Clinical trial NCT02472353
Conditions: Breast Cancer Breast Tumors
Keywords: breast cancer doxorubicin metformin cardiotoxicity ejection fraction LVEF
Sponsor: Avera McKennan Hospital & University Health Center
Start date: 2014-07-01; Completion date: 2018-05-23
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to determine if co-administration of metformin and doxorubicin in breast cancer patients receiving neoadjuvant or adjuvant therapy will reduce the number of patients who develop a significant change in left ventricle ejection fraction (LVEF).

Detailed description:
This is a randomized, open-label, phase II design pilot study in patients with breast cancer requiring neoadjuvant or adjuvant chemotherapy. Eligible patients will be equally randomized to either receive metformin plus standard of care therapy or standard of care therapy alone. Patients receiving metformin will continue drug until the doxorubicin-containing cycles are complete, unless unacceptable toxicity occurs or the patient decides to withdraw from the study. Both arms of the study will undergo echocardiograms with contrast at baseline, upon completion of doxorubicin-containing cycles (within 28 days of completion), and at the one-year and seven-year time points. Additionally biomarker labs will be obtained to explore if there is a correlation between change in cardiac activity and the activity of metformin. If willing, all enrolled patients will provide a sample of whole blood for further exploratory analysis. Symptoms reported during the study will be correlated with know single nucleotide polymorphisms (SNPs) found during an exploratory genomic analysis.

Arms: arm 1: Patients will receive standard of care for their breast cancer with no metformin during their treatment with doxorubicin. arm 2: Patients will receive metformin during their treatment with doxorubicin for their breast cancer.
Interventions: intervention 1: Metformin intervention 2: Doxorubicin
Intervention descriptions: intervention 1: Metformin will begin to be administered prior to treatment with doxorubicin. Metformin will continue to be given throughout doxorubicin cycles until the completion of doxorubicin therapy. intervention 2: Standard of care treatment with doxorubicin

Protocol documents:
Prot_SAP_000.pdf: 
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MET001 - A Phase II Pilot Study Using Metformin to Reduce 
 Cardiac Toxicity in Breast Cancer Patients 
NCT#: 02472353  
Clinical Investigators 
Kirstin Williams, MS, RN, CNP 
 
Keith Miskimins, PhD 
 
Brian Leyland-Jones, MBBS, PhD 
Casey Williams, PharmD 
 
Amy Krie, MD  
 
Mark Gordon, MD 
Aireen Guzman, MS 
 
 
Jessica Klein, CNP 
 
Chris Gant, CNP 
Richard Conklin, MD 
 
 
Tricia Merrigan, MD 
 
Julianne Reiland, MD 
Benjamin Solomon, MD  
 
Christopher Nelson, CNP 
Missy Hoogeveen, CNP 
Ayham Deeb, MD 


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TABLE OF CONTENTS 
Table of Contents ............................................................................................................................... 2 
Protocol Summary ............................................................................................................................. 4 
Treatment Schema ............................................................................................................................. 6 
1.0 Background Information and Rationale ...................................................................................... 7 
1.1 Pre-clinical Data .............................................................................................................. 8 
1.2 Background Therapeutic Information ............................................................................ 9 
1.3 Metformin Mechanism of Action ................................................................................... 10 
1.3.1 
Pregnancy Safety Data ................................................................................ 10 
1.3.2 
Pharmaceutical Data ................................................................................... 10 
1.4  Chemotherapy and Concomitant Metformin ................................................................ 10 
1.5 Echocardiogram .............................................................................................................. 11 
1.6 Correlative Studies ......................................................................................................... 11 
1.7 Study Checklists and Questionnaires ............................................................................. 12 
1.7.1 
Treatment-Related Symptom Checklist (TRSC) .......................................... 12 
1.7.2 
Symptom Alleviation Self-Care Methods (SASCM)  .................................... 12 
1.7.3 
Health-Related Quality of Life Linear Analogue Self-Assessment  
(HRQOL-LASA) …………………………………………………………………………………………12 
1.8 Whole Blood Banking ..................................................................................................... 12 
2.0 Study Design ................................................................................................................................ 12 
3.0 Objectives .................................................................................................................................... 13 
3.1 Primary Objective ........................................................................................................... 13 
3.2 Secondary Objective ....................................................................................................... 13 
4.0 Patient Selection.......................................................................................................................... 13 
4.1 Inclusion Criteria ............................................................................................................. 13 
4.2 Exclusion Criteria ............................................................................................................ 14 
5.0 Treatment Plan ............................................................................................................................ 14 
5.1 Identification of Potential Subjects ................................................................................ 14 
5.2 Randomization ............................................................................................................... 14 
5.3 Metformin Dispensing and Administration .................................................................... 14 
5.4 Pre-Treatment Evaluation .............................................................................................. 15 
5.5 Evaluation During and After Protocol Treatment .......................................................... 16 
5.6 Follow-Up Period ............................................................................................................ 16 
5.7 Patient Monitoring ......................................................................................................... 17 
5.8 Other Circumstances ...................................................................................................... 18 
5.8.1 
Surgery ........................................................................................................ 18 
5.8.2 
Diagnostic Imaging ...................................................................................... 18 
5.8.3 
Medically Necessary ................................................................................... 18 
5.8.4 
Adverse Events ............................................................................................ 18 
5.8.5 
Concomitant Medications........................................................................... 18 


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5.8.6 
Duration of Therapy .................................................................................... 18 
6.0 Serious Adverse Event Reporting ................................................................................................ 19 
7.0 Patient Discontinuation ............................................................................................................... 19 
8.0 Data Analysis ............................................................................................................................... 19 
8.1 Sample Size Determination ............................................................................................ 20 
9.0 .. Study Administration ................................................................................................................. 20 
9.1 Informed Consent ........................................................................................................... 20 
9.2 Institutional Review Board Approval .............................................................................. 20 
9.3 Modification of the Protocol .......................................................................................... 21 
9.4 Protocol Compliance ...................................................................................................... 21 
9.5 Case Report Forms ......................................................................................................... 21 
9.6 Study Records ................................................................................................................. 21 
References …………………………………………………………………………………………………………………………………….23 
Appendices ………………………………………………..………………………………………………………………………………….26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SUMMARY 
TITLE OF THE STUDY 
A Phase II Pilot Study Using Metformin to Reduce 
Cardiac Toxicity in Breast Cancer Patients 
STUDY OBJECTIVES 
Primary 
 
To determine if co-administration of 
metformin and doxorubicin in breast cancer 
patients receiving neoadjuvant or adjuvant 
therapy will reduce the number of patients 
who develop a significant change in left 
ventricular ejection fraction (LVEF) (≥ 5% 
Decrease) 
Secondary 
 
To assess and compare the number of patients 
in each group who develop a decrease in LVEF 
of ≥10% from baseline  
 
To assess the potential changes in diastolic 
function and compare the changes between 
the treatment arms 
 
To explore whether the following biomarkers 
correlate with a change in cardiac function and 
activity of metformin: Troponin I, BNP, 
glutathione, circulating adiponectin, AMPK 
phosphorylation, and lipid peroxidation,) 
 
To explore whether symptoms expressed on 
the TRSC correlate with known SNPs 
STUDY DESIGN 
Randomized, open-label 
STUDY POPULATION 
Inclusion criteria: 
 
Histologically confirmed breast cancer 
requiring neoadjuvant or adjuvant 
chemotherapy with doxorubicin 
 
Baseline lab work should be completed within 
28 days prior to randomization. Biochemistry 
investigations should reflect values within the 
following parameters: 
o AST ˂ 2.5 X ULN 
o ALT ˂ 2.5 X ULN 
o Alkaline Phosphatase ˂ 2.5 X ULN 
o Serum Creatinine ˂ 1.5mg/dL  
o Serum bilirubin ˂ ULN 
 
ECOG Performance Status of 0 or 1 (at baseline 
evaluation visit within 28 days prior to 
randomization) 
 
Age ≥21 years of age  
 
Protocol treatment should begin within 28 
working days of patient randomization 
 
Patient must sign consent form prior to 


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randomization or registration 
Exclusion criteria: 
 
Known diabetes (Type I or Type 2) 
 
History of cardiac arrhythmias or symptomatic 
cardiac disease 
 
Currently taking antiarrhythmic medications, 
beta-blockers or other rate controlling cardiac 
medications 
 
Subjects who are already taking metformin 
and/or sulfonylureas 
 
Known hypersensitivity or intolerance to 
metformin 
 
Baseline ejection fraction of <50% measured 
by echocardiogram 
 
Risk factors associated with increased risk of 
metformin-associated lactic acidosis (e.g. 
congestive heart failure, history of acidosis, 
habitual intake of 3 or more alcoholic 
beverages per day) 
 
Currently pregnant 
TOTAL NUMBER OF PATIENTS 
The planned sample size is 44 patients with breast 
cancer requiring neoadjuvant or adjuvant therapy 
(80% power to detect significant change in LVEF 
with alpha=0.05) 
STUDY TREATMENT 
Patients will be equally randomized to either 
receive metformin concomitantly with standard of 
care therapy, or to receive standard therapy alone. 
Treatment with metformin on the experimental 
arm will commence approximately 7-10 days prior 
to the start of doxorubicin-containing cycles, and 
will stop once doxorubicin-containing cycles are 
complete (approximately 3-4 months) 
STUDY EVALUATIONS 
The following assessments will be performed: 
 
Echocardiogram (assessment of LVEF) 
performed at baseline, post doxorubicin 
containing cycles, 1 year follow up, and 7 year 
follow-up 
 
Biomarkers: Troponin I, BNP, glutathione, 
circulating adiponectin, AMPK 
phosphorylation, and lipid peroxidation. 
Biomarkers EXCEPT for Troponin I will be 
obtained prior to each doxorubicin infusion 
and within 28 days of last dose with other 
standard of care labs for a total of 5 times. 
Troponin I will be drawn at baseline and 2-3 
days after each doxorubicin dose. Biomarkers 
will be assessed for a correlation with cardiac 


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function as well as metformin activity 
 
Whole blood banking: one tube whole blood 
will be obtained and banked for potential 
future, exploratory genomic analysis 
 
Treatment Related Symptom Checklist (TRSC): 
obtained prior to each cycle of doxorubicin to 
assess symptoms experienced by patient. 
Symptoms reported on the TRSC will be 
correlated with known SNPs during genomic 
analysis (exploratory) 
DURATION OF STUDY PERIOD 
Treatment will continue until doxorubicin-
containing cycles have been completed (within 28 
days of completion), unless unacceptable toxicity 
occurs or the patient decides to withdraw from 
participation for any reason 
STUDY PERIOD 
Planned start date: 7/1/2014 
Planned accrual start date: 7/15/2014 
Planned accrual closure: 7/15/2015 
Planned study closure: 7/15/2025 
 
Treatment Schema 
The study population will include adult women (≥21 years of age) who have received a diagnosis of 
breast cancer that requires neoadjuvant or adjuvant therapy with doxorubicin. After obtaining informed 
consent, subjects will be equally randomized to the experimental or control arm: 
Breast cancer patient 
 
 
 
R 
 
 
Metformin 
Requiring neoadjuvant or adjuvant 
 
A 
 
 
850mg po BID during  
therapy with Doxorubicin 
 
 
N 
 
 
doxorubicin cycles 
 
 
 
 
 
 
D 
 
 
 
 
 
 
O 
 
 
 
 
 
 
M 
 
 
 
 
 
 
I 
 
 
 
 
 
 
 
 
Z 
 
 
No metformin during 
 
 
 
 
 
 
E 
 
 
doxorubicin cycles 
 
Patients will be excluded if they are already taking metformin, have a known hypersensitivity or 
intolerance to metformin, have abnormal renal or liver function, history of cardiac arrhythmias and/or 
symptomatic cardiac disease, are currently taking antiarrhythmic medications, beta-blockers, or other 
rate controlling cardiac medications, are already taking metformin and/or sulfonylureas, or have 
conditions associated with an increased risk for metformin-associated lactic acidosis. 
 
Treatment with metformin on the experimental arm will commence approximately 7-10 days prior to 
the start of doxorubicin-containing cycles, and will stop once doxorubicin-containing cycles are complete 


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(within 28 days of completion). The patient will have an approximate total of 3-4 months of treatment 
with metformin.  
1.0 
BACKGROUND INFORMATION AND RATIONALE 
About 2.6 million living women in the US have been previously diagnosed with breast cancer 
(http:// seer.cancer.gov/statfacts/html/breast.html). A large portion of these women will have 
been treated with adjuvant therapies that include four cycles of doxorubicin. Half of them will 
be under age 61 and many are expected to have long-term survival and thus increased risk for 
late effects. Since the goal of adjuvant therapy is cure, the benefits should outweigh the risk of 
short and long-term toxicities [1]. 
 
The anthracycline doxorubicin is a potent chemotherapeutic agent used to treat a broad 
spectrum of cancers. A serious side effect of doxorubicin is cardiotoxicity. Acute toxicity is 
predicted to occur in less than 1% of patients immediately after treatment and is generally 
considered to be transient in nature [2]. Chronic cardiotoxicity is much more serious and often 
culminates in irreversible congestive heart failure (CHF) [3-5]. Onset is generally within 1 year 
after treatment but it can also present 10-20 years later [2]. Patients that develop doxorubicin-
related cardiomyopathy have a very poor prognosis [6, 7]. Paradoxically, longer survival is a 
significant risk factor for doxorubicin-related heart problems in breast cancer patients [8].  
 
The incidence of cardiotoxicity is well documented in the literature. In a trial of more than 3,000 
patients receiving adjuvant breast therapy with doxorubicin, a 1%-2% incidence of CHF after 
treatment was seen [9]. A pivotal trial by Perez et al evaluated changes in left ventricular 
ejection fraction (LVEF) before and after treatment with doxorubicin [1]. Results demonstrated 
out of 1538 patients evaluated, over 50% of patients had a change in LVEF from baseline and 
over 23% of patients had either grade 1 or grade 2 LVEF toxicity as graded by NCI criteria. Using 
the SEER database, a cumulative 38% rate of CHF in women aged 66 years and older that had 
received anthracyclines during adjuvant therapy was found [10]. Furthermore, a systematic 
review by Smith et al reported that anthracyclines increased the risk of clinical cardiotoxicity by 
5.43 fold, subclinical cardiotoxicity by 6.25 fold, risk for cardiac death by 4.94 fold, and any 
cardiotoxicity by 2.27 fold [8]. 
 
Cardiotoxicity limits the dose of doxorubicin that can be used in cancer therapy and thus the 
total cumulative dose of the drug must be watched very carefully. Cumulative doses exceeding 
300mg/m2 have been linked with increased cardiac damage [1]. Studies have shown that 
doxorubicin-induced CHF can occur in 3%-5% of patients with maximum doses at 400mg/m2; at 
550mg/m2 the incidence increased to 26% [2]. For this reason, the maximum lifetime 
cumulative dose of doxorubicin is 400mg/m2 to 550mg/m2 [2]. This value can be even lower 
depending on age, pre-existing conditions, and combinations with other drugs. Beyond reducing 
the total cumulative dose of doxorubicin, other strategies for limiting its cardiotoxicity have 
been pursued. Attempts to develop chemical analogs that retain anti-tumor properties but have 
reduced cardiotoxicity have had minimal success [11]. Among numerous compounds tested, 


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only dexrazoxane, an iron chelator, has been approved for clinical use due to its ability to 
decrease doxorubicin-dependent free radical generation and reduce cardiac damage [12, 13]. 
However, dexrazoxane may lead to myelosuppression and potential interference with 
chemotherapeutic efficacy [14]. Thus a major impact would be realized by identifying new 
compounds that protect against doxorubicin-induced heart damage while at the same time 
maintaining or enhancing the antitumor activity of the drug.  
 
1.1 
Pre-Clinical Data 
Metabolism-targeted drugs that promote mitochondrial function have potential as 
protective agents against doxorubicin-induced heart damage. While the major 
mechanism by which doxorubicin kills cancer cells is to induce DNA damage [5], 
doxorubicin cardiotoxicity is related to cellular metabolism. Mitochondrial damage plays 
a central role in this process [15-21]. Doxorubicin has been shown to enter the 
mitochondria where it can accept an electron from Complex I, forming a free radical. 
Subsequent donation of an electron to O2 produces superoxide, leading to 
mitochondrial damage and cellular oxidative stress [17, 18]. Doxorubicin treatment is 
associated with loss of mitochondrial membrane potential and inhibition of oxidative 
phosphorylation [22, 23]. Mitochondrial dysfunction following doxorubicin treatment 
causes a shift from preferentially using β-oxidation of fatty acids for energy metabolism 
to anaerobic glycolysis [24]. Maintaining mitochondrial integrity and sustaining 
mitochondrial oxidative metabolism is protective against doxorubicin cardiotoxicity [25]. 
Thus metabolism-targeted drugs that enhance mitochondrial quality control and 
promote efficient oxidative phosphorylation are expected to be effective against 
doxorubicin induced heart damage. 
 
Laboratory data from Asensio-Lopez et al demonstrated that in adult mouse 
cardiomyocytes, metformin reduced oxidative stress and cardiomyocyte apoptosis in 
the presence of doxorubicin [26 ]. Metformin was also found to modulate the 
adiponectin system, which plays a pivotal role in the mechanism of protection against 
doxorubicin induced cardiac damage [26 ]. Futhermore, data from the same laboratory 
has recently identified the ability of metformin to upregulate gene and protein 
expression of the ferritin heavy chain (FHC), a crucial role in the protection of 
cardiomyocytes from doxorubicin damage [27]. 
We propose that drugs which inhibit glycolysis and/or promote mitochondrial function 
and integrity, like metformin, will protect against doxorubicin cardiotoxicity. Metformin 
has been associated with decreased risk of heart failure in diabetic patients [28]. Long-
term use of metformin is linked to reduced cardiovascular mortality [29]. Population 
studies indicate that diabetics taking metformin have significantly reduced risk of cancer 
and lower cancer-related mortality than diabetics not taking metformin [30-32]. For 
diabetic patients with breast cancer, patients on metformin had a significantly better 
response to neoadjuvant chemotherapy than patients not on metformin [32] Numerous 


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studies have revealed a cardioprotective role for metformin under various pathological 
conditions [33-37].  
The proposed study, if successful, is likely to have a major impact on breast cancer 
patients receiving therapy for a curative intent. Additionally, doxorubicin is used in 
many types of cancer, thereby creating the potential to study metformin and 
doxorubicin in other populations. Specifically, the proof-of-concept from this project 
could be rapidly translated into use for cancer patients because metformin has already 
been used in clinical settings for different purposes. Data from this study will also be 
used to leverage access to large data sets from ECOG, IBCSG, and others to 
retrospectively substantiate our findings. 
1.2 
Background Therapeutic Information  
Metformin is a well-known oral agent used to treat Type 2 diabetes as well as insulin 
resistance. It is readily available and generally well tolerated. Its most potentially 
dangerous toxicity is lactic acidosis, with an estimated incidence of 3 cases per 100,000 
patient years. Due to results from a meta-analysis, debate exists on whether the lactic 
acidosis that occurs in diabetics receiving metformin is due to metformin, or to the 
presence of diabetes. The meta-analysis showed comparable rates of lactic acidosis 
among diabetics who did, and who did not receive metformin, as well as a failure to 
correlate metformin levels in diabetics with lactic acidosis. Additionally, an increase in 
lactic acidosis rates was not seen after the introduction of metformin in the United 
States. Nevertheless, when lactic acidosis occurs it can be fatal. Therefore, individuals 
with increased risk factors for developing lactic acidosis should avoid the use of 
metformin. Risk factors include: greater than 80 years of age, individuals with current or 
past congestive heart failure, renal or hepatic insufficiency, excessive alcohol intake, and 
individuals with a prior history of metabolic acidosis. It is believed that the risk for lactic 
acidosis increases after surgery and with the use of radiologic contrast material, 
therefore metformin should be temporarily discontinued for approximately 48 hours in 
these circumstances. Common side effects of metformin (occurring in ˃1/10) are 
generally gastrointestinal in nature and include diarrhea, nausea, vomiting, abdominal 
bloating, flatulence, anorexia, and metallic taste. These side effects are usually transient 
and resolve spontaneously with continued treatment. Other toxicities are as follows: 
rash (˂1/10,000), subnormal vitamin B12 (9% after 6 months, therefore a Vitamin B level 
and hemoglobin levels are monitored at 6-12 months), hepatic dysfunction (˂1/10,000), 
elevations in TSH (˂1/10,000), modest weight loss (up to 5 pounds) is common. 
Metformin does not normally cause hypoglycemia. Rarely, extreme caloric restriction or 
excessive physical activity without adequate caloric intake may lead to hypoglycemia. 
Metformin has been used for many years without cumulative adverse effects. 
Name and Chemical Information 
N,N – dimethyl biguanide hydrochloride 
 


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1.3 
Mechanism of Action 
Metformin HCl is a biguanide derivative producing an antihyperglycemic effect which 
can only be observed in man or a diabetic animal and only when insulin is secreted. 
Metformin has no effect on pancreatic beta cells. The mode of action of metformin is 
not fully understood, but it has been postulated that metformin may potentiate the 
effect of insulin or reduce hepatic gluconeogenesis. 
Absorption of metformin may extend over approximately six hours. The drug is excreted 
in urine at high renal clearance rates, about 450mL/min. Initial elimination is fairly rapid 
with a half-life varying between 1.7 and 3 hours. Terminal elimination is slow with a 
half-life between 9-17 hours, and accounts for about 4-5% of the absorbed dose. 
Metformin is not metabolized. Main sites of concentration are the intestinal mucosa 
and the salivary glands. 
Some drugs can potentiate the effect of metformin, specifically the sulfonylurea types of 
drugs in the treatment of type 2 diabetes. Simultaneous administration of metformin 
and sulfonylurea can produce a hypoglycemic reaction, particularly if patients are 
receiving other drugs that can potentiate the effect of sulfonylureas such as long-acting 
sulfonamides, tubercolostatics, phenylbutazone, clofibrate, monoamine oxidase 
inhibitors, salicylates, probenecid, and propanolol. Metformin is less likely to interact 
with highly protein-bound drugs (i.e. salicylates, sulfonamides, chloramphenicol, and 
probenecid) given its negligible binding to plasma proteins; sulfonylureas are extensively 
bound to serum proteins.   
1.3.1 
Pregnancy Category B 
Animal studies show no risk or adverse fetal effects but controlled human 1st 
trimester studies are not available. No evidence of 2nd or 3rd trimester risk. 
Lactation is probably safe. Limited information in animals and/or humans 
demonstrates no risk/minimal risk of adverse effects to infant/breast milk 
production; caution advised. 
1.3.2 
Pharmaceutical Data 
 
Metformin: 850mg tablet 
Storage: Store at room temperature in well-closed containers 
Route of administration: Orally, with food 
 
 


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1.4 
Chemotherapy and Concomitant Metformin 
Metformin is routinely taken in patients with type 2 diabetes that are also receiving 
chemotherapy for cancer. The chemotherapies used in standard of care neoadjuvant or 
adjuvant therapy for breast cancer are not contraindicated or listed as interacting drugs 
with metformin in standard drug information guides like Micromedex. The most likely 
concern warranting close monitoring is the patient’s renal function, which is standard of 
care and built into this protocol. 
Unlike other drugs used for cardioprotection such as dexrazoxane, which potentially 
interfere with the efficacy of the chemotherapy, metformin has been shown to inhibit 
the growth of cancer cells [34-37]. Furthermore, a recent retrospective trial was 
completed on breast cancer patients receiving neoadjuvant chemotherapy, comparing 
diabetic patients taking metformin, diabetic patients not taking metformin, and 
nondiabetic patients [32]. The large database (N=2,529) found that diabetic patients 
receiving metformin and neoadjuvant chemotherapy had a significantly higher rate of 
pathologic complete responses (pCR) [32]. Other observational studies have associated 
diabetics receiving metformin with reduced cancer incidence and or mortality [29-31]. 
1.5 
Echocardiogram 
Echocardiograms will be performed to assess LVEF as an indication of left ventricular 
systolic function. Additionally, since diastolic dysfunction is detected earlier on 
echocardiograms in patients that are exposed to anthracyclines, diastolic function will 
also be assessed with each echocardiogram as a secondary endpoint. Cardiotoxicity due 
to anthracyclines can be acute and/or manifest years after treatment; therefore 
echocardiograms will be obtained at baseline, upon completion of the doxorubicin 
containing cycles (within 28 days of completion), and at the one year and seven year 
follow-up time points.    
Echocardiography creates an image of the heart using high-frequency sound waves. It is 
a non-invasive, safe procedure that does not require special preparation. An 
echocardiogram procedure usually lasts between 30-60 minutes. The use of contrast 
echocardiography (Definity contrast) will be preferred for each patient given the 
reduced variability and increased accuracy in LVEF measurements. If patients have 
already had an echocardiogram at baseline before consenting to this study, then a non-
contrast echocardiogram will be accepted. If patients have a known hypersensitivity to 
contrast used with echocardiograms, then a non-contrast echocardiogram will be 
accepted. All attempts will be made to maintain the same echocardiogram type 
(contrast or no contrast) that the patient has at baseline for the remainder of the study.      
All attempts will be made to have the same cardiologist read the echocardiograms for 
each patient enrolled in the study. Additionally, all attempts will be made to have the 


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echocardiogram procedure for each patient completed by one of two experienced 
technicians chosen for this study in order to reduce potential variation in technique.   
1.6 
Correlative Studies 
Correlative studies will be incorporated into this pilot study. The following biomarkers 
will be correlated with cardiac function measured on echocardiogram: Troponin I, 
glutathione, and BNP. Troponin I is released when cardiomyocyte destruction occurs, 
thereby indicating cardiomyocyte damage. Glutathione levels reflect oxidative stress, 
which is part of the mechanism for cardiomyocyte damage. BNP is secreted by the 
ventricles of the heart in response to excessive stretching of the cardiomyocytes, which 
occurs with left ventricular dysfunction.   
The following biomarkers will be obtained to correlate the effects of metformin: AMPK 
phosphorylation, adiponectin, and lipid peroxidation. 
1.7 
Study Checklists and Questionnaires 
1.7.1 
Treatment-Related Symptom Checklist 
The Therapy-Related Symptom Checklist (TRSC) is a patient self-report tool that 
allows for the subjective measure of therapy-related symptom severity [38] 
(Appendix 1). Patients rate 25 symptoms on severity using a five-point scale; 
other symptoms may be added and rated as well. A higher total score on the 
TRSC indicates greater frequency and severity of symptoms. Prior studies have 
indicated that TRSC scores correlate inversely with the Karnofsky scales, 
showing the TRSC’s construct validity. Additionally, use of the TRSC has led to 
improved symptom documentation and management, thereby affecting 
patients’ quality of life [38,39]. The TRSC has demonstrated good psychometric 
properties in previous studies. 
1.7.2 
Symptom Alleviation: Self-Care Methods (SASCM) 
Based on the TRSC symptoms, the Symptom Alleviation: Self-Care Methods 
(SASCM) tool will record self-care strategies used by patients to alleviate the 
symptoms reported and whether the method helped or did not help [40-45] 
with reported Cronbach’s alpha of .89.[40] (Appendix 2). This will be a one-time 
measure at the end of treatment that is completed by the patients. 
1.7.3 
Health-Related Quality of Life Linear Analogue Self-Assessment (HRQOL-LASA) 
Patient quality of life (QOL) will be assessed using the Health-Related Quality of 
Life Linear Analogue Self-Assessment (HRQOL-LASA), which is completed by the 
patient. The HRQOL-LASAS measures six items on a 10-point scale from 0 (as 
bad as can be) to 10 (as good as can be). These items have been validated as 
measures of global QOL constructs in numerous settings [46-49] (Appendix 3). 
 
 


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1.8 
Whole Blood Banking 
If willing, all enrolled patients will provide a sample of whole blood. DNA and RNA will 
be extracted from the whole blood sample and banked for further exploratory analysis.  
2.0 
STUDY DESIGN 
This is a randomized, open-label, phase II design pilot study in patients with breast cancer 
requiring neoadjuvant or adjuvant chemotherapy. Eligible patients will be equally randomized to 
either receive metformin plus standard of care therapy or to standard of care therapy alone. 
Approximately 7-10 days prior to the first doxorubicin dose patients randomized to the 
experimental arm will begin taking metformin per the ramp up period schedule (see section 
5.4). Patients receiving metformin will continue the drug until the doxorubicin-containing cycles 
are complete, unless unacceptable toxicity occurs or the patient decides to withdraw from the 
study. Both arms of the study will undergo echocardiograms at baseline, upon completion of 
doxorubicin containing cycles (within 28 days of completion), and at the one year and seven 
year follow up time points. Additionally, biomarker labs will be obtained prior to each 
doxorubicin infusion for all enrolled patients with the exception of Troponin I, which will be 
drawn two to three days post each doxorubicin infusion. Prior to each doxorubicin containing 
cycle, the TRSC will be used for symptom assessment for all enrolled patients. If willing, all 
enrolled patients will provide a sample of whole blood for further exploratory analysis. 
Symptoms reported on the TRSC will be correlated with known SNPs found during an 
exploratory genomic analysis. The study will be conducted at the Avera Cancer Institute in Sioux 
Falls, SD, as well as Avera St. Luke’s Cancer Center in Aberdeen, SD.   
3.0 
OBJECTIVES 
3.1 
Primary Objective 
To determine if co-administration of metformin and doxorubicin in breast cancer 
patients receiving neoadjuvant or adjuvant therapy will reduce the number of patients 
who develop a significant change in left ventricular ejection fraction (LVEF) indicated by 
a decrease in LVEF of ≥5% from baseline.  
3.2 
Secondary Objectives 
 
To assess and compare the number of patients in each group who develop a 
decrease in LVEF of ≥10% from baseline  
 
To assess the potential changes in diastolic function and compare the changes 
between the treatment arms 
 
To explore whether the following biomarkers correlate with changes in cardiac 
function and with the activity of metformin: Troponin I, BNP, glutathione, 
circulating adiponectin, AMPK phosphorylation, and lipid peroxidation 
 
To explore whether symptoms expressed on the TRSC correlate with known 
SNPs found during exploratory genomic analysis 
 
Whole blood banking for future, exploratory genomic analysis 


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4.0 
PATIENT SELECTION 
To be eligible for this study, the following inclusion and exclusion criteria must be met: 
 
4.1 
Inclusion Criteria 
 
Histologically confirmed breast cancer requiring neoadjuvant or adjuvant 
chemotherapy with doxorubicin 
 
Baseline lab work should be completed within 28 days prior to randomization. 
Biochemistry investigations should reflect values within the following 
parameters: 
o AST ˂ 2.5 X ULN 
o ALT ˂ 2.5 X ULN 
o Alkaline Phosphatase ˂ 2.5 X ULN 
o Serum Creatinine ˂ 1.5mg/dL  
o Serum bilirubin ˂ ULN 
 
ECOG Performance Status of 0 or 1 (at baseline evaluation visit within 28 days 
prior to randomization) 
 
Age ≥21 years of age  
 
Protocol treatment should begin within 28 working days of patient 
randomization 
 
Patient must sign consent form prior to randomization or registration 
 
4.2 
Exclusion Criteria  
 
Known diabetes (Type I or Type 2) 
 
Subjects who are already taking metformin and/or sulfonylureas 
 
Known hypersensitivity or intolerance to metformin 
 
History of cardiac arrhythmias or symptomatic cardiac disease 
 
Currently taking antiarrhythmics, beta-blockers or other rate controlling cardiac 
medications  
 
Baseline ejection fraction of <50% as measured by echocardiogram 
 
Risk factors associated with increased risk of metformin-associated lactic 
acidosis (e.g. congestive heart failure, history of acidosis, habitual intake of 3 or 
more alcoholic beverages per day) 
 
Currently pregnant 
5.0 
TREATMENT PLAN 
5.1 
Identification of Potential Subjects 
Potential subjects will be identified by the breast surgeons and medical oncologists, as 
well as during multidisciplinary breast tumor conferences. Subjects will be adult (≥21 
years of age) who have received a diagnosis of breast cancer that requires neoadjuvant 
or adjuvant therapy.  
  
5.2 
Randomization 
After obtaining informed consent, subjects will be randomized using a permuted block 
randomization. 
 


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Patients will be equally randomized to one of the following arms: 
ARM AGENT 
DOSE 
ROUTE 
DURATION 
1 
Metformin 
850mg 
P.O. (with food) 
Twice daily during 
doxorubicin-containing cycles 
(approximately 3 months) 
2 
Standard of care – no metformin 
N/A 
N/A 
N/A 
 
5.3 
Metformin Dispensing and Administration  
There will be a ramp-up period for the metformin dosing and will occur as follows: 
 
One, 850mg tablet daily for ideally 7-10 days prior to starting therapy. However 
if the patient needs to start chemotherapy sooner than the ramp up period 
allows, the treating physician can choose to increase the metformin to twice 
daily sooner than 7 days 
 
Approximately 2-3 days prior to treatment with doxorubicin, increase to one, 
850mg tablet twice daily until 28 days post last infusion of doxorubicin . Goal is 
to have subject on 850mg of metformin twice daily prior to commencement of 
doxorubicin 
 
The usual recommended starting dose of metformin is 500mg or 850mg daily. 
Metformin is then titrated by adding 500mg/week or 850mg/2 weeks to a maximum 
dose of 2550mg/day. The dose of 850mg twice daily was chosen based on standard 
dosing and acceptable tolerability; the same dose is being used in breast cancer patients 
in larger scale studies where overall survival is the primary endpoint [50].   
Metformin will be ordered by the cancer center’s pharmacy which will maintain a 
careful record of the drug’s receipt and disposition. Metformin pills will be dispensed to 
the patient by the research coordinator. Patients should bring their labeled pill bottles 
to the research coordinator at every protocol-mandated visit and at the end of the 
treatment period. A calendar schedule containing a place to mark when a dose of 
metformin is taken will be provided to each patient (see Appendix 4). The calendar will 
be used as a way to monitor treatment adherence, in addition to pill counts. 
 
5.4 
Pre-Treatment Evaluation 
 
Investigations 
Timing 
History and Physical Exam 
including: 
Performance Status, alcohol 
intake, cardiac history, 
demographic information 
Within 28 days prior to 
randomization  
Pathology 
Confirmation of breast cancer 
Any time prior to randomization 
Hematology 
CBC with differential 
Within 28 days prior to 
randomization  
Biochemistry 
Comprehensive metabolic panel 
Within 28 days prior to 


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randomization  
Pregnancy Testing (for women 
of child-bearing potential) 
Serum Pregnancy Test 
As close to randomization as 
possible 
Medication Reconciliation 
Current medications and 
indications 
Within 28 days prior to 
randomization 
Adverse Events 
Evaluation of baseline adverse 
events 
Within 28 days prior to 
randomization 
Whole blood banking 
Exploratory analysis 
Whole blood is one time draw 
(during regularly scheduled labs 
any time during study) 
Therapy-Related Symptom 
Checklist 
Baseline evaluation of 
symptoms 
Prior to first cycle of 
chemotherapy (can occur anytime 
between consent and initiation of 
C1D1 of chemotherapy) 
HRQOL-LASA 
Baseline health-related quality 
of life measure 
Prior to first cycle of 
chemotherapy (can occur anytime 
between consent and initiation of 
C1D1 of chemotherapy) 
Echocardiogram  
Baseline LVEF, diastolic function 
assessment 
Within 28 days prior to 
randomization (± 2 weeks) 
 
5.5 
Evaluation During and After Protocol Treatment 
All subjects on study should be evaluated according to the schedule below: 
 
Investigations 
Timing 
History and Physical Exam 
including: 
Compliance with metformin 
At minimum Day 1 of 
doxorubicin-containing chemo 
cycles 
Labs 
Biochemistry (Complete 
Metabolic Panel) in addition to 
other standard of care labs 
At minimum Day 1 of 
doxorubicin-containing cycles 
Echocardiogram  
LVEF, diastolic function 
assessment  
Within 28 days of last doxorubicin 
infusion (± 2 weeks) 
Biomarkers* 
BNP, glutathione, AMPK 
phosphorylation, lipid 
peroxidation, adiponectin 
Prior to each cycle of doxorubicin 
containing cycles and within 28 
days of last dose 
Biomarker 
Troponin I 
Prior to C1D1 of doxorubicin 
(baseline) and 2-3 days after each 
doxorubicin infusion 
Adverse Events  
 
Graded using CTC 4.0 
 
Day 1 of doxorubicin-containing 
cycles 
Symptoms 
Therapy-Related Symptom 
Checklist (TRSC) 
Day 1 of doxorubicin-containing 
cycles 
Self-care methods 
SA:SCM 
End of treatment visit 


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Health-related quality of life 
HRQOL-LASA 
End of treatment visit 
*Will attempt to draw all biomarkers (except Troponin I)  at the same time as other standard of care labs 
are drawn 
5.6 
Follow-Up Period 
 
Investigation 
Timing 
History and physical exam 
Clinical assessment 
Each clinic visit (per discretion of 
treating physician) 
Echocardiogram  
LVEF, diastolic function 
assessment 
12 months post last doxorubicin 
infusion (± 60 days); 7 years post 
last doxorubicin infusion (±3 
months) 
 
Other follow up exams are per the investigator’s discretion. 
 
5.7 
Patient Monitoring  
Patients will be assessed prior to each cycle of doxorubicin-containing therapy for 
medication compliance and toxicity. Since the major toxicity of metformin is 
gastrointestinal in nature, the dose may need to be adjusted during the ramp up period. 
If subjects are experiencing gastrointestinal symptoms they should be encouraged to 
take metformin with food. If there is no improvement, subjects can try taking metformin 
every other day for one week, every day for one week, then twice per day thereafter. If 
subjects are still not tolerating metformin, they may go off study. Pills should not be 
split or crushed.   
Toxicity 
Grade 
Action 
Bilirubin ˃ULN (except for 
Gilbert’s disease) 
Grade 1 (or 
higher) 
Hold metformin for up to 2 weeks. If bilirubin 
returns to normal during the 2 week period, restart 
metformin per the ramp up dosing 
AST or ALT=2.5 -3.0 X ULN 
Use CTC 4.0 for 
grading 
Repeat AST and ALT in 2 weeks. If either ˃2.5 X ULN 
then continue at investigator’s discretion, 
monitoring labs at least every 2 weeks 
AST or ALT = 3.0 X ULN 
Use CTC 4.0 for 
grading 
Hold metformin and repeat labs in 2 weeks. If AST 
or ALT ˂2.5 X ULN then restart metformin based on 
the ramp up dosing. If AST or ALT 2.5 – 3.0 X ULN 
then continuation of metformin is per the 
investigator’s discretion with frequent lab 
monitoring 
If still 3.0 X ULN or higher come off study 
Creatinine ≥ 1.5 
Use CTC 4.0 for 
grading 
Hold metformin for up to 2 weeks. When/if 
resuming, use the ramp up dosing schedule 
Acidosis (Lactate ≥5.0mM; 
Use CTC 4.0 for 
Stop metformin and do not restart. Report as 


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pH ˂7.3) 
grading 
serious adverse event 
GI toxicity of any type 
Grade 1 
Encourage patient to stay on schedule as side 
effects are usually transient 
GI toxicity (nausea, diarrhea, 
etc.) 
Grade 2 or 
higher 
Reduce metformin to 1 tablet daily x 1 week. If 
tolerates, resume full dose. If grade 2 or higher 
toxicity reoccurs, reduce to 1 tablet for the 
remainder of the study. If unable to tolerate dose 
reduction to 1 tablet, stop metformin completely 
Hospitalization (any reason) 
Use CTC 4.0 for 
grading 
Hold metformin. Investigator should determine if 
safe to restart and should be restarted based on 
ramp up dosing 
Other 
Use CTC 4.0 for 
grading 
Contact PI with questions 
 
5.8 
Other circumstances 
5.8.1 
Surgery 
If surgery necessitating anesthesia is required for any reason, metformin should 
not be taken on the morning of surgery and for 48 hours after surgery. 
Metformin can be restarted at full dose provided there is evidence of normal 
renal function. 
5.8.2 
Diagnostic Imaging 
If the subject needs any CT scan requiring IV contrast material, metformin 
should be stopped 24 hours before the procedure and held for 48 hours after 
the procedure. Metformin can then be resumed at full dose as long as there is 
no evidence of renal dysfunction. Creatinine should be checked prior to 
restarting the metformin.   
If contrast is used for the echocardiogram then the contrast used is Definity 
contrast, which is filtered through the lungs and therefore does not affect the 
kidneys. Metformin does not need to be held for the Definity contrast.    
5.8.3 
Medically Necessary 
The investigator can hold metformin for any situation deemed medically 
necessary. The investigator can determine if resumption of metformin is 
appropriate. The ramp up dosing schedule should be followed when restarting if 
off of metformin for greater than 1 week. 
5.8.4 
Adverse Events 
Adverse events will be graded using the NCI Common Terminology Criteria 
version 4.0. 


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5.8.5 
Concomitant Medications 
Concomitant medications need to be documented in the medical record. 
Certain medications are not permitted and include: sulfonylureas, 
thiazolidenediones, insulin, antiarrhythmics, beta-blockers, or other rate 
controlling cardiac medications. If these drugs are necessary to treat a new 
diagnosis or for any other reason, the patient will have to come off study. If 
there is a question regarding the appropriateness of a medication, please 
contact the principle investigator (PI).   
5.8.6 
Duration of Therapy 
Subjects will take metformin twice daily with food, 850mg in the am and 850mg 
in the pm. Treatment will continue until doxorubicin-containing cycles have 
been completed (approximately 28 days after last doxorubicin infusion), unless 
unacceptable toxicity occurs or the subject decides to withdraw from 
participation for any reason.   
6.0 
SERIOUS ADVERSE EVENT (SAE) REPORTING 
All SAEs must be reported to the PI within 24 hours and be documented on the case report 
forms. An update on the SAE should be reported to the PI within 7 days.   
All SAEs that are unexpected and related to the study drug, in this case metformin, need to be 
reported within 24 hours to the PI, including events occurring during the study period and 
within 30 days after the last dose of metformin is taken. 
A SAE is any adverse event that at any dose: 
 
Results in death 
 
Is life threatening 
 
Results in permanent or significant disability  
 
Requires inpatient hospitalization 
 
Results in congenital anomaly or birth defect 
 
7.0 
PATIENT DISCONTINUATION 
The treating physician will make every reasonable effort to keep each patient on study. If, 
however, a patient is removed from the study or the patient declines further participation, a 
final assessment of the patient’s LVEF and diastolic function and biomarkers should be obtained. 
These results, along with the reason for study discontinuation, must be recorded in the CRF.   
Patients will discontinue treatment if any of the following occur: 
 
Unacceptable toxicity 


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 
Patient withdrawal of consent of HIPAA Authorization 
 
Investigator/treating physician decision 
 
New diagnosis of diabetes requiring other medications such as sulfonylureas 
 
8.0 
DATA ANALYSIS 
The primary outcome of interest is a decrease in systolic function defined as a drop in LVEF of 
≥5%. To assess differences between groups we will use a Fischer’s exact test to compare 
proportions. In addition, the logistic regression model will be done as a secondary analysis. This 
will allow us to include patient and treatment characteristics that may be unbalanced at 
baseline due to the relatively small number of subjects included in the trial. Secondary analysis 
will be performed to assess the relationship between the change in biomarker levels and the 
change in LVEF using logistic or linear regression as appropriate and will include a term for 
treatment group as well as an interaction with treatment group since the patterns of change 
may be different based on treatment with metformin. Model assumptions will be assessed and 
transformations and/or nonparametric methods will be used where necessary. 
8.1 
Sample Size Determination 
With standard treatment, we expect that 50% of patients will have a significant 
decrease in LVEF while in those taking concomitant metformin only 10% of patients will 
have a significant decrease in LVEF. Assuming a significance level of 0.05, we will have 
80% power to detect such a difference between the two groups with 19 subjects in each 
group. To account for potential drop-out, estimated to be 15%, we will enroll 22 
subjects in each group.  
9.0 
STUDY ADMINISTRATION 
This study will be conducted in compliance with the protocol, the principles of Code of Federal 
Regulations (CFR), ICH GCP and the Declaration of Helsinki as amended in Edinburgh (2000) 
(Appendix 5). 
9.1 
Informed Consent 
The principles of informed consent and GCP guidelines in FDA-Regulated Clinical Trials 
are described in the 21 CFR 50, Protection of Human Subjects. 
These regulations must be followed in conducting and monitoring clinical investigations. 
Consent for participation in the study will be obtained and documented. 
The investigator/physician will thoroughly explain to the patient the purpose and 
methods of the study, as well as any expected effects and adverse reactions, before any 
study-specific screening procedures are conducted. The patient will be provided with a 
copy of the consent and will be given sufficient time and opportunity to inquire about 
the details of the trial and to decide whether or not to participate. The patient and the 


21 
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person with whom the informed consent is discussed will sign and date the consent 
form. 
The investigator/treating physician will explain that the patient is completely free to 
refuse to enter the study or to withdraw from it at any time and for any reason. 
Similarly, the investigator/treating physician and/or Sponsor will be free to withdraw 
the patient at any time for safety or administrative reasons. Any other requirements 
necessary for the protection of the human rights of the patient will also be explained, 
according to current CFR (21, parts 312D, 50 and 56), ICH (ICH E6 1997) and GCP 
guidelines and the Declaration of Helsinki, 1964 [as amended in Edinburgh (2000)]. A 
copy of the Declaration of Helsinki is provided in Appendix 5. 
9.2 
Institutional Review Board Approval 
This study must be approved by an appropriate institutional review board/committee as 
defined by Federal Regulatory Guidelines (Federal Register Vol. 46, No. 17, January 27, 
1891, Part 56) and the Office of Human Research Protection (45 CFR 46). Prior to 
screening any patients for participation into this study, the investigator/treating 
physician must obtain and provide written documentation of IRB review and approval of 
the protocol and the informed consent document to study sponsor. 
The IRB must also be informed of any protocol amendments prior to implementation. 
The investigator/treating physician must provide reports of any change in research 
activity (e.g. the completion, termination or discontinuation of the study) to the IRB. 
9.3 
Modification of the Protocol 
Protocol amendments to the ongoing study that could potentially adversely affect the 
safety of participating patients, or that alter the scope of the investigation, the scientific 
quality of the study, the experimental design, duration of therapy, assessment variables, 
the number of patients treated or patient selection criteria must be made only after 
consultation with the Lead Principal Investigator. 
Protocol amendments will be prepared, reviewed and signed by the Lead Principal 
Investigator.  
Any amendments to the protocol that are made after receipt of initial IRB approval must 
be submitted by the investigator to the IRB and Regulatory Authorities (where required) 
in accordance with local procedures and regulatory requirements, before the changes 
can be implemented. Amendments to the protocol that eliminate an apparent 
immediate hazard to patients do not require pre-approval by the IRB. 
Administrative amendments that do not affect the conduct of the study or patient 
safety, and do not significantly reduce the scientific value of the protocol; will not be 


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resubmitted for formal ethics review or lead to a change in the patient information 
sheet. Such amendments will be sent to the IRB for information only. 
9.4 
Protocol Compliance 
Deviations from the approved study protocol will be noted during the monitoring 
process and will be required to be reported to the IRB by the investigator/treating 
physician per their governing IRB policy for reporting protocol deviations/violations. 
 
 


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9.5 
Case Report Forms (CRFs) 
CRFs will be used to collect the data, and all data management activities will be carried 
out by Avera Research. The investigator/treating physician is responsible for maintaining 
accurate, complete and up-to-date records for each patient. The investigator/treating 
physician is also responsible for maintaining all source documentation related to the 
study. All CRFs should be completed in a neat, legible manner to ensure accurate 
interpretation of the data. 
9.6 
Study Records 
The investigator/treating physician must maintain adequate and accurate records to 
enable the conduct of the study to be fully documented and the study data to be 
subsequently verified. Documents include the protocol and protocol amendments (if 
applicable), CRFs, CRF query forms, IRB and regulatory authority approval with 
correspondence, informed consent, screening and enrollment logs, staff résumé and 
authorization forms and other appropriate documents and correspondence. Patient 
clinical source documents will include patient and/or hospital clinical records, 
physician's and nurse's notes, appointment book, original laboratory reports, ECG and 
imaging reports, pathology and special assessment reports, consultant letters, and other 
relevant documents and correspondence. 
The patient's involvement in the study should be clearly documented in the clinical 
records. Details should include the study protocol number, the hospital/ clinic unit code, 
the patient's identification number, the patient's consent to take part in the study 
(including the date of consent), the dates of eligibility confirmation by 
investigator/treating physician, dates of all study visits, date of procedure to obtain 
tissue specimen for study, and date and reason for study discontinuation. 
The original reports, tracings and films must be retained by the investigators/treating 
physician for future reference. Copies of the CRFs must be retained by the investigators/ 
treating physicians, for as long as is legally required after completion of the study, to 
comply with CFR/ICH GCP guidelines. All data relating to the study, including study 
master file contents, CRFs and source data will be stored by the investigator/treating 
physician for at least 15 years. 
If the investigator/treating physician cannot guarantee this archiving requirement for 
any or all the documents at the investigational site, arrangements must be made 
between the investigator/treating physician and the Sponsor, to store these in a secure 
archive facility outside the site; they can therefore be returned to the investigator/ 
treating physician in case of a regulatory audit. Where source documents are required 
for the continued care of the patient, appropriate copies should be made for storing 
outside the site. 


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41. Heinze S. Symptoms, BDNF gene polymorphisms, daily activities, self-care, quality of life in 
breast cancer survivors, PhD dissertation, University of Kansas School of Nursing. 2012. Kansas 
City, KS. 
42. Piamjariyakul U, Williams P, Kim M, Park L, Rojjanasrirat W, Williams A. Cancer therapy-
related symptoms and self-care in Thailand. European Journal Oncology Nursing. 2010; 14, 
387-394. 
43. Williams PD, Balabagno O, Manahan L, Piamjariyakul U, et al. Symptom monitoring and self-
care practices among Filipino cancer patients. Cancer Nursing 2010; 33, 37-46. 
44. Williams PD, Lopez V, Chair S, Piamjariyakul U, Wang W, Hung G. Symptom monitoring and 
self-care practices among oncology adults in China. Cancer Nursing 2010; 33, 184-193. 
45. Williams PD, William DD, Smith J, Heinz S, Greenfield A, Bryant K. Patient-reported symptoms, 
alleviation and self-care methods, daily activities, and health-related quality of life during 
outpatient cancer treatments in the U.S.A. (poster). Seventh Nursing Symposium on Cancer 
Care and Fifth Pan-Pacific Nursing Conference 2011; Hong Kong. 
46. Bretscher M, Rummans T, Sloan J, Kaur J, Bartlett A, Borkenhagen L, Loprinzi C. Quality of life 
in hospice patients: A pilot study. Psychosomatics 1999, 40,309-313. 
47. Degner LF, Sloan J. Symptom distress in newly diagnosed ambulatory cancer patients and as a 
predictor of survival in lung cancer. J of Pain Symptom Management 1995, 10: 423-431. 
48. Grunberg SM, Groshen S, Steingass S, Zaretsky S, Meyerowitz B. Comparison of conditional 
quality of life terminology and visual analogue scale measurements. Quality of Life Research 
1996, 5: 65-72. 
49. Hyland ME, Sodergren SC. Development of a new type of global quality of life scale, ad 
comparison and preference for 12 global scales. Quality of Life Research. 1996, 5, 469-480. 
50. Goodwin PJ, Stambolic V, Lemieux J, Chen BE, Parulekar WR, Gelmon KA, Hershman DL, Hobday 
TJ, Ligibel JA, Mayer IA, Pritchard KI, Whelan TJ, Rastogi P, Shepard LE: Evaluation of metformin 
in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-
cancer agents. Breast Cancer Res Treat 126: 215-20, 2011. 


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Appendix 1 
THERAPY-­­RELATED SYMPTOMS CHECKLIST (TRSC) 
Name:                                                              Hospital #                   Date:            
  
PLEASE CHECK THE PROBLEMS YOU HAVE HAD IMMEDIATELY AFTER AND SINCE 
YOUR LAST TREATMENT.    PLEASE CIRCLE HOW SEVERE THE PROBLEM WAS 
ACCORDING TO THE FOLLOWING SCALE:  
  
0 = NONE          1 = MILD         2 = MODERATE         3 = SEVERE             4 = VERY SEVERE  
  
 
CHECK  
 
EXAMPLE  
Pain  
Degree of Severity (CIRCLE)  
0  
1  
2  
  
4  
 Taste Change  
0  
1  
2  
3  
4  
 Loss of appetite  
0  
1  
2  
3  
4  
 Nausea  
0  
1  
2  
3  
4  
 Vomiting  
0  
1  
2  
3  
4  
 Weight loss  
0  
1  
2  
3  
4  
 Sore mouth  
0  
1  
2  
3  
4  
 Cough  
0  
1  
2  
3  
4  
 Sore throat  
0  
1  
2  
3  
4  
 Difficulty swallowing  
0  
1  
2  
3  
4  
 Jaw pain  
0  
1  
2  
3  
4  
 Shortness of breath  
0  
1  
2  
3  
4  
 Numbness in fingers and/or toes  
0  
1  
2  
3  
4  
 Feeling sluggish  
0  
1  
2  
3  
4  
 Depression  
0  
1  
2  
3  
4  
 Difficulty concentrating  
0  
1  
2  
3  
4  
 Fever  
0  
1  
2  
3  
4  
 Bruising  
0  
1  
2  
3  
4  
 Bleeding  
0  
1  
2  
3  
4  
 Hair loss  
0  
1  
2  
3  
4  
 Skin changes  
0  
1  
2  
3  
4  
 Soreness in vein where chemotherapy  
was given  
0  
1  
2  
3  
4  
 Difficulty sleeping  
0  
1  
2  
3  
4  
 Pain  
0  
1  
2  
3  
4  
 Decreased interest in sexual activity  
0  
1  
2  
3  
4  
 Constipation  
0  
1  
2  
3  
4  
 Other problems (please list below)  
  
  
  
  
  
 
0  
1  
2  
3  
4  
 
0  
1  
2  
3  
4  
Phoebe D. Williams, PhD ©Copyright 1995 University of Kansas Medical Center  
 
 


28 
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Appendix 2 
 
TRSC Symptom Alleviation: Self-Care Methods (SA:SCM) 
ID# ______________Date: ____________ 
Data Collector: _____________________________________________________________________ 
 
 
 
ALLEVIATION METHODS DONE OR USED 
*How often 
Done? 
4, Very Often Done; 
3, Often Done; 
2, Done Occasionally; 
1, Seldom Done; 
0, Not Done 
Did 
it 
Help? 
 
(Yes/No) 
 
 Taste Change 
 
 
 
 Loss of appetite 
 
 
 
 Nausea 
 
 
 
 Vomiting 
 
 
 
 Weight loss 
 
 
 
 Sore mouth 
 
 
 
 Cough 
 
 
 
 Sore throat 
 
 
 
 Difficulty swallowing  
 
 
 Jaw pain 
 
 
 
 Shortness of breath 
 
 
 
 Numbness in fingers   
and/or toes 
 
 
 
 Feeling sluggish 
 
 
 
 Depression 
 
 
 
 Difficulty  
concentrating 
 
 
 
 Fever 
 
 
 
 Bruising 
 
 
 
 Bleeding 
 
 
 
 Hair loss 
 
 
 
 Skin changes 
 
 
 
 Soreness in vein 
where chemotherapy 
given 
 
 
 
 Difficulty sleeping 
 
 
 
 Pain 
 
 
 
 Decreased interest 
in sexual activity 
 
 
 


29 
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ALLEVIATION METHODS DONE OR USED 
*How often 
Done? 
4, Very Often Done; 
3, Often Done; 
2, Done Occasionally; 
1, Seldom Done; 
0, Not Done 
Did 
it 
Help? 
 
(Yes/No) 
 
 Constipation 
 
 
 
 Other problems  
(please list below) 
 
 
 
 
 
 
 
 
 
 
 
*Rate each alleviation method used-- each reported symptom would have a mean rating 
Copyright© 2009 Phoebe D. Williams, PhD 
 
 


30 
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Appendix 3 
Health-Related Quality of Life (HRQOL), Linear Analogue Self Assessment (LASA) 
Patient Name: ________________________ Date: ______________________ 
Patient Number:  ______________________________ 
 
 
Directions: Please circle the number (0-10) best reflecting your response to the following 
that describes your feelings during the past week, including today. 
How would you describe: 
 
1. your overall Quality of Life? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
2. your overall mental (intellectual) well-being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
3. your overall physical well-being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
4. your overall emotional well-being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
5. your level of social activity? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
6. your overall spiritual well-being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
it can be 
 
 
 
 
 
 
 


31 
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Appendix 4   
 Example of Study Calendar 
◄ Dec 2013 
~ January 2014 ~ 
Feb 2014 ► 
Sun 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
 
 
1  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
2  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
3  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
4  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
5  
AM Metformin ___ 
PM Metformin ____ 
6  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
7  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
8  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
9  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
10  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
11  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
12  
AM Metformin ___ 
PM Metformin ____ 
13  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
14  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
15  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
16  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
17  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
18  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
19  
AM Metformin ___ 
PM Metformin ____ 
20  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
21  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
22  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
23  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
24  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
25  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
26  
AM Metformin ___ 
PM Metformin ____ 
27  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
28  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
29  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
30  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
31  
AM Metformin ___ 
 
 
 
PM Metformin ____ 
Notes: 
 
EXAMPLE ONLY 
 
 


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APPENDIX 5.  DECLARATION OF HELSINKI 
 
World Medical Association Declaration of Helsinki 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, 
October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, 
Somerset West, Republic of South Africa, October 1996 and the 52nd 
WMA General Assembly, Edinburgh, Scotland, October 2000 
 
A.  INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects. Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people. The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with the words, 
"The health of my patient will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act only in the patient's interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the 
patient." 
4. Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
5. In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis 
of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility and 
quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights. Some research populations are vulnerable and need special 
protection. The particular needs of the economically and medically disadvantaged must be 
recognized. Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with 
care. 


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9. Research investigators/treating physician should be aware of the ethical, legal and regulatory 
requirements for research on human subjects in their own countries as well as applicable 
international requirements. No national ethical, legal or regulatory requirement should be 
allowed to reduce or eliminate any of the protections for human subjects set forth in this 
Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
1. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subject. 
2. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and on adequate laboratory and, where appropriate, animal experimentation. 
3. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
4. The design and performance of each experimental procedure involving human subjects should 
be clearly formulated in an experimental protocol. This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator/treating physician, 
the sponsor or any other kind of undue influence. This independent committee should be in 
conformity with the laws and regulations of the country in which the research experiment is 
performed. The committee has the right to monitor ongoing trials. The researcher has the 
obligation to provide monitoring information to the committee, especially any serious adverse 
events. The researcher should also submit to the committee, for review, information regarding 
funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for 
subjects. 
5. The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration. 
6. Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility 
for the human subject must always rest with a medically qualified person and never rest on the 
subject of the research, even though the subject has given consent. 
7. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others. This does not preclude the participation of healthy volunteers in medical 
research. The design of all studies should be publicly available. 
8. Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians should cease any investigation if the risks are found to 
outweigh the potential benefits or if there is conclusive proof of positive and beneficial results. 


34 
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9. Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject. This is especially important 
when the human subjects are healthy volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research.  
11. The subjects must be volunteers and informed participants in the research project. 
12. The right of research subjects to safeguard their integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
patient's information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
13. In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of 
the researcher, the anticipated benefits and potential risks of the study and the discomfort it 
may entail. The subject should be informed of the right to abstain from participation in the 
study or to withdraw consent to participate at any time without reprisal. After ensuring that the 
subject has understood the information, the physician should then obtain the subject's freely-
given informed consent, preferably in writing. If the consent cannot be obtained in writing, the 
non-written consent must be formally documented and witnessed. 
14. When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress. In that case the informed consent should be obtained by a well- informed physician who 
is not engaged in the investigation and who is completely independent of this relationship. 
15. For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator/treating physician must obtain 
informed consent from the legally authorized representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to promote 
the health of the population represented and this research cannot instead be performed on 
legally competent persons. 
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator/treating physician must obtain that 
assent in addition to the consent of the legally authorized representative. 
17. Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 
informed consent is a necessary characteristic of the research population. The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee. The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
18. Both authors and publishers have ethical obligations. In publication of the results of research, 
the investigators/treating physicians are obliged to preserve the accuracy of the results. 
Negative as well as positive results should be published or otherwise publicly available. Sources 
of funding, institutional affiliations and any possible conflicts of interest should be declared in 


35 
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the publication. Reports of experimentation not in accordance with the principles laid down in 
this Declaration should not be accepted for publication. 
C.  ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
1. The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical 
research is combined with medical care, additional standards apply to protect the patients who 
are research subjects. 
2. The benefits, risks, burdens and effectiveness of a new method should be tested against those 
of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the 
use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or 
therapeutic method exists. 
3. At the conclusion of the study, every patient entered into the study should be assured of access 
to the best proven prophylactic, diagnostic and therapeutic methods identified by the study. 
4. The physician should fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study must never interfere with the patient-
physician relationship. 
5. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods 
do not exist or have been ineffective, the physician, with informed consent from the patient, 
must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in 
the physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, these measures should be made the object of research, designed to 
evaluate their safety and efficacy. In all cases, new information should be recorded and, where 
appropriate, published. The other relevant guidelines of this Declaration should be followed. 
 
 


36 
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APPENDIX 6 
Schedule of Events 
Procedure 
Screening/ 
Enrollment 
Start of 
Treatmentl 
On Study 
End of 
treatment 
Follow Up 
12 months 
Follow Up 
7 years 
Window 
Within 28days 
prior to 
randomization 
-14 to 0 
Day 1 of 
each 
doxorubicin 
containing 
cycle  
Within 28 
days of last 
doxorubici
n infusion 
± 2 months 
± 3 months 
Informed 
Consent/HIPPA 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
Xg 
 
 
 
 
Patient 
Registration 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
Xi 
X 
X (+/-) 2 
weeks 
X 
 
Physical Exam 
X 
Xi 
X 
X (+/-) 2 
weeks 
X 
 
Performance 
Status – ECOG 
X 
Xi 
X 
X(+/-) 2 
weeks 
X 
 
 
Medication 
Reconciliation 
X 
Xi 
X 
X(+/-) 2 
weeks 
X 
 
Hematologya  
X 
 
 
 
 
 
Chemistry Panelb 
X 
Xi 
X 
X(+/-) 2 
weeks 
 
 
Biomarkersc 
(except Troponin I) 
 
Xi 
X 
X 
 
 
Troponin I 
 
Xi 
Xd 
X 
 
 
Echocardiogram  
X (± 2 weeks) 
 
 
X (± 2 
weeks) 
X 
X 
Adverse Effects 
X 
Xi 
X 
X(+/-) 2 
weeks 
X 
 
TRSC 
 
Xj 
X 
X(+/-) 2 
weeks 
X 
 
HRQOL-LASAe 
 
X 
 
X(+/-) 2 
weeks 
 
 
Whole blood 
banking 
 
X 
 
 
 
 
Pregnancy Testg 
X 
 
 
 
 
 
SA:SCM k 
 
 
 
X(+/-) 2 
weeks 
 
 
Compliance with 
metformin 
 
X 
X 
X 
 
 
Dispense 
Metformin 
X 
X 
 
 
 
 
Survival Status 
 
 
 
 
X 
X 
a  CBC, differential, platelet count, hemoglobin 
b  ALT/SGPT, AST/SGOT, Alk Phos, total bilirubin, creatinine, electrolytes 


37 
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c  Biomarkers (EXCEPT TROPONIN I) will be drawn at the same time as other standard of care labs, and will include 
BNP, glutathione, lipid peroxidation, AMPK phosphorylation, and adiponectin. With the exception of BNP and 
Troponin I, other blood samples for other biomarkers will be frozen, stored, and processed in batches 
d  Troponin I will be drawn 2-3 days after each doxorubicin infusion   
e  Health-related quality of life to be completed prior to starting treatment (can occur anytime between consent 
and initiation of C1D1 of chemotherapy) and at end of treatment visit 
f  The whole blood sample can be drawn anytime during the active study phase, and should be collected in EDTA 
tubes 
g  Mandatory for women of child-bearing potential (serum test) 
h  Investigator/treating physician will need to ensure that patient’s baseline evaluations still meet eligibility criteria 
or will report any exclusionary criteria to the PI for review prior to starting patient on treatment 
i  Screening clinical evaluations and laboratory assessments may be used as the baseline evaluations if they are   
done within 14 days prior to starting the recommended treatment 
j Baseline TRSC can occur anytime between consent and initiation of C1D1 of chemotherapy 
k  Symptom Alleviation: Self-Care Methods to be completed at end of treatment visit 
l Start of doxorubicin