss weight arm 3: This group will be given the study drug called Metformin. Metformin comes in tablet form that you take with meals

Interventions: intervention 1: Metformin intervention 2: Coach Directed Behavioral Weight Loss intervention 3: Self-control weight loss
Intervention descriptions: intervention 1: Participants will receive metformin, an oral medication for type 2 diabetes.Participants randomized to the metformin intervention will receive metformin up to 2,000 mg per day.Dosing can be flexible, two or three times per day with meals as tolerated for 12 months. intervention 2: Behavioral-based telephonic coaching with web-based support to promote healthy lifestyle and weight loss in overweight and obese adults.The goal of this intervention is to achieve at least 5% weight loss in the first six months of the intervention and maintain these improvements through month twelve by meeting dietary and exercise goals intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
TRIAL IN CANCER SURVIVORS   
   
   
   
1   
   
    
TRIAL OF BEHAVIORAL WEIGHT LOSS AND METFORMIN TREATMENT TO 
LOWER INSULIN GROWTH FACTOR IN CANCER SURVIVORS   
   
Protocol   
Version 1.2   
# J14148   
NCT02431676  
  
Revision date: January 21, 2017   
   


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2   
Table of Contents   
1. 
INTRODUCTION  
............................................................................................................................... 5   
2. 
SPECIFIC AIMS  
................................................................................................................................ 6   
3. 
BACKGROUND AND RATIONALE  
................................................................................................... 7   
3.1 
Epidemiology of Overweight/Obesity among Cancer Survivors  
................................................. 7   
3.2 
Evidence of Association between Overweight/Obesity and Cancer  
........................................... 7   
3.3 
Weight Gain and Weight Loss in Cancer  
................................................................................... 8   
3.4 
Insulin Growth Factor and Adiposity  
........................................................................................... 9   
3.5 
Insulin Growth Factor and Cancer Incidence and Recurrence ................................................. 
10   
3.6 
Metformin and Cancer Risk ...................................................................................................... 
10   
3.7 
Metformin and Weight Loss ...................................................................................................... 
11   
3.8 
Metformin and Insulin Growth Factor ....................................................................................... 
11   
3.9 
Current Public Health Recommendation .................................................................................. 
12   
3.10 
Practicality of Intentional Weight Loss among Cancer Survivors ............................................. 
12   
3.11 
Rationale for a Randomized Clinical Trial of Weight Loss and Metformin on IGF among   
Cancer Survivors .................................................................................................................................  
13   
4. 
OVERVIEW OF TRIAL DESIGN ..................................................................................................... 
14   
5. 
STUDY POPULATION .................................................................................................................... 
14   
5.1 
Inclusion Criteria .......................................................................................................................  
14   
5.2 
Exclusion Criteria .....................................................................................................................  
14   
5.3 
Inclusion of Minorities ............................................................................................................... 
15   


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3   
6. 
RECRUITMENT .............................................................................................................................. 
15   
7. 
RANDOMIZATION AND ASSIGNMENT ......................................................................................... 
16   
8. 
INTERVENTIONS ........................................................................................................................... 
16   
8.1 
Self-Directed Weight Loss .................................................................................................... 
16   
8.2 
Coach-Directed Behavioral Weight Loss .............................................................................. 
17   
8.3 
Metformin Pharmacologic Intervention ................................................................................ 19   
9. 
VISITS AND FOLLOW-UP .............................................................................................................. 
22   
Approach to Data Collection and Visits ...........................................................................................  
22   
Pre-Screening Call ..........................................................................................................................  
22   
Screening Visit .................................................................................................................................  
22   
Baseline Visit ...................................................................................................................................  
23   
Follow-Up Visits ...............................................................................................................................  
23   
10. 
DATA COLLECTION AND OUTCOME MEASURES .................................................................. 
24   
Data Collection Schedule ................................................................................................................  
24   
Primary Outcome Measure ..............................................................................................................  
24   
Secondary Outcome Measures .......................................................................................................  
25 Other Outcomes ................................................................................ Error! Bookmark not 
defined.   
Stored Specimens .........................................................................................................................  
26   
11. 
MASKING OF DATA COLLECTION ............................................................................................ 
26   
12. 
DISCONTINUATION OF SUBJECTS .......................................................................................... 
27   
Reimbursement ...................................................................................................................................  
27   


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13. 
ADVERSE EVENT ....................................................................................................................... 
27   
13.1 
General .....................................................................................................................................  
27   
13.2 
Potential Risk from Intervention ............................................................................................... 
29   
13.3 
Alert Levels ...........................................................................................................................  
31   
14. 
DATA AND SAFETY MONITORING ........................................................................................... 
31   
14.1 
Data Management System ....................................................................................................... 
31   
14.2 
Meetings ...................................................................................................................................  
31   
14.3 
DATA Safety Monitoring Board ................................................................................................ 
31   
15. 
STUDY ADMINISTRATION ......................................................................................................... 
32   
Trial Organization ................................................................................................................................  
32   
Ethics and Good Clinical Practice .......................................................................................................  
32   
Funding Mechanism and Sponsors ..................................................................................................... 
32   
16. 
SAMPLE SIZE .............................................................................................................................  
32   
17. 
DATA ANALYSIS & STATISTICAL CONSIDERATION ............................................................... 
33   
17.1 
Analysis Overview ................................................................................................................ 
33   
17.2 
General Statistical Approach  
....................................................................................................... 34   
Missing and incomplete data ...............................................................................................................  
35   
On-treatment Analyses .......................................................................................................................  
35   
18. 
STUDY TIMETABLE .................................................................................................................... 
36   
19. 
HUMAN SUBJECTS .................................................................................................................... 
36   


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Description of Consent Process ..........................................................................................................  
36   
Confidentiality ......................................................................................................................................  
37   
20. 
BIBLIOGRAPHY ..........................................................................................................................  
37   
   
                          
1. INTRODUCTION   
   
The ability to diagnose and treat cancer at early stages has led to an increased number of 
cancer survivors, and this has prompted the study of behavioral and pharmacologic 
interventions for improving survival and quality of life in cancer survivors.    
Insulin-like growth factor-1 (IGF-1) is a central biomarker of interest for the study of 
interventions in survivors of solid tumors, and is associated with increased risk of several 
common cancers including breast, colorectal, prostate, and lung.1  Some studies suggest 
higher IGF-1 levels are associated with higher mortality in patients with cancer,2 and it has 
been hypothesized that reducing IGF-1 might prevent cancer in persons without cancer 
(primary prevention) and cancer recurrence among cancer survivors (secondary prevention).     
IGF-1 is a mitogen that promotes cell-cycle progression and cellular transformation by rapid 
cell turnover. Over 80% of IGF-1 circulating in blood is bound to the insulin-like binding protein 
(IGFBP)-3.  Two putative strategies that might lower IGF-1 include pharmacologic (e.g., 
metformin) and non-pharmacologic (e.g., weight loss) approaches.  Metformin and weight loss   
are particularly appealing interventions, given their beneficial effects in treating other 
conditions, their widespread use, and their well-documented safety profiles.   
Metformin is associated with decreased risk of several types of cancer in patients with 
diabetes3-5. There are multiple mechanisms by which metformin might inhibit cancer 
development and growth. In addition to its effects on glucose lowering and insulin sensitivity, 6 
preliminary evidence suggests that metformin may decrease circulating levels of IGF-I and 
other growth factors.   
While the relationship of IGF-1 with adiposity is inconsistent, 7-9 there is a positive association 
between IGFBP-3 (reflective of bound IGF-1) and BMI, indicating lower biologically active IGF1 
levels among obese women.10 Also, lifestyle changes including weight loss and other healthy 
behaviors have also been shown to improve insulin sensitivity   
In this context, we propose a randomized, 3-arm trial to compare the effects of self-directed 
weight loss, coach-directed weight loss, and metformin treatment on IGF-1 and the IGF-1 to 
IGFBP3 ratio. This trial will enroll ~120 cancer survivors (~50% female, ~50% African 
American) who will be randomized to one of 3 arms:   
A. Self-Directed Weight Loss    


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B. Coach-Directed Behavioral Weight loss   
C. Metformin Treatment   
The duration of intervention and follow-up will be 12 months.  The primary outcomes will be 
changes in IGF-1 and the IGF-1:IGFBP-3 ratio at 6 months. Primary outcome assessment will 
occur at 6 months to maximize data collection at the time of the most anticipated weight loss 
and to minimize a decrease in sample size due to censoring from recurrent cancer.  However, 
data from 12 months will also be reported.   
2. SPECIFIC AIMS   
   
Primary Aims    
1) 
Test the hypothesis that participants in the coach-directed behavioral weight loss arm 
will experience greater decreases in IGF-1 and IGF-1:IGFBP3 than those in the self-directed 
weight loss arm at 6 months.   
2) 
Test the hypothesis that participants in the metformin arm will experience greater 
decreases in IGF-1 and IGF-1:IGFBP3 than those in the self-directed weight loss arm at 6 
months.   
Secondary Aims   
3) Test the hypothesis that participants in the metformin arm will experience greater decreases 
in IGF-1 and IGF-1:IGFBP3 than those in the coach-directed behavioral weight loss arm at 
6  
months.   
4) Determine the effects of coach-directed behavioral weight loss and metformin separately on 
IGF-1 and IGF-1:IGFBP3 at 12 months (Aims 1 – 3 at 12 months)   
5) Determine the effects of coach-directed behavioral weight loss and metformin separately on 
the following outcomes at 6 and 12 months:   
- 
Weight, Body Mass Index   
- 
EuroQol   
- 
Dietary intake and physical activity   
- 
Glucose, insulin, hemoglobin A1c   
- 
IL-6, IL-8, CRP   
- 
Side effects questionnaire   
6) Conduct exploratory analyses (Aims 1 – 5 above) in key, pre-specified subgroups, defined 
by sex, race, type of cancer, and baseline levels of IGF-I and the IGF-1: IGFBP-3 ratio.   


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7) Explore the association of physical activity levels with IGF-1 and the IGF-1: IGFBP-3 ratio.    
8) Collect and store specimens of blood and stool for other assays.  Candidate assays 
include leptin, adiponectin, VEGF, HGF, and EGF, SLC22A1, SLC22A2, and SLC47A1 
gene variants and 16S bacterial whole genome sequencing (stool).   
   
   
   
3. BACKGROUND AND RATIONALE   
3.1   
Epidemiology of Overweight/Obesity among Cancer Survivors   
   
Obesity is a prevalent and modifiable factor that negatively affects the risk of cancer, and 
survival from solid tumor cancers.11-14 In the United States, rates of overweight and obesity as 
measured by Body Mass Index (BMI) have been steadily increasing since the 1960s.15 In 
2011-2012, 68.5% of US adults were obese or overweight (BMI ≥25 kg/m2).11 In Maryland, the 
prevalence of obesity is 27.1%,16in Baltimore city, 33.8 % of adults were found to be obese in 
the 2010 Baltimore City Community Health Survey.17 Due to the high prevalence of overweight 
and obesity in the general population, as well as the association between obesity and 
incidence of many common cancers,13 it is likely that obesity and overweight are common 
among cancer survivors.   
There are an estimated 14.5 million cancer survivors living in the United States in 2014,18 and 
this number is expected to increase due to improvements in treatment and early detection as 
well as the aging of the general population.19 Among male cancer survivors in the US, the 
most common forms of cancer are prostate (43%), colon & rectum (9%), and melanoma (8%); 
for female cancer survivors, breast (41%), uterine corpus (8%) and colon & rectum (8%) 
cancers are most common.18 In the 2009 Behavioral Risk Factor Surveillance System 
(BRFSS) study sample, 27.5% of cancer survivors were obese (with significant variation by 
state), and 31.5 % of cancer survivors had not completed any leisure-time physical activity in 
the last 30 days.19    
   
3.2   
Evidence of Association between Overweight/Obesity and Cancer   
   
Incidence: In 2007, The International Agency for Research on Cancer (IARC) published a 
comprehensive review of the association between obesity and cancer. This report concluded 
that there is “convincing” evidence that greater body fatness, most commonly measured by  
BMI, is a cause of cancers of the esophagus, pancreas, colon and rectum, breast 
(postmenopause), endometrium, and kidney; and is likely a cause of cancer of the 
gallbladder.12  Additionally, the available evidence is “suggestive” of an association of body 
fatness with liver cancer. 12 Lung cancer is an exception to the general pattern of increased 
risk of cancer with increasing BMI. IARC concludes that despite epidemiological evidence that 
high BMI is protective of lung cancer, associations are likely due to residual confounding from 
cigarette smoking or reverse causation stemming from weight loss among those with 


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undiagnosed lung cancer.12 A recent study of electronic medical records from the United 
Kingdom followed over 5 million individuals to evaluate the relationship between average 
effects of a 5 kg/m² increase in BMI on cancer risk. An elevated risk of incident cancer was 
found for cancers of the esophagus, colon, rectum, liver, gallbladder, pancreas, 
postmenopausal breast, cervix, uterus, ovaries, kidney, brain, thyroid, and leukemia.13    
Survival: In one prospective study of nearly 900,000 men and women in the Cancer 
Prevention Study II cohort, the risk of death from any cancer was significantly higher among 
men and women in the highest BMI categories (calculated from self-reported height and 
weight at study enrollment), compared to normal weight men and women.20 BMI was 
significantly associated with increased risk of death from cancer of the esophagus, colon and 
rectum, liver, gallbladder, pancreas, and kidney among men and women. Additionally, among 
men, greater BMI was associated with death due to stomach and prostate cancer; for women, 
death from breast, uterine, cervical, and ovarian cancer.20 A pooled analysis from a recent 
review of 82 studies of breast cancer and survival related to body mass index found that BMI 
in the obese and overweight range prior to diagnosis of breast cancer was significantly 
associated with an increased risk of both all-cause mortality and breast cancer mortality, 
compared to normal weight women.21 Additionally, higher BMI measured within a year after 
diagnosis and one year or later after diagnosis was still associated with all-cause and breast 
cancer specific mortality.21  In a retrospective cohort study of 4376 Swedish men with prostate 
cancer, obese men had a 47% (HR 1.47, 95% CI 1.03-2.10) higher risk of mortality from any 
cause compared to men of normal weight, but no significant association was found between 
BMI and prostate specific mortality or prostate cancer progression..14 However, men who 
gained more than 5% of their bodyweight after diagnosis had a significantly increased risk of 
prostate-specific cancer risk.14    
Recurrence: Among participants in the Nurse’s Healthy Study with a diagnosis of breast 
cancer, BMI prior to diagnosis was positively correlated with recurrence, among neversmokers 
and post-menopausal women.22 Obesity is also associated with increased risk of prostate 
cancer recurrence,23-24. Obesity both five years before surgery and 1 year after surgery was 
associated with an increased risk of recurrence, compared to those of normal weight, in a 
prospective study of 1337 men who had received a prostatectomy from the same surgeon.24 
Thus, it is likely that obesity confers increased risk of cancer recurrence for several types of 
cancer, and that decreasing rates of obesity might decrease the rates of cancer recurrence in 
cancer survivors.   
   
3.3   
Weight Gain and Weight Loss in Cancer    
   
Weight gain after diagnosis of breast cancer has been well documented. According to a review 
of studies evaluating weight gain after breast cancer diagnosis, between 50-96% of women 
diagnosed with early stage breast cancer were found to have gained weight after diagnosis.25 
Results from the same review suggest that weight gain is associated with the type of 
treatment, with women receiving chemotherapy more likely to gain weight than those receiving 


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surgery and/or radiation.25  Data from the WHEL study demonstrated that only 10% of women 
returned to their pre-diagnosis weight after six years of follow-up.26  Among survivors of 
prostate cancer, patterns of weight gain and weight loss are less clear. In a study of Swedish 
men diagnosed with localized prostate cancer, 14.8% reported a weight gain of more than 5% 
after diagnosis, but 8.9% experienced a loss of more than 5%, among those still alive after a 
median of four years after diagnosis.14  Joshu et al found similar results in a retrospective 
cohort study of men who had received a prostatectomy: 13.9% of men gained more than 2.2kg 
and 12.7% of men lost more than 2.2kg between 5 years prior to the surgery and one year 
after.24    
The weight gain that accompanies cancer diagnosis and treatment has been linked to 
increased recurrence of cancer. Of the 50 studies reviewed by Vance et al, ten evaluated the 
effect of weight gain after survival on recurrence of cancer. 25  Six of these studies found no 
relationship between weight gain after diagnosis and recurrence of breast cancer, but four of 
the studies found that weight gain was associated with increased recurrence, including a 
subsample of the Nurses’ Health Study.25  In the study by Joshu et al. mentioned above, the 
risk of recurrence was twice as high for men who gained more than 2.2kg compared to men for 
whom weight remained stable.24  Bonn and colleagues also found an almost two-fold increase 
in the prostate-cancer specific mortality among men who gained more than 5% of their weight 
at diagnosis, compared to men with stable weight.14     
3.4   
Insulin-Like Growth Factor and Adiposity   
   
Insulin-like growth factor I (IGF-1) is a mediator of growth hormone (GH) and is important for 
cell development and replication. When IGF-1 binds to the insulin-like growth factor I receptor 
(IGF-1R), pathways for the expression of genes related to cell growth, replication, and 
apoptosis  are activated.27 IGF binding proteins, including the most common, IGFBP-3, 
regulate IGF by increasing the half-life of IGFs and controlling their ability to bind to 
receptors.27  IGFBP-3 may also stimulate apoptosis and block cell proliferation through 
mechanisms independent of IGFs.1     
Several recent observational, cross-sectional studies suggest that IGF-1 has a U-shaped 
relationship with BMI, with a peak in IGF-1 occurring around a BMI of 25 and then falling at 
higher BMI levels.28-31 Another observational study using a racially diverse NHANES sample 
found that BMI was inversely associated with IGF-1 levels for all sex and race/ethnicity 
subgroups.32  In obese people, average total IGF-1 is often much lower than total IGF-1 
among normal weight people, while free IGF-1 increases as BMI increases.33   
The relationship between weight loss and IGF-1 is unclear. In a small study, 71 obese women 
were randomized to receive restricted calorie diets or restricted calorie diets plus the weight 
loss drug Orlistat. Women in the Orlistat group lost more weight and had larger increases in 
IGF-1 after six months. However, it is unclear if the changes in IGF-1 are a function of the 
increased weight loss or Orlistat.34 An earlier study of 20 women did not find any change in 
IGF-I related to weight loss after eight weeks of a low-calorie, low-carbohydrate diet.35 In a 
recent clinical trial evaluating the effects of diet and exercise interventions on 68 postpartum 


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women who were overweight or obese prior to pregnancy, neither the diet nor the exercise 
intervention were associated with significant changes to IGF-I levels, despite weight loss in 
both intervention groups at both 12 weeks and 1 year.36   
A cross-sectional analyses among 700 breast cancer patients indicated higher physical activity 
levels were associated with lower IGF-I and IGF-3 levels.37 Clinical trials have also 
demonstrated that exercise programs among breast cancer patients result in lower IGF 
levels.38,39 . It was suggested that the strongest association among physical activity and IGF 
levels among breast cancer patients was associated with higher BMI, lower baseline physical 
activity levels and the absence of tamoxifen therapy.38 However many of the extant trials have 
focused on exercise programs that were independent of weight loss efforts. It is not clear if 
aerobic exercise recommendations associated with a weight loss also result in decreases of 
IGF levels. Moreover the association among physical activity and IGF appears strongest 
among breast cancer survivors. No association was found between physical activity and IGF 
among prostate cancer survivors in three different trials.38    
There is some evidence that the type of diet can influence IGF-1 levels. A high-protein diet has 
been shown to increase IGF-1 among men with prostate cancer,40 men with type II diabetes,41 
and among middle-aged non-obese persons.42 Reduction in calories, however, has not been 
noted to lead to decreased IGF-1 levels,35,42,43 except when weight loss was substantial.34   
Among healthy adults, IGF-1 measurements have been shown to be stable over time.44-47 For 
example, In a study of over 800 older adults, a correlation of r=0.94 was found for IGF-1 levels 
measured by Immunoradiometric assay 8-54 days apart.44 In a study of 1000 Brazilian adults 
21-70, IGF-1 levels measured 12 weeks apart had a correlation of r=0.91, and the variation 
between the two measurements was 20% or less in 99% of people.47 Regardless of body 
mass index, IGF-1 and IGFBP-3 were stable throughout a 24-hour observation period in both 
normal weight and overweight and obese participants.48 IGF-1 has also been demonstrated to 
be stable in cancer patients, both throughout the day49 and across several months.50-52    
   
3.5   
Insulin-like Growth Factor and Cancer Incidence and Recurrence   
   
High levels of circulating IGF-1 have been implicated in the development of cancer.27 High 
levels of circulating IGF-1 are associated with an increased risk of some common cancers, 
such as prostate, premenopausal breast, and colorectal; while high levels of circulating  
IGFBP-3, the main binding protein of IGF-1, is associated with a decreased risk of these 
cancers.1 In vitro studies provide evidence that IGF-IR is over expressed on some types of 
cancer cells and that IGF-IR is enhances cell replication and decreases apoptosis.53  In animal 
models with decreased IGF-1 production, decreased tumorogenesis was seen, while mouse 
models with high IGF-1 had increased occurrence of cancer.53     
In epidemiological studies, there is also evidence that higher levels of IGF-1 are associated 
with cancer risk. Using data from The European Prospective Investigation into Cancer and 


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Nutrition (EPIC) study, a prospective study of more than 500,000 Europeans, researchers 
have found that higher level of IGF-1 increased incidence of prostate cancer 54, estrogen 
receptor positive breast cancer,55 and thyroid cancer.56 High levels of circulating IGF-1 have 
also been implicated in increased risk of colon and lung cancer.27  Pathways of Metformin on  
Cancer potentially works on different pathways,57 it may augments the effect if various 
chemotherapy, decreases level of oxidation, decrease production of reactive oxygen species, 
it may promote weight loss, and most importantly it may decrease the level of insulin-like 
growth factor 1.   
   
3.6   
Metformin and Cancer Risk   
   
Metformin, an oral biguanide antihyperglycemic agent, is the drug most often prescribed to 
treat type 2 diabetes.  The American Diabetes Association Clinical Practice Recommendations 
2014 recommend metformin as the first line therapy for type 2 diabetes.58 Metformin lowers 
glucose by inhibiting glucose production in the liver by activating the AMP-activated protein 
kinase pathway, through a liver kinase BI (LKBI) dependent pathway.57,59 Metformin also 
improves sensitivity to insulin and slows absorption of glucose by the gastrointestinal tract, 
which lowers glucose levels in the blood.57 Several large retrospective studies suggest that 
individuals with diabetes maintained on metformin vs. other types of diabetic drugs have a 
lower incidence of several types of cancer, including hepatocellular, pancreatic, and colon 
cancers3 The mechanism by which metformin might decrease cancer incidence is unknown, 
and does not appear to be due to glycemic control alone.60  Other possible mechanisms 
include metformin-associated reductions in weight, IGF-1, and other growth factors.   
   
3.7   
Metformin and Weight Loss   
   
In addition to its direct impact on glucose homeostasis, metformin use is associated with 
minimal but sustained weight loss in patients with and without diabetes.  In a meta-analysis 
including >5,000 patients with diabetes, metformin decreased weight by 2.6 and 2.7 kg 
compared to sulfonylureas and thiazolidinediones, respectively.61 In the Diabetes Prevention 
Program trial, participants randomized to the lifestyle intervention group lost more weight than 
those in the metformin or placebo groups, although those in the metformin group did 
experience weight loss.62 Mean weight loss was 0.1, 2.6, and 5.6 kg in the placebo, metformin, 
and weight loss groups, respectively.62 These results continued during 7-8 years of follow-up 
on the open label extension study, with the metformin group having reduced body weight 
compared to the placebo group.63 Several small trials of metformin in patients with other 
conditions (polycystic ovarian syndrome,64, and antipsychotic-related weight gain65)  have 
demonstrated similar effects of metformin on weight reduction.    
   


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3.8   
Metformin and Insulin-like Growth Factor   
   
As noted above, metformin has its primary action on glucose homeostasis through  
LKB1dependent activation of AMPK.66  Outside of effects on glucose levels, activation of  
AMPK has generally catabolic and anti-synthetic effects, including inhibition of fatty acid and 
protein synthesis; in the setting of tumorigenesis, which is dependent on unregulated cell 
growth, AMPK activation would be expected to be inhibitory.67  AMPK activation may also 
more directly inhibit the cell cycle.67   
Consistent with the anti-synthetic effects of metformin as an AMPK activator, metformin 
appears to lower IGF-1 in preclinical and human studies.  Studies of cancer cell lines and 
mouse models suggest that metformin may decrease levels of IGF-1.57 It also lowers levels of 
insulin, which is known to promote the growth of cancer.57 Using human pancreatic cancer cell 
lines, Karnevi et al demonstrated in pancreatic cancer cells that treatment with metformin 
decreased cell proliferation and plasma IGF-1, through an activation of the AMP-activated 
protein kinase AMPKThr172 and blocking the IGF-1 receptor activation and insulin receptor 
signal (IRS-1).68    
In humans, metformin treatment has reduced IGF-1 levels in trials in patients with diabetes;69 
in a small study (n=40) of patients with endometrial cancer after four weeks of treatment;5 in 
women with polycystic ovary syndrome;70 and in healthy men (n=15).71     
Taken together, several preclinical studies and small, short-term human studies suggest that 
metformin lowers IGF-1 levels, but additional evidence in clinical trials, especially with cancer 
survivors, is necessary to confirm these results.    
   
3.9   
Current Public Health Recommendation   
   
The International Agency for Research on Cancer recommends, when possible and when not 
recommended otherwise by a medical professional, that cancer survivors also follow the 
recommendations for the general population for maintaining a healthy weight, diet, and 
physical activity.12 This includes maintaining a stable body weight in the normal range and 
avoiding weight gain and increases in waist circumference.12 The dietary recommendations of 
IARC include limiting intake of energy-dense foods, sugar sweetened beverages, starchy 
foods, red meat, alcoholic beverages, salt, and processed grains; and eating the 
recommended five servings of fruits and vegetables each day. IARC also recommends a 
minimum of 30 minutes of physical activity each day, with a goal of 60 minutes of moderate or 
30 minutes of vigorous physical activity per day.12 Recommendations for cancer survivors 
published by the American Cancer Society,72 the American Institute for Cancer Research,73 
and the Centers for Disease Control and Prevention74 echo IARC’s recommendations.     


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3.10 Practicality of Intentional Weight Loss among Cancer Survivors   
   
A recent review of ten small randomized controlled trials of weight loss intervention among 
breast cancer survivors concluded that “there is a small but growing body of evidence to 
suggest that weight loss is feasible and safe in women following treatment for breast cancer.75   
Of the ten RCTs included in the review, only three included information about adverse events, 
and none reported a serious adverse event.75 A recent study aimed at increasing physical 
activity among 86 young adult cancer survivors used a social media-based intervention.  
Participants in the intervention group reported that they enjoyed participating in the study and 
that they would recommend the intervention to other cancer survivors. Weight loss was seen 
in the intervention group, although this was not a primary outcome of the trial, and no adverse 
events were reported.76 A larger study of older adult colorectal, prostate, and breast cancer 
survivors spanning two years found that the study group made changes in diet and physical 
activity, and also lowered BMI from an average of 29.1 at baseline to 28.3 at the 2 year 
followup (p< .001). Of the events reported during the course of the study, six were found to be 
attributable to the intervention, and only one was serious (hospitalization for dehydration).77 
These studies support the IARC and ACS recommendations that cancer survivors maintain a 
healthy body weight, through weight loss if necessary.12     
   
   
   
3.11 Rationale for a Randomized Clinical Trial of Weight Loss and Metformin on IGF  
among Cancer Survivors   
   
As treatment and early detection of cancer continues to improve, the US will be faced with a 
growing population of cancer survivors. Many of these cancer survivors will be overweight or 
obese, and maintaining a healthy weight is an important element of healthy survival.12 The 
time after cancer diagnosis represents a potentially important time for intervention in the 
overall health of survivors.    
Every year, more than 24,000 people living in Maryland are diagnosed with cancer:78 prostate, 
female breast, lung, and colon & rectum are most common types in both Maryland and the US 
as a whole.79 Cancer is the second leading cause of death in the state of Maryland.78 The 
Maryland Comprehensive Cancer Control Plan estimates that the annual cost of cancer in the 
state of Maryland is $3.9 billion, including $1.5 billion in direct medical costs.78    
As we mentioned previously, High levels of circulating IGF-1 have been implicated in the 
development of cancer. High levels of circulating IGF-1 are associated with an increased risk 
of some common cancers. Prostate, female breast, lung, and colon & rectum cancer have all 
been associated with higher levels of if IGF-1.1 Other studies have suggested that higher 
levels of IGF-1 are also associated with increased risk of mortality among cancer patients.2 It 


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14   
has been hypothesized that reducing IGF-1 might prevent cancer in persons without cancer 
(primary prevention) and cancer recurrences among cancer survivors (secondary prevention).    
Metformin is a low-cost therapy with few major side effects.57 Among patients with diabetes, it 
has been observed that metformin decreases the incidence of certain cancers, and animal and 
cell line studies suggest that metformin may lower IGF-1 levels.3-5,57 Promising results from in 
vitro, human, and epidemiological studies suggest that metformin may inhibit cancer 
development and progression through IGF-related pathways among non-diabetic patients as 
well. The weight loss program has been shown effective among the general population, is 
easily scalable and is expected to have very few negative side effects.    
A wealth of evidence depicts the relation between IGF-1 and cancer. However, there is a 
paucity of data on the impact of weight loss or metformin on IGF-1, especially clinical trials 
among cancer survivors. A randomized trial in cancer survivors to test the effects of weight 
loss or metformin on IGF-1 level will help clarify the relationship between these variables, and 
could identify new methods to decrease risk of cancer recurrence amongst cancer survivors.   
   
   
   
   
   
   
   
   
   
   
   
   
4. OVERVIEW OF TRIAL DESIGN   
   
This is a prospective, single-center randomized trial with three arms, and an allocation ratio of  
1:1:1. The study design is an efficacy study to evaluate the effect of metformin and 
coachdirected behavioral weight loss versus self-directed weight loss on IGF-1 and IGF-1 to 
THE IGFBP-III ratio blood levels after 6 and 12 months of intervention. The coach-directed 
Behavioral Weight Loss arm is a web-based remote delivery and communication system that 
promotes healthy behavioral changes. The Metformin arm is a pharmaceutical intervention of 
oral metformin. This is a secondary prevention study for men and women who have survived 
solid malignant tumors.   
   
5. STUDY POPULATION   
   
Participants are cancer survivors – persons who self-report a malignant solid tumor diagnosis 
and have completed curative intent treatment and have no ongoing or planned active treatment 
(surgery, radiation therapy or chemotherapy (other than chemoprophylaxis)). We aim to recruit 


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15   
~120 participants, ~40 participants in each of the three arms. Eligibility will be determined by a 
series of web, phone, and in-person contacts.   
5.1 Inclusion Criteria   
• 
Women and men ages 18 or older      
• 
Have been previously diagnosed with a malignant solid tumor, completed their required 
surgical, and/or chemotherapy and/or radiation curative intent therapy at least three 
months prior to enrollment, and have an anticipated treatment-free life span of 12 
months or longer. Chemoprophylaxis with tamoxifen or aromatase inhibitors for breast 
cancer in women and anti- LHRH therapy for prostate cancer in men will be permitted.     
• 
Have a BMI of 25 kg/m2 or greater and weight <=400 lbs.   
• 
Willingness to accept randomization to each of the three arms   
• 
Willingness to change diet, physical activity, and weight    
• 
Regular access to computer with a reliable Internet connection   
• 
Ability to send and receive emails   
• 
Ability to complete online forms   
• 
Access to phone   
• 
Willingness to provide written informed consent    
   
5.2 Exclusion Criteria    
• 
Women who are breastfeeding, pregnant, or planning pregnancy within the next year   
• 
Medication-treated diabetes    
• 
Non-fasting blood glucose >=200 mg/dL, or HbA1C >=7%    
• 
Current or prior regular use of metformin within the past 3 months   
• 
Uncontrolled concurrent medical condition likely to limit compliance with the study 
interventions    
• 
Received any chemotherapy (unless anti-hormonal therapy) and/or radiation three 
months or less prior to the proposed intervention date   
• 
Have a prior history of lactic acidosis by self-report   
• 
Prior or planned bariatric surgery   
• 
Have significant renal disease or dysfunction defined as eGFR<45   
• 
Have significant hepatic dysfunction (AST/ALT ≥ 2 x ULN or reported liver disease)   
• 
Self-reported average consumption of > 14 alcoholic drink per week   
• 
Currently enrolled or planned to enroll in weight loss program   
• 
Hemoglobin <9 g/dl   
• 
Platelet count <100   
• 
WBC <2.5   
• 
Plans to relocate from the area within one years   
• 
Use of prescription weight loss medication(s) (e.g., lorcaserin, topiramate/phentermine, 
phentermine, liraglutide, and bupropion/naltrexone), including off label use of drugs for 


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16   
weight loss or over-the-counter weigh loss medications such as Orlistat within the past 6 
months.   
Study clinicians will meet regularly to review the eligibility of screenees.   
   
5.3 Inclusion of Minorities   
Men and women of all races and ethnic groups are eligible to participate in this trial. We aim to 
enroll ~50% women, ~50% African Americans.   
   
6. RECRUITMENT    
   
This trial will recruit cancer survivors who are overweight or obese and who reside in the  
Baltimore Metro area.  Trial investigators recognize the challenges of recruiting participants.  
Accordingly, they will simultaneously implement several recruitment strategies and will also 
develop backup plans should initial recruitment efforts fail to yield the required number of 
participants. Targeted mailings to cancer survivors is likely to be the most efficient and 
effective approach to enrolling participants.  Accordingly, the primary recruitment strategies will 
include targeted mailings of invitational materials (invitational letter and/or brochure) to lists of 
persons who are cancer survivors.  Such lists are publicly available from commercial vendors. 
Specifically, this study is using the Mt Royal Printing Company. The investigative team will not 
receive names or addresses of the people who are on the vendor’s mailing lists. Secondary 
strategies will include a) placement of brochures in physician offices in Hopkins-affiliated 
clinics and distribution of flyers in various community settings (e.g. health fairs), b) direct 
referral from study physicians, c) word-of-mouth, and d) advertisement in local newspapers. 
Enrollment of participants will take place at the ProHealth clinic in Woodlawn (West Baltimore), 
where data collection visits will take place.   
A public website (spirittrial.org), managed by the study team, will be listed on recruitment 
materials. The home page displays brief information about the study and provides a way for 
interested persons to submit their contact information, which would be stored on the Qualtrics 
server, which is approved by the  ICTR for the secure storage of PHI. We also provide general 
information about SPIRIT. Text for these sections is primarily pulled from IRB-approved 
materials. We also list contact information for ProHealth in case people would prefer to contact 
the study staff directly rather than leave their own contact information.    
In addition, we will conduct online advertising with paid banner ads on websites (Google, 
Facebook, and possible other sites) that direct individuals to the SPIRIT website's landing 
page (spirittrial.org).    
Interested individuals will be asked to contact us by phone or email. After the individual 
provides verbal consent, a pre-screen telephone interview will occur over the phone. Those 
who remain interested and eligible will be invited to attend a screening visit at the ProHealth 


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17   
research clinic. During the in-person screening visit, written informed consent will be obtained, 
along with other baseline measurements.    
Recruitment will be conducted by the study coordinator and ProHealth staff. All recruitment 
material and potential participants' data will be protected in an encrypted study computer with 
password protection. Hard copies will be locked in a secure cabinets and rooms.  Locally, we 
will retain the identifiers of those persons who provide written informed consent, as well as 
those who agree to be contacted for future studies.  The identifiers of other participants will be 
destroyed.   
   
7. RANDOMIZATION AND ASSIGNMENT   
   
Participants will be randomized to one for the three following arms:   
- 
Self-Directed weight loss    
- 
Coach-Directed Behavioral weight    
- 
Metformin treatment    
Randomization will be stratified by race and BMI. To prevent prediction of randomization, we 
will generate the randomization schedule in variable blocks sizes. A biostatistician will 
generate the allocation sequence. Randomization will take place after the study coordinator 
confirms that all screening activities have occurred, individual meets all eligibility criteria, and 
all baseline data have been collected. Individuals who do not meet eligibility or who lack proper 
documentation of eligibility or key data elements will not be randomized. An unmasked study 
coordinator or staff member who is not involved in follow-up data collection will carry out 
assignment allocation.   
   
8. INTERVENTIONS   
   
8.1   
Self-Directed Weight Loss   
   
Participants in this arm will continue to receive care from their primary care provider and/or 
oncologist. Participants in this arm will receive an informational visit with a staff member 
immediately following the randomization process. At this visit the participant will also receive 
the National Institutes of Health booklets, Aim for a Healthy Weight and What I need to know 
about Physical Activity and Diabetes. They will also receive a link to the Centers for Disease 
Control and Prevention website Healthy Weight.   
   
8.2   
Coach-Directed Behavioral Weight Loss    
   


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The Remote Lifestyle Coaching intervention is based on the Call Center Directed intervention 
from the POWER Hopkins Trial.80,81 The Lifestyle Coaching intervention has a social cognitive 
theoretical framework that draws upon the strengths of various approaches including 
Bandura’s Social Cognitive Theory.82,83 The behavioral approaches include teaching 
participants strategies to increase their self-efficacy, develop social support, and enhance 
motivation. Both self-efficacy and social support are key components in social cognitive theory 
and have been identified as important determinants of behavior change.84,85 Specific strategies 
that will be encouraged among the participants will include self-monitoring, goal setting, 
problem solving.    
The coach-directed behavioral weight loss arm is based on the POWER-Remote arm of the 
POWER Trial, which provided behavioral-based telephonic coaching with web-based support 
to promote healthy lifestyle and weight loss in overweight and obese adults. We will partner 
with Healthways, a disease management company, to implement the Coach-Directed 
Behavioral Weight loss intervention. Johns Hopkins Medicine has an ongoing collaboration 
with Healthways, the Innergy program, to translate POWER intervention to employees at 
Hopkins and Healthways. The proposed study will be built on this existing relationship and the 
intervention will be customized to the cancer survivor population.   
   
Methodology   
The goal of this intervention is to achieve at least 5% weight loss in the first six months of the 
intervention and maintain these improvements through month twelve by meeting dietary and 
exercise goals shown in Table 1. Participants will receive coaching by a Hopkins coach and 
have access to a study website for self-monitoring and learning modules. Coaching sessions 
will be weekly for the first three months and monthly for months 4 through12. There is a 
reengagement process includes both automated emails and coach follow-up .The website 
sends series of automated email reminders to login if there has been no login in the last 7 
days. There is a personal coach follow up of emails and calls if the automated email did not 
prompt a login after 14 days. There is provision of up to two supplemental coaching calls per 
any sixmonth period to assist individuals with challenging or difficult personal situations. In 
addition to coaching, the trial will provide bathroom scales to the participants. The scale will be 
used to track and record weight changes. The study website/phone app calculates calories for 
all foods and beverages tracked. Participants who do not have access to a phone will be 
provided with a prepaid cellphone with enough minutes to cover the intervention requirements.    
Calls may be recorded for quality control purposes. Audio records will be stored in HIPPA 
compliant Johns Hopkins cloud based server. Audio records will be destroyed after study 
completion. .   
Table 1. Weight Goals and Behavioral Recommendations      
Weight Loss Goal    
  Month Six    
Minimum 5% weight loss, individually tailored   


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19   
  Month 12   
Maintain or exceed 5% weight loss, individually tailored   
Behavioral Recommendations   
  Total Caloric Intake   
Achieved weight loss < 5%   
1200 kcal/d if ≤ 170 lb   
1500 kcal/d if > 170 lb and < 220 lb   
1800 kcal/d if > 200 lb and < 270 lb   
 
Achieved weight loss ≥ 5% Women: 1500 – 1800 kcal/d  
Men: 1800-2200 Kcal/d   
  Diet   
DASH dietary pattern:   
7-12 servings of fruits/vegetables   
2-3 servings of low fat dairy  Low 
sodium   
≤ 25% of calories from fat   
  Exercise    
Build to ≥ 180 minutes/week of moderate intensity physical 
activity in bouts ≥ 10 minutes in length   
Self-Monitoring Recommendations: Achieved Weight Loss < 5%   
  Weight    
Weekly   
  Dietary Intake   
Daily   
  Exercise   
Daily   
  Login Study Website   
At least weekly, preferably daily or daily use of study app   
Self-Monitoring Recommendations: Achieved Weight Loss ≥ 5%   
  Weight    
Daily   
  Dietary Intake   
Daily   
  Exercise   
Daily   
  Login Study Website   
At least weekly, preferably daily or daily use of study app   
   
   
Table 2. Contact Schedule   
   
Coaching Calls   
  
  Months 1-3   
Weekly Calls   
  Months 4-12   
Monthly Calls   
Re-engagement   
  
  Automated email reminders   
Reminders if no login in the last 7,11 and 30 days   
  Coach reminders   
Follow-up emails and calls if no login after 14 days   
Supplemental Calls   
  


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20   
  Coaching Calls   
Tailored, no more than 2 per six month period   
   
Phases and Self-Monitoring   
Self-monitoring recommendations have subtle yet important differences depending on the 
focus of the participant on weight loss or weight loss maintenance.   
Weight Loss Focus: The following recommendations are for participants who have not yet 
achieved 5% weight loss or are working toward a goal of more than 5% weight loss:   
- 
Track dietary intake (all food and beverages) and exercise daily on either the 
study website or using the related app.    
- 
A self-reported weight should be entered at least weekly on the study website.   
Weight Maintenance Focus: The following recommendations are for participants who 
have achieved at least 5% weight loss and are focused on weight loss maintenance:   
- 
Track dietary intake (all food and beverages) and exercise daily on either the 
study website or using the related app.    
- 
A self-reported weight should be entered daily on the study website.   
Adherence   
Adherence will be assessed by completion of coaching sessions and online self-monitoring.   
Health Care Provider Engagement   
Participants in this arm will continue to receive care from their primary care provider and/or 
oncologist. The participant will update their physician and care providers on their progress 
in the lifestyle intervention by printing a summary form from the intervention website to 
bring to a regular physician visit. These summary forms are designed to provide an 
overview of progress on both lifestyle change and self-reported weight. Based on selfreport 
from the website, they illustrate weight loss trends, tracking and participation over time and 
may facilitate conversations about weight change during the course of a standard physician 
visit.   
Website Operation and Support   
We will collaborate with Healthways, a disease management company, who maintained the 
website in the original POWER trial and will do so in the current trial. Johns Hopkins 
Medicine has an ongoing collaboration with Healthways.  Together, Healthways and 
Hopkins investigators and staff from the POWER trial developed Innergy, a commercial 
version of the POWER Remote intervention.  The trial will use the Innergy website, adapted 
for used in this trial by including materials relevant to cancer survivors.     
   
  
8.3    
Metformin Pharmacologic Intervention   
   


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21   
Participants in this arm will continue to receive care from their primary care provider and/or 
oncologist and/or other providers. Participants in this arm will receive medication-related 
education and counseling from a study staff member immediately following randomization. 
Participants will receive metformin, an oral medication for type 2 diabetes. It primarily 
reduces hepatic production of glucose without increasing insulin secretion.  Metformin is 
not currently approved for use as a cancer prevention medication. This study is designed to 
investigate its efficacy in reducing Insulin-like Growth Factor 1(IGF-1) and IGFBP-III, which 
in turn may reduce cancer cell growth among cancer survivors.  This study is not intended 
to study the treatment of cancer or prevention of cancer recurrence with metformin.  An 
application for an IND waiver has been submitted , and approved by FDA. FDA granted the 
approval to use this product for an indication that is not FDA-approved.   
Participants randomized to the metformin intervention will receive metformin up to 2,000  
mg per day.86 Dosing can be flexible, two or three times per day with meals as tolerated for 
12 months. See Section 5.2 for exclusion criteria.      
Metformin is primarily excreted by the kidney, and the risk of adverse events, although low, 
increases in patient with impaired renal function. Because aging is associated with reduced 
renal function, the FDA recommends “treatment should not be initiated in patients ≥80 
years of age unless measurement of creatinine clearance demonstrates that renal function 
is not reduced “.  Because we will measure kidney function and estimate GFR, we will 
excluded based on renal function rather than age.86   In this fashion, we will increase the 
opportunity for older individuals to participate in this trial.   
Dosing   
Oral titration of metformin in an open-label fashion will occur as follows:    
1) 500 mg by mouth once daily with breakfast for 7 days or longer if needed for tolerance;    
2) If tolerated, increase metformin to 500mg by mouth twice daily with breakfast and dinner 
for 7 days or longer if needed for tolerance;    
3) If tolerated, increase metformin to 1000 mg by mouth in the morning and 1000 mg in the 
evening for 7 days or longer if needed for tolerance;    
   
Dose modifications: The major limiting side effect for metformin is gastrointestinal discomfort.  
We do not anticipate other side effects or toxicity.  Therefore, determination of tolerance 
will be based on GI symptoms.  We will titrate the dose of metformin to the highest tolerated 
daily dose possible (based on GI side effects) up to 2,000  mg per day.   
   
Restarting and titration will be based on standard protocols and FDA guidelines in addition 
to clinical judgment, side effects, and the amount of time off metformin.    
   
Participants who are deemed to have an allergic reaction to metformin will not be continued 
on metformin.  Metformin will be stopped in participants in whom other side 
effects/toxicities are limiting or unsafe, and restarting of metformin will be based on clinical 
judgment after discussion with participant, the study’s clinical review committee, and the 
Data Safety and Monitoring Board if needed.   


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Planned Stopping and Restarting   
Rules for stopping and restarting metformin for medical reasons are as follows:   
A- Hospitalization   
In case of hospitalization, a participant will discontinue metformin.  A plan to restart will 
be considered after a careful assessment of the cause of hospitalization (including 
conditions which increase risk of lactic acidosis) and review of eligibility criteria specific 
to safety of metformin (e.g. eGFR and hemoglobin).  Participants in the metformin arm 
will be provided with card and a letter indicating the potential risk for lactic acidosis 
associated with certain medical conditions and procedures.   
   
B- Radiological procedures with iodinated contrast media   
Participants using metformin who undergo a radiological procedure that involves 
iodinated contrast material may develop renal insufficiency and resulting lactic acidosis. 
Any participant planning undergo such a procedure will be advised to stop metformin 24 
hours prior to the procedure and for 48 hours after the contrast administration. At least 
Forty-eight hours after contrast administration, eGFR should be checked. If the eGFR is 
>45 and stable compared to the baseline eGFR, a study clinician can approve restarting 
metformin. Participants in the metformin arm will be provided with a card and a letter 
indicating the potential risk for lactic acidosis associated with certain medical conditions 
and procedures..   
   
C- Surgical Procedures   
Major surgical procedures under general anesthesia carry a risk of metabolic acidosis. 
Participants in the metformin arm will stop metformin 24 hours prior to procedure involving 
general anesthesia. In conjunction with the clinicians providing peri-operative care, a 
decision to restart metformin can be approved by a study clinician after a review of 
metformin-specific eligibility criteria related to safety (e.g. eGFR and hemoglobin).  
Participants in the metformin arm will be provided with a card and a letter indicating the 
potential risk for lactic acidosis associated with certain medical conditions and 
procedures.   
   
D- Hypoxia and Hypoperfusion   
Participants who develop acute myocardial infection or congestive heart failure are at risk 
of lactic acidosis because of hypoperfusion and/or hypoxia associated with these 
conditions. Participants in the metformin arm who experience these conditions will be 
instructed to stop metformin immediately.  In conjunction with the clinicians providing care 
for these conditions, a decision to restart metformin can be approved by a study clinician 
after a review of metformin-specific eligibility criteria related to safety (e.g. eGFR and 
hemoglobin).  Participants in the metformin arm will be provided with a card and a letter 
indicating the potential risk for lactic acidosis associated with certain medical conditions 
and procedures.    
   


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E- Pregnancy and breastfeeding   
Women who are pregnant or who plan to become pregnant and women who are 
breastfeeding or plan to breastfeed will be excluded from this study.  Premenopausal 
women will be educated regarding the risk of pregnancy while taking metformin and will 
be instructed to use a reliable form of birth control while taking metformin.  Women who 
become pregnant during the study will be instructed to stop metformin immediately.  
Premenopausal women will be asked to stop metformin and contact the study if they 
believe they may be pregnant or if their menses become irregular. A pregnancy test may 
be ordered.    
   
Adherence   
Assessing participants’ adherence to metformin and identifying non-adherent participants will 
help optimize adherence to the prescribed medicine. Participants in the metformin arm will 
receive one-on-one education with study staff at baseline and educational materials covering 
common side effects, administration of metformin, and contact information of study staff and 
physician. In addition to scheduled face-to-face data collection visits, follow-up phone calls at 2 
week and 1 month will be conducted by trained study staff on a one-to-one basis to ensure 
adherence and address questions. The following are methods to assess adherence among 
metformin arm participants:   
- 
Pill count by visual inspection during visits when participants bring their containers for 
refill. In the absence of pill containers, participants will be interviewed about their pill 
compliance.   
- 
Follow-up phone calls at 2nd week and 1 month. Participants will be instructed to contact 
study staff if they experience any side effects, especially gastrointestinal symptoms such 
as nausea and diarrhea.    
   
9. VISITS AND FOLLOW-UP  Approach to Data Collection and Visits   
Study investigators and staff recognize the need to accommodate participant needs and 
accordingly will be flexible in implementing the expected data collection procedures.  For 
example, some participants may need to split visits (e.g. having 2 baseline visits), while 
others might prefer to bundle data collection into fewer visits (e.g. bundling screening and 
baseline visits).  Our general approach will be to accommodate such requests, as long as 
we collect the required data.    
Pre-Screening Call   
Recruitment materials will direct interested individuals to contact the study by e-mail, 
postcard, or the telephone contact information provided in the mailed recruitment materials. 
A pre-screening phone call will then occur. During the phone call, study staff will provide 
information about the trial, obtain verbal informed consent, and collect data on eligibility.   


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24   
Screening Visit 1   
Those who remain interested and potentially eligible will be asked to attend the first screening 
visit in the clinic center in person and meet with study staff. Trained study staff will obtain the 
following measures:   
- 
Weight & height   
- 
Blood pressure   
- 
non-fasting labs    
- 
Questionnaires (See Table 3)   
All potential participants will demonstrate the ability to send and receive emails, ability to 
complete online forms, and sufficient phone minutes for coaching calls during this visit.   
Screening Visit 2   
Participants, who remain eligible after the screening visit 1, will be asked to attend the second 
screening visit after at least 9 hours of fasting. The following activities and measurers will 
take place:   
- 
Orient the participant about each intervention arm, expectations and related details. -  
 Weight   
- 
Blood pressure   
- 
Fasting labs   
- 
HbA1c   
- 
Current medication   
- 
Questionnaires (See Table 3)    
Randomization Visit   
During this visit, study staff will reconfirm the eligibility. Weight and blood pressure will be 
measured. Each participant will be re-oriented to each intervention arm. Each participant will 
be randomized and assigned to one of the three interventions arm: self-directed weight loss, 
coach-directed behavioral weight loss or metformin.   
Follow-Up Visits   
There are three types of follow-up based on the contact mode: in-person, telephone and 
website.    
In-person follow-up visits will take place at ProHealth at 3-month, 6-month, and 12-month 
intervals. Participants will be asked to attend those visits after having fasted for at least 9 
hours. The following will take place during these visits:   
- 
Weight   
- 
Blood pressure   
- 
Fasting labs and HbA1c   
- 
Patient reported outcomes (EuroQol;)   
- 
Current medication    


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- 
Fat screener, fruit screener, physical activies, general symptoms form   
- 
Pill counts for adherence, challenges and enabling factors for adherence   
- 
Any adverse events   
- 
Any other issues raised by the participant that can be addressed within the scope of the 
study   
   
Additional telephone contacts, for the metformin arm, will take place at the following times 
after baseline visit: every 2 weeks for the first month and otherwise as needed throughout 
the intervention period. During these calls, the study staff will ask about adherence and 
side effects using a standardized study questionnaire.   
Throughout the study, email and web contacts will take place to remind participants in the 
coach-directed behavioral weight loss arm to enter their self-monitoring data, and to followup 
on adherence and check for adverse events. In-person visits will take place on the 3rd, 6th 
and the twelfth month for the same reasons.   
10. DATA COLLECTION AND OUTCOME MEASURES   
   
All measurements and sample collection will be conducted by trained, certified staff. Any 
measure-specific devices, instruments, and equipment will be calibrated and standardized. All 
lab measures will be analyzed in the same labs, and all patient-reported outcomes will be 
captured by standardized forms. Eligibility, baseline, and follow-up data will be collected by 
phone, over the web, and at in-person visits. To the extent possible, questionnaire data will be 
collected through website (for the coach-directed arm) or telephone, rather than on-site.  
Inperson data collection visits will be conducted mainly at ProHealth, with satellite sites at 
SKCCC and Johns Hopkins Bayview if needed. Below are the primary and secondary 
measures that will take place at specific contact points across all arms.   
Data Collection Schedule   
   
Table 3: Data Collection Schedule, All Participants   
   
Prescreen Screening  Randomization  3 
months   
6 
months  
12 
months  
Data collection   
   
   
   
   
   
   
Eligibility/Interest   
X   
X   
   
   
   
   
Informed consent   
X   
X   
   
   
   
   
Weight   
   
X   
   
X   
X   
X   
Height   
   
X   
   
   
   
   
Blood pressure   
   
X   
X   
X   
X   
X   
IGF-1/IGFBP-III   
   
X    
X    
X§   
X§    
X§    
Metabolic Panel labs    
   
X   
   
X   
X   
X   


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26   
CBC   
   
X    
   
   
   
X    
HbA1c§    
   
   
X   
   
X   
X   
CRP. IL-6, IL-8   
   
   
X   
   
X   
X   
Stored specimens ɫ   
   
   
X   
   
X   
X    
Stool Sample   
   
   
X   
   
X   
X   
Randomization   
   
   
X   
   
   
   
Questionnaires   
   
   
   
   
   
   
  Demographics   
   
X   
   
   
   
   
  Diet/physical activity   
   
X   
   
X   
X   
X   
  Eurol-Qol   
   
X   
   
X   
X   
X   
  Medical history   
   
X   
   
   
   
   
  Medications   
   
X   
X   
X   
X   
X   
  Interim events   
   
   
X   
X   
X   
X   
§ Processed as a batch from frozen specimens. ɫ Stored.      
Primary Outcome Measure   
Insulin-like Growth Factor I (IGF-1): At each in-person visit, participants will be asked to 
have fasted for at least 9 hours. Phlebotomy, processing, and storage will be done by trained 
staff members and according to a standardized protocol.  Frozen samples will be transported 
to the University of Maryland School of Medicine Pathology Laboratory  where assays for 
IGF-1 will be conducted using the IMMULITE 2000 Assays.   
   
   
Insulin-like Growth Factor Binding Protein III (IGFBP-III): At each in-person visit, 
participants will be asked to have fasted for at least 9 hours. Phlebotomy, processing, and 
storage will be done by trained staff members and according to a standardized protocol.  
Frozen samples will be transported to the University of Maryland School of Medicine   
Pathology Laboratory  where assays for IGFBP-III will be conducted using immunoassays  
Secondary Outcome Measures   
Height: This is a onetime measure during the first in-person visit. Participants will stand 
straight without shoes, and a standard calibrated wall mounted stadiometer will be used. 
Precision of height is up to 0.1 of a centimeter.    
Weight: At each in-person visit, staff blinded to randomized assignments will measure weight 
while the participant is shoeless and in light clothing. A calibrated, standardized electronic 
weight-measuring scale will be used. Measurements are in pounds and later converted to kg 
for analysis. Weight will be measured twice; if the difference between the two measures is 
more than 0.1 kg, then another measure will be taken.   
Body Mass Index: BMI will be calculated as (weight in kg/height2 in meters)   


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27   
Other Outcome Measures   
Lipids: Total cholesterol, triglycerides, and HDL will be measured from overnight fasting 
plasma. LDL will be calculated by the Friedewald equation.   
Glucose and Insulin: Fasting glucose and insulin will be measured after overnight fasting 
from plasma.   
HbA1c: HbA1c measures will be measured from whole blood.    
Demographics and Medical History: A self-reported assessment of basic patient 
characteristics will be collected which will include age, gender, race/ethnicity tobacco use, , 
health insurance status, , income, employment, education level, post-menopausal status and 
current health status and co-morbid conditions (e.g., diabetes and hypertension).  Additional 
details on solid tumor malignancy will also be obtained, including organ of origin, date of 
diagnosis, stage of disease at diagnosis, treatments received, and date of completion of 
treatment(s).    
Diet and Physical Activity: Diet will be assessed with standardized questionnaires. 
Physical activity will be assessed by both a standardized questionnaire and an 
accelerometer.    
• 
Fruit & Vegetable Screener is a brief self-report measure of daily fruit and vegetable 
intake, portion size, frequency and type.    
• 
Block Fat Screener is a brief self-report assessment of percent energy intake from 
fat; this measure comes from the National Cancer Institute’s Risk Factor Monitoring 
and Methods staff.   
• 
Physical Activity will be measured using the Godin Physical Activity Measure. It will 
be used to estimate levels of moderate and vigorous physical activity from the 
previous week.   
• 
87,88.87 91,92   
Quality of Life: The EuroQol measure is drawn from the EQ-5D measure and has 6 
questions. The EQ-5D descriptive system consists of five dimensions: 1) mobility; 2) 
selfcare; 3) usual activities; 4) pain/discomfort; 5) anxiety/depression.    
Current Medications: Current medication use will be assessed by self-report of medication 
names, dosages, routes of intake and frequency.   
Serious Adverse Events will be measured using the Serious Adverse Event Form 
(SAEForm). This form measures the event, characteristics, onset, and severity.   
IL-6, IL-8 , both will be measured using commercial sandwich-based enzyme linked 
immunosorbent assays (ELISAs).   
   
hs-CRP will be analyzed by quantitative immunoturbidimetry.   
   


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Stored Specimens   
Serum and plasma samples of all our participants will be stored at -800C for future 
investigation of other studies. In addition, fecal samples will be collected at baseline visit, 
and 6th month. Samples will be transported on dry ice to N2 Vapor Freezers or Mechanical 
Ultra Low Freezers (-800C) in the Tissue Bank of the Hopkins Conte Digestive Diseases 
Basic and Translational Research Core Center for long-term storage and analysis at a later 
time.    
Future measures: the following are future measures that are not supported by this trial:   
-  leptin, adiponectin, VEGF, HGF, and EGF; SLC22A1, SLC22A2, and SLC47A1 gene 
variants; and 16S bacterial whole genome sequencing of gut microbiome.   
11.  MASKING OF DATA COLLECTION   
   
Upon confirmation of eligibility and baseline data collection, 120 participants will be 
randomized in a 1:1:1 ratio to one of the three intervention arms. Randomization will be 
stratified by race and baseline BMI. Password-protected randomization software will ensure 
authorized access to the group assignment, which is restricted to designated study personnel 
only during the execution of the trial. The randomization scheme will be generated by the 
biostatistician. Intervention assignment is not blinded to the trial participants, nor the 
intervention staff. However, study staff involved in follow-up data collection will be masked to 
the randomization assignments. Moreover, the primary outcomes will be measured by labs; 
and staff in the lab will be blinded to the randomization assignment.   
   
12.   DISCONTINUATION OF SUBJECTS    
   
Reasons for discontinuation and withdrawal will be documented in participant’s medical record. 
All study interventions expected to last for 12 months, unless the participant fulfills one or more 
of the following conditions:   
- 
Diagnosis of new or recurrent illness that may require the participant to stop the 
intervention, based on the judgment of the principal investigator.   
- 
Diagnoses of recurrent cancer that may require a change in therapy plan, which may 
prevent the participant from continuing the study’s specific intervention.   
- 
Pregnancy   
- 
Patient request to discontinue due to inability to take or tolerate metformin   
Reimbursement   
Participants enrolled and randomized in the intervention study arms will receive $50-150 
compensation in check for every follow-up visit for a possible total of $300. Participants who 
need transportation, cost may be compensated.   


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13.  ADVERSE EVENT   
13.1 General   
National Cancer Institute/Common Terminology Criteria for Adverse Events (CTCAE) v4.0 will 
be the guideline for this study in describing, grading, and reporting of adverse events. Adverse 
events believed to be related to weight loss or metformin will be reported. Adverse event 
information will be collected during each in-person visit from screening phase onward. Only 
adverse events possibly, probably or definitely related to study interventions will be tabulated 
and reported according to NIH guideline (insert reference). All serious adverse events, 
regardless of relation to study interventions must be reported to the principle investigator. All 
adverse and serious adverse events will be reported to the local institutional review board. Any 
modification to consent and/or study protocol, resulting from an adverse event, will be provided 
to IRB with the report of the adverse event.   
Definitions    
• 
Adverse event (AE): Any undesirable sign, symptom, or medical condition occurring after 
starting therapy, even if the event is not considered to be related to the study. An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia), or abnormal results of a procedure (e.g., laboratory findings, biopsies).   
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment and are believed to be related 
to the weight loss or metformin intervention.   
• 
Serious adverse event or reaction: Any untoward medical occurrence secondary to therapy 
that: results in death, is immediately life-threatening, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant disability, or is an  
important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.   
The definition of a serious adverse event (experience) also includes an important medical 
event. Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious.   
   
A hospitalization planned before the start of the study agent(s) and/or for a preexisting 
condition that has not worsened does not constitute a serious adverse event (e.g., elective 
hospitalization for breast reconstruction). A hospitalization for a social reason in the absence of 
an adverse event also does not meet the criteria for a serious adverse event.   
• 
Unexpected adverse event: An adverse event, which varies in nature, intensity or 
frequency from information on the investigational intervention provided in the Investigator’s 


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30   
Brochure, package insert, or safety reports. Any adverse event that is not included in the 
informed consent is considered “unexpected”.   
• 
Expected (known) adverse event: An adverse event, which has been reported in the 
Investigator’s Brochure. An adverse event is considered “expected”, only if it is included in 
the informed consent document as a risk.   
Relationship   
An investigator will assess the relationship between adverse events to study intervention as 
follows:   
- 
Definitely: An adverse event, which has a timely relationship to the administration of the 
investigational drug/agent, follows a known pattern of response, for which no alternative 
cause is present.   
- 
Probably: An adverse event, which has a timely relationship to the administration of the 
investigational drug/agent, follows a known pattern of response, but for which a potential 
alternative cause may be present.   
- 
Possibly: An adverse event, which has a timely relationship to the administration of the 
investigational drug/agent, follows no known pattern of response, but a potential 
alternative cause does not exist.   
- 
Unlikely: An adverse event which does not have a timely relationship to the 
administration of the investigational drug/agent, follows no known pattern of response, 
does not reappear or worsen after re-administration of the investigational drug/agent (if 
applicable), and for which there is evidence that it is related to a cause other than the 
investigational drug/agent.   
- 
Unrelated: An adverse event, for which there is evidence that it is definitely related to a 
cause other than the investigational drug/agent. In general, there is no timely 
relationship to the administration of the investigational drug/agent, or if there is a timely 
relationship, the event does not follow a known pattern of response, and there is an 
alternative cause.   
13.2 Potential Risk from Intervention    
   
Side effects associated with weight loss, such as anxiety, may occur. Unlike with our intended 
lifestyle weight loss target (5% weight loss from baseline), a major weight loss may be 
associated with side effects including dehydration, electrolyte imbalance, malnutrition, nausea, 
tachycardia and headaches. Side effects from metformin include nausea, diarrhea, abdominal 
bloating, metallic taste, anorexia, or flatulence, vitamin B12 deficiency, and rarely, lactic 
acidosis. When blood samples are collected from participants, blood draw procedures may 
produce risk.   


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31   
The followings are potential risk associated with the followings:   
Potential risks associated with Coach-Directed Behavioral Weight Loss intervention and 
respective measures to minimize risk:   
A- Nutrient Intake   
Inadequate nutrition or excessive, rapid weight loss can result from calorie restriction. 
To minimize these risks, participants are encouraged to maintain adequate calorie level 
and eat a variety of foods from all food groups. Participants will be advised about 
serious health risks associated with sustained caloric restriction. Intervention can be 
suspended, and participant will be referred to the PCP if nutritional deficiency is 
suspected and participant is unresponsive to advice from study staff.   
B- Hypoglycemia   
Low blood glucose level can result from severe caloric restriction and exercise. To 
minimize this risk, participants will be educated about the signs and symptoms of low 
blood sugar, when to contact their PCP, and adequate calorie levels and the food 
groups to consume while under the lifestyle intervention. The study team will engage 
the PCP in this intervention arm.   
C- Symptomatic Hypotension   
For those who use anti-hypertensive medication, lifestyle medication interventions have 
the potential to increase the risk of hypotension. Participants are educated about 
symptoms of hypotension and urged to contact their PCP if they have symptoms 
suggestive of hypotension. Overall blood pressure management will be under the PCP 
responsibility.   
D- Cardiovascular Events   
All participants with cardiovascular disease (CVD) require approval from their PCP prior 
to enrolling. PCPs are provided with information about safety guidelines for physical 
activity for people with CVD. In addition, participants are educated about CVD 
symptoms and urged to contact 911 in case of emergency or their PCP if they have a 
change in their CVD symptoms. In case a participant develop any CVD event, the 
intervention will be suspended until a decision to restart is authorized by the 
participant’s PCP and the study principle investigator. Overall CVD management 
remains under the control of the participants PCP.   
   
Potential risks associated with Metformin interventions and measures to minimize potential 
risks.   
   
   
A- Gastrointestinal symptoms   
B- Nausea, diarrhea, abdominal bloating, metallic taste, anorexia, and flatulence are 
associated with metformin use. If a participant develops mild symptoms that can be 
tolerated, then metformin will continue. If symptoms are difficult to tolerate, metformin 
will be stopped temporarily to establish association with the symptoms. Weekly or 
lessfrequent titration to maximum tolerated dose will be used to minimize 


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32   
gastrointestinal symptoms.  Restarting and continuation of metformin will be based on 
clinical judgment regarding severity of symptoms and tolerance of symptoms by 
participant.   
C- Lactic Acidosis   
Metformin is rarely associated with lactic acidosis (approximately 0.03 cases/1000 
patient-years; no cases reported in 20,000 patient-years of exposure to metformin in clinical 
trials).86 If a participant is hospitalized and develops metabolic acidosis, metformin will be 
stopped.  Clinical judgment will guide the decision to restart metformin after resolution of 
acidosis based on understanding of the etiology of the cause of the acidosis. D- Anemia  
Vitamin B12 blood levels decrease to sub-normal levels without any clinical manifestations in 
approximately 7% of patients treated with metformin in clinical trials;86 this is very rarely 
associated with anemia. However in long term high dose use,there may be a slightly lower 
hemoglobin level.63 If anemia or vitamin deficiency is suspected, study physician will order 
vitamin B12 test.    
E- Hypersensitivity to metformin   
Participants who develop an allergic reaction or hypersensitivity to metformin will 
discontinue metformin.   
F- Other adverse events   
Interim events will be ascertained every three months, and serious adverse events will 
be reported per institutional review board and FDA regulations.   
   
Safety Monitoring and Measures to Reduce Potential Drug-Related Side Effects 
Standard laboratory studies will be done for each participant in the metformin arm. eGFR 
and complete blood count will be measured for eligibility.  A complete blood count, and 
basic metabolic panel (including eGFR) will be measured at 12 months.    
The most common side effects, reported by 28% of persons taking metformin, are 
gastrointestinal symptoms, among which nausea, diarrhea, abdominal bloating, metallic 
taste, anorexia, or flatulence are included.63 These side effects are usually transient and 
resolve spontaneously or can be controlled by graduate dosing. Rarely, metformin can 
cause lactic acidosis among persons with renal of hepatic insufficiency, especially during 
episodes of hypoxia or circulatory failure. In addition, about 6-9% persons on metformin 
develop reduced vitamin B12 levels.86   
Potential risks associated with blood draw procedure and measures to minimize potential 
risks   
   
A- Blood draw may produce discomfort, pain, bruises, and rarely, infection, syncope, or 
bleeding. Out trained staff will follow standard phlebotomy protocol for infection 
prevention and control, safety equipment and best practices.   
   
13.3 Alert Levels   
   


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33   
Laboratory studies and physical measurements will be obtained.  For laboratory studies, we 
will use the alert values of the laboratory that performs the assays.  For example, if the 
laboratory reports an alert level, study staff will be notified, and a clinician (either study nurse 
or physician) will contact the participant.  Study physicians will also review and sign/initial each 
laboratory report, which we will then provide participants.  ProHealth, a major clinical research 
unit for cardiovascular disease prevention studies, also has well established procedures and 
thresholds for other measurements such as blood pressure.  If a participant’s blood pressure is 
elevated, study staff will advise the participant to see their personal provider, using 
wellaccepted BP thresholds.      
14. DATA AND SAFETY MONITORING   
14.1 Data Management System    
All information will be collected through the study website or using case-report forms. All 
studyrelated data will be reviewed for accuracy by the Project Manager or Database Manager. 
A periodic review will be done by the data analysis team.   
14.2 Meetings   
Regular meetings between the co-investigators and the study team will take place; additional 
meetings will be called as needed. Periodic meetings between the principal investigator, study 
coordinator, biostatistician, and data manager will take place to discuss study, progress, protocol 
adherence and objectives.   
14.3 DATA Safety Monitoring Board   
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan (12/6/2012). The 
Clinical Research Office will perform an audit after the first subject has been treated and then 
periodically depending on the rate of accrual and prior audit results. All trial monitoring and 
reporting will be reviewed annually by the SKCCC Safety Monitoring Committee. The PI is 
responsible for internally monitoring the study. Data must be reviewed to assure the validity of 
data, as well as, the safety of the subjects. The PI will also monitor the progress of the trial, 
review safety reports, and clinical trial efficacy endpoints and to confirm that the safety 
outcomes favor continuation of the study   
   
   
15. STUDY ADMINISTRATION  Trial Organization   
This is a single center randomized clinical trial. The Steering Committee (SC) will act as the 
regulatory, policy, and decision-making body for the study. The SC will have complete 
oversight over study implementation, provide scientific decisions and advice, monitor protocol 
adherence, and provide overall management. For the initial part of the trial, the following 
subcommittees will work with the SC:   
- 
Administrative Sub-Committee: in charge of protocol approval, update, and 
administrative matters.   
- 
Recruitment Sub-Committee: in charge of developing recruitment strategies and 
monitoring recruitment progress.   


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34   
- 
Metformin Sub-Committee: concerned with the scientific details and implementation of 
metformin intervention arm   
- 
Coach-Directed Behavioral Weight Loss Sub-committee: concerned with the scientific 
details and implementation of life style modification arm.   
- 
Data Management and Analysis Sub-committee: concerned with randomization, data 
management, data quality control, report(s) to DSMB, and statistical analysis.    
- 
Clinician Review Committee: in charge of reviewing eligibility, adverse events, and 
safety.   
Ethics and Good Clinical Practice   
This study must and will be implemented according to protocol and Good Clinical Practice as 
described in:   
- 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.   
- 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations).   
- 
Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996).   
Funding Mechanism and Sponsors   
This study is supported by the State of Maryland Cigarette Restitution Fund. The Johns 
Hopkins Kimmel Cancer Center is providing additional support.    
16. SAMPLE SIZE   
The trial has sufficient resources to enroll ~120 participants, who will be randomly allocated in 
equal proportions to each of 3 arms:   
- 
Group A: Self-directed weight loss arm.   
- 
Group B: Coach-Directed Behavioral weight loss intervention arm.    
- 
Group C: Pharmacological intervention using metformin.    
The primary contrasts are (C vs. A) and (B vs. A). The (C vs. B) contrast is secondary and is 
not considered in computing power.   
The required sample size for the study was powered for testing 2 primary contrasts of change 
in IGF-1 over time in (1) lifestyle (arm B) vs. self-directed comparison (arm A), and (2) 
metformin (arm C) vs. self-directed comparison (arm A), each with 80% power and a 2-sided z 
test with alpha of 0.025. Assuming common SD at baseline and 6-month visit of 60 ng/ml, 51 
and a correlation of 0.90 between IGF-1 measures at baseline and 6-month47, a total sample 
of 120 individuals (i.e. N=40 per arm) will allow the detection of a difference of 17.4 ng/ml 
(~10% reduction) or greater in change of IGF-1 over time between an active intervention arm 
and the control arm. With 20% random attrition, this trial will still be able to detect a difference 


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35   
of 19.4 ng/ml or greater in change of IGF-1 over time between an active intervention arm and 
the control arm.     
With the same sample size, the minimal detectable between arm difference in change of 
IGF1:IGFBP3 ratio over time were evaluated in a similar fashion for (1) arm B vs. A, and (2) 
arm C vs. A, each with 80% power and a 2-sided alpha of 0.025. Assuming common SD at 
baseline and 6-month visit of 11 using data available from the POWER trial, 81and a correlation 
of 0.80 between IGF-1:IGFBP3 ratio at baseline and 6-month47, a total sample of 120 
individuals (i.e. N=40 per arm) will allow the detection of a difference of 5.01 (~15% reduction) 
or greater in the change of IGF-1:IGFBP3 ratio over time between an active intervention arm 
and the control arm. With 20% random attrition, this trial will still be able to detect a difference 
of 5.67 or greater in change of IGF-1:IGFBP3 ratio over time between an active intervention 
arm and the control arm. We will explore the difference in outcome changes over time between 
arm B and C but this trial is not powered for this test, as the difference between these 2 arms 
may be small.    
17. DATA ANALYSIS & STATISTICAL CONSIDERATION   
17.1  Analysis Overview   
This is a single center, randomized clinical trial, designed to test the effect of Behavioral   
Weight Loss and metformin versus self-directed weight loss on blood levels of Insulin-like 
Growth Factor 1 (IGF1) and IGF1 to Insulin-like Growth Factor Binding Protein III (IGFBP-III) 
ratio over 12 months among men and women who survived malignant solid tumor after 
completing all local therapy and/or adjuvant chemotherapy. Participants will be randomized at 
a 1:1:1 ratio to self-directed weight loss (Group A), Coach-Directed Behavioral Weight Loss 
(Group B), or metformin pharmaceutical intervention (Group C). Randomization will be 
stratified by race and BMI, and we are aiming to recruit ~50% African American in this trial. 
120 individuals will be enrolled, with 40 participants in each arm.   
The distribution of baseline characteristics of the participants by intervention arms will be 
described using mean and standard deviation for the continuous variables, and % frequency 
for the categorical variables. The primary analyses will follow the intention-to-treat principles, 
and be carried out using likelihood based mixed effects linear regression modeling. Evaluation 
of potential impacts due to missing data, should it occur, on intervention effect estimates will 
be anchored on analyses assuming missing at random, and supplemented by sensitivity 
analyses under plausible informative missing scenarios using multiple imputation approach. 
Potential impacts of treatment adherence on estimates of intervention effects will be explored 
by on treatment analyses paying special attention to adjusting for characteristics associated 
with treatment adherence. These analyses will be carried out using the propensity score 
approaches.   
17.2 General Statistical Approach   
The primary endpoint of this trial is the 6-month change in level of IGF-1 and IGF1 to IGFBP-III 
ratio among the Coach-Directed Behavioral Weight Loss arm versus self-direct arm (B vs. A), 
and metformin arm compared to self-direct arm (C vs. A). Intervention effects will be analyzed 
using intent-to-treat. Each active intervention arm will be compared with the control arm using 


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36   
likelihood based mixed effects linear regression models utilizing data from all 3 time points, i.e. 
baseline, 6, and 12 months, simultaneously, as following.    
The primary analysis model: The mean model for the mixed effects regression will be 
structured to include 2 binary intervention arm indicators (for Group B and C), 3 binary 
followup time indicators (for 3-, 6- and 12-month follow-up), and the cross-product interaction 
terms between the group and time indicators (6 interaction terms), and the covariance model 
will employ a 4x4 unstructured covariance matrix to allow different outcome variances and 
account for the intra-individual outcome correlations over time. Race and baseline BMI levels, 
the variables used for stratifying the randomization, will be included in the mean model. Other 
variables found not to be balanced between the trial arms will also be included as necessary. 
Outcomes may be transformed as needed to satisfy the distributional assumptions for the 
likelihood approach.    
The primary testing contrasts of this trial will be the 2 aforementioned pairwise comparisons at  
6 months, which will be evaluated through the regression coefficients of the Group B by 
6month interaction term (B vs. A), and Group C by 6-month interaction term (C vs. A), 
respectively. The secondary testing contrasts include B vs. C of change in outcomes at 
6month, and the 3 pairwise group comparisons of outcome changes at 12 months, which will 
be evaluated using the same model through the corresponding group by time interaction 
terms.    
For outcomes such as IGF-1, IGF-1:IGFBP3 ratio, weight, BMI, and measures assessed 
through the metabolic panel labs, where data will be available at 3-month, these information will 
be utilized through the primary model to enhance model estimation, especially in the event of 
missing data encountered at 6- and/or 12-month, events though the effect size of the 
intervention at 3-month is not part of the primary or secondary goals. For outcomes such as 
EQ-5D, questionnaire outcomes on dietary intake and physical activity, HbA1c, IL-6, IL-8, and 
CRP, where data will not be available at the 3-month visit, the analysis models will not include 
any independent variables terms related to that visit.   
We will also conduct subgroup analyses to explore for potential differential intervention effects 
across these pre-specified subgroups. Statistical significance of these subgroup analyses will 
be evaluated though incorporating appropriate subgroup by intervention by visit interaction 
terms. To explore the association of physical activity levels with the outcomes of IGF-1 or the 
IGF-1: IGFBP-3 ratio, time dependent physical activity measures will be further included to 
augment the primary analysis model to explore for the degree of attenuation of intervention 
effect by physical activities. Similar analyses could be done for body weight and BMI.   
We will also explore for possible treatment effect modification by baseline BMI level to better 
understand the potential heterogeneity of treatment effects to inform future trials and studies. 
This will be carried out by including the 3-way interaction terms (Group indicator by Time 
indicator by BMI) in the primary analysis model. We will also estimate total intervention costs 
for future trials in a large population.   


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Missing and incomplete data    
Prevention is far superior to a statistical cure, and every effort will be made to collect outcome 
data on all randomized participants.   For example, we will collect outcomes on individuals who 
have stopped participating in the trial intervention.   Due to the high longitudinal correlation, 
missed “interior” visits won’t decrease information very much for a linear trend.  However, they 
are needed to assess departures from a linear trend.    
As detailed in Little and Rubin 2002 and discussed by Mealli , the underlying missing data 
process determines the biasing effects of missing data and structures valid analytic strategies. 
93,94 If data are missing completely at random (MCAR), then there is no induced bias and a 
complete case analysis, while inefficient, is valid. If the probability of a potential observation 
being missing depends on what has been observed, but not on what hasn’t been observed,   
i.e., data is missing at random (MAR), then estimates based on an appropriate analytic model 
(on both the mean and error structure) for the observed data will not be biased. Use of a valid 
statistical model for the observed data would allow the missing data process to be ignored. In 
this situation either multiple imputation (MI) or development of a valid statistical model for the 
observed data (appropriate mean structure and correlation structure) will allow valid statistical 
inferences on the intervention effects. To use all participants when comparing treatments on 
the (12 month - baseline) outcome changes between groups, we will take advantage of the 
statistical association between outcomes at baseline, 6 and 12 months, and build a 
longitudinal model and then use one of these essentially equivalent approaches   
In the third type of missing data process the probability of being missing depends on what 
would have been observed (e.g., the IGF-1 that would have been measured).  In this case, 
neither MI nor developing a model for the observed data will completely eliminate bias.  One 
can never empirically rule out this situation, but comprehensive statistical modeling coupled 
with sensitivity analysis can assess the stability of findings. We will anchor our sensitivity 
analyses under the assumption of MAR, and derive a valid model for the observed data under 
MAR, then alter the mean structure of the model under plausible non-MAR scenarios, and 
estimate intervention effects though MI approach to examine the robustness of the finding 
under MAR assumption.      
On-treatment Analyses   
Primary analyses will be performed on an intention-to-treat basis. However, interpretation of 
the trial outcomes is complicated because of drop-out from the intervention group and drop-in 
from the control group.  Particularly common are early drop-outs, i.e. individuals randomized to 
intervention who attend only a few intervention sessions, sometimes none.  Such persons are 
included in ITT analyses.  In this setting, we will compute “on treatment” comparisons and 
variations on this approach that adjust such an analysis for differential correlates of adherence 
in the treatment groups.     
Care is needed in answering such questions, and Bellamy et al. and Mealli et al. provide a 
useful framework for such analyses.94,95 For a basic case, we consider how to handle 
participants who complete at most 2 intervention “courses”.  They will be included in the 
primary, as randomized, intent to treat analysis.  A secondary question is, “how do the 


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38   
treatment groups compare for those who adhered to treatment?”  A straightforward 
comparison of treatments based only on “compliers” is attractive, but is biased if the compliers 
differ among the treatment groups.  A valid comparison depends on adjusting for these 
differences, being careful not to adjust away the treatment effect.  Propensity score 
approaches using information available at randomization and up through the first “course” 
could adjust for this imbalance.   More sophisticated approaches using time-varying 
propensities allow accommodating more complicated patterns of non-adherence.    
18.  STUDY TIMETABLE    
   
Table 5: Study Time Line   
   
2014     
2015     
  
2016     
2017   
   
   
Quarter   
q3   q4   q1   q2   q3   q4   q1   q2   q3   q4   q1   q2   Q3  Q4  
Refine protocol   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
Staff Training    
   
   
   
   
   
   
   
   
   
   
   
   
   
   
Pilot and finalize forms   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
Database Development   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
Modify intervention platform       
   
   
   
   
   
   
   
   
   
   
   
   
   
Recruitment   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
Intervention *   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
Follow-up**   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
Adverse event monitor   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
Analysis   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
Paper writing   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
19. HUMAN SUBJECTS   Description of Consent Process    
Each potential participant will meet with a staff member during in-person visits including the 
screening visit and randomization visit. Before randomization, a staff member will go 
through the consent form. The consent form is a printed form created using simple 
language and approved by the IRB. The staff member will start by explaining the nature 
and purpose of the trial, the interventions, study length, any potential risks and benefits, 
and the expectations for participants and study administrators. In addition, participants will 
be informed that participation is voluntary and that they can withdraw at any point, and that 
their refusal to participate will have no effect on their current of future treatment with the 
care provider. Each potential participant will be given time to read the consent form, and if 
he/she decides to join the study, he/she will sign and date the form. A copy of the signed, 
dated consent form will be given to the participant.   


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In accordance with the Health Insurance Portability and Accountability Act (HIPAA), the 
written informed consent document will include a subject authorization to release medical 
information to the project sponsor and supporting agencies and/or allow these bodies, a 
regulatory authority, or Institutional Review Board access to subjects’ medical information 
that includes all hospital records relevant to the project, including subjects’ medical history.   
Confidentiality   
All participants’ data will be protected. Hard copies will be locked in a secured cabinet or 
locked room, and digital copies will be protected in  encrypted secure hard drive. Any 
communication and data transfer will be done using a de-identified data set with a study ID 
number. Data transfer agreement will be prepared if needed.   
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