Pilot Study of Metformin to Mitigate Sequelae of Radioactive Iodine Treatment for Well-Differentiated Thyroid Cancers
Phase: PHASE2
Conditions: Thyroid
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University

 
 
 
 
Protocol version 6.3 (2019-03-15) 
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THOMAS JEFFERSON UNIVERSITY 
Sidney Kimmel Cancer Center 
 
Pilot study of metformin to mitigate sequelae of radioactive iodine 
treatment for well-differentiated thyroid cancers. 
 
 
Principal Investigator: 
Joseph Curry, MD  
Department of Otolaryngology  
925 Chestnut Street, 6th floor 
Philadelphia, Pennsylvania 19107 United States 
Phone: 215-503-6828; Fax: 215-955-923-4532  
 
Co-Investigator(s): 
Ubaldo Martinez-Outschoorn, MD (co-PI) 
Department of Medical Oncology  
925 Chestnut St 
Suite 420A 
Phone 215-955-8874; Fax 215-955-2340 
Jennifer M Johnson, MD, PhD 
Department of Medical Oncology 
1015 Walnut Street, Suite 700 
Philadelphia, PA 19107 
215-955-8875 
Ralph Zinner, MD 
Department of Medical Oncology 
925 Chestnut St Suite 320A 
Phone: (215) 955-8874; Fax: (215) 503-7697 
David Cognetti, MD 
Department of Otolaryngology  
925 Chestnut Street, 6th floor 
Phone: 215-503-6828; Fax: 215-955-923-4532 
Adam Luginbuhl, MD 
Department of Otolaryngology  
925 Chestnut Street, 6th floor 
Phone: 215-503-6828; Fax: 215-955-923-4532 
Edmund Pribitkin, MD 
Department of Otolaryngology  
925 Chestnut Street, 6th floor 
Phone: 215-503-6828; Fax: 215-955-923-4532 
Benjamin  Leiby, PhD (Statistician) 
Department of Pharmacology and Experimental Therapeutics 

 
 
 
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1015 Chestnut St, Suite 520 
Larry A. Harshyne, PhD 
Department of Dermatology 
1020 Locust Street 
Jefferson Alumni Hall, Suite 454 
(215) 503-9893 
Andrew P. South, PhD 
Department of Dermatology 
Bluemle Life Sciences Building, Room 406 
233 S. Tenth Street 
(215) 955-1934 
Intekhab Ahmed, MD 
Department of Endocrinology 
Walnut Towers, Suite 600 
211 S. 9th Street 
(215) 955-1925  
Grace Lu Yao, PhD, MPH 
Department of Medical Oncology 
Bluemle Life Sciences Building, Suite 1034 
233 S. Tenth Street 
(215) 503-7970 
Christopher Fundakowski 
Department of Otolaryngology  
925 Chestnut Street, 6th floor 
Phone: 215-503-6828; 
Funding Sponsor: 
Departmentally funded 
Regulatory Sponsor: 
Thomas Jefferson University 
IND Number: 
N/A 
Study Product: 
Metformin 
Protocol Number: 
JT#9411/IRB#16D.564 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Version: Date: 
1.0 
6/1/16 
2.0 
6/19/16 
3.0 
7/13/16 
3.1 
08/18/16 
3.1.1 
09/13/16 
3.2 
01/09/17 
4.0 
04/12/17 
4.1 
06/29/17 
5.0 
01/26/2018 
6.0 
05/21/2018 
6.1 
03/13/2019 
6.2 
03/15/2019 
6.3 
03/15/2019 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of THOMAS JEFFERSON 
UNIVERSITY.  No part of it may be transmitted, reproduced, published, or used by 
other persons without prior written authorization from the study sponsor. 
 
 

 
 
 
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Table of Contents 
STUDY SUMMARY 
 
1 
INTRODUCTION 
 
1.1 
SPECIFIC AIMS AND HYPOTHESIS 
 
1.2 
BACKGROUND 
 
1.3 
STUDY THERAPY 
 
1.4 
PRECLINICAL DATA 
 
1.5 
CLINICAL DATA TO DATE 
 
1.6 
DOSE RATIONALE AND RISK/BENEFITS 
 
2 
STUDY OBJECTIVES 
 
2.1 
PRIMARY OBJECTIVE 
 
2.2 
SECONDARY OBJECTIVE(S) 
 
3 
STUDY DESIGN 
 
3.1 
GENERAL DESIGN 
 
3.2 
PRIMARY STUDY ENDPOINTS 
 
3.3 
SECONDARY STUDY ENDPOINTS 
 
3.4 
PRIMARY SAFETY ENDPOINTS 
 
4 
SUBJECT SELECTION AND WITHDRAWAL 
 
4.1 
INCLUSION CRITERIA 
 
4.2 
EXCLUSION CRITERIA 
 
4.3 
GENDER/MINORITY/PEDIATRIC INCLUSION FOR RESEARCH 
 
4.4 
SUBJECT RECRUITMENT AND SCREENING 
 
4.5 
EARLY WITHDRAWAL OF SUBJECTS 
 
4.5.1 
When and How to Withdraw Subjects 
 
4.5.2 
Data Collection and Follow-up for Withdrawn Subjects 
 
5 
STUDY DRUG/THERAPY 
 
5.1 
DESCRIPTION 
 
5.2 
TREATMENT REGIMEN 
 
5.3 
RISKS 
 
5.4 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS 
 
5.5 
PREPARATION AND ADMINISTRATION OF STUDY DRUG/THERAPY 
 
5.6 
SUBJECT COMPLIANCE MONITORING 
 
5.7 
PRIOR AND CONCOMITANT THERAPY 
 
5.8 
PACKAGING 
 
5.9 
BLINDING OF STUDY DRUG 
 
5.10 
RECEIVING, STORAGE, DISPENSING AND RETURN 
 
5.10.1 
Receipt of Drug Supplies 
 
5.10.2 
Storage 
 
5.10.3 
Dispensing of Study Drug 
 
5.10.4 
Return or Destruction of Study Drug 
 
6 
STUDY PROCEDURES 
 
6.1 
STUDY VISIT SCHEDULE 
 
6.2 
DEFINITION OF DOSE LIMITING TOXICITIES 
 
6.3 
DOSE DELAYS AND DOSE MODIFICATIONS. 
 
7 
STATISTICAL PLAN 
 

 
 
 
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7.1 
SAMPLE SIZE DETERMINATION 
 
7.2 
STATISTICAL METHODS 
 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS 
 
8 
SAFETY AND ADVERSE EVENTS 
 
8.1 
DEFINITIONS 
 
8.2 
RECORDING OF ADVERSE EVENTS 
 
8.3 
UNBLINDING PROCEDURES 
 
8.4 
STOPPING RULES 
 
8.5 
DATA AND SAFETY MONITORING PLAN 
 
8.5.1 
Medical Monitoring and AE/SAE Reporting 
 
8.5.2 
Data and Safety Monitoring Committee 
19 
9 
DATA HANDLING AND RECORD KEEPING 
 
9.1 
CONFIDENTIALITY 
 
9.2 
SOURCE DOCUMENTS 
 
9.3 
CASE REPORT FORMS 
 
9.4 
RECORDS RETENTION 
 
10 
STUDY MONITORING, AUDITING, AND INSPECTING 
 
10.1 
STUDY MONITORING PLAN 
 
10.2 
AUDITING AND INSPECTING 
 
10.2.1 
Independent External and Internal Audits 
24 
11 
ETHICAL CONSIDERATIONS 
 
12 
STUDY FINANCES 
 
12.1 
FUNDING SOURCE 
 
12.2 
CONFLICT OF INTEREST 
 
12.3 
SUBJECT STIPENDS OR PAYMENTS 
 
13 
PUBLICATION PLAN 
 
14 
REFERENCES 
 
15 
APPENDICES 
27 
 
 
 

 
 
 
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List of Abbreviations 
 
AKT: also named protein kinase B  
ALC: absolute lymphocyte count 
AMPK: adenosine monophosphate protein kinase  
ANC: absolute neutrophil count 
ATP: adenosine triphosphate 
CAFs: cancer associated fibroblasts  
cAMP: cyclic adenosine monophosphate  
CBC: complete blood count 
HOMA: homeostatic model assessment 
HNSCC: head and neck squamous cell carcinoma 
IHC: immunohistochemistry  
Ki67: Kiehl-67 antibody 
LKB1: liver kinase B1 
lncRNA: long noncoding RNA 
miRNA: microRNA 
mTOR: mammalian target of rapamycin 
OXPHOS: oxidative phosphorylation 
PDE3B: phosphodiesterase 3B  
PET: positron emission tomography  
PI3K: phoshoinositide 3 =kinase 
PTC: papillary thyroid cancer 
RAI: radioactive iodine  
RBC: red blood-cell count 
ROS: reactive oxygen species 
WBC: white blood-cell count 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Study Summary 
Title 
Pilot study of metformin in thyroid cancer patients undergoing radioactive iodine 
treatment.  
Short Title 
Metformin in radioactive iodine treatment 
Protocol 
Number 
JT#9411/IRB#16D.564  
Phase 
Pilot 
Methodology/
Study Design 
Preliminary Efficacy trial 
Study 
Duration 
60 months 
Study 
Center(s) 
Single Center - Jefferson 
Objectives 
To assess the effect of metformin on radioprotection in normal tissue for 
subjects undergoing radioactive iodine treatment.  We will evaluate the ability of 
metformin to attenuate the myelosuppression and decrease xerostomia, 
xerophthalmia, and dysgeusia. 
Number of 
Subjects 
32 
Diagnosis 
and Main 
Inclusion 
Criteria 
Subjects with a biopsy proven diagnosis of differentiated thyroid cancer, and 
who have a scheduled appointment for definitive resection of the tumor followed 
by treatment with radioactive iodine at TJUH are eligible to participate. 
Study 
Therapy, 
Dose, Route, 
Regimen 
Metformin is the therapeutic agent in the protocol. The initial starting dose will 
be 500 mg orally daily for 3 days which then will be increased to 500 mg twice 
daily and, if tolerated, further increased to 1000mg twice daily after day 6. 
Subjects will maintain 1000 mg twice a day dosing or highest tolerated dosing  
until two weeks post radiation. 
Subjects will be randomized to 1:1 to take metformin or placebo.   
Duration of 
administratio
n and follow-
up 
The initial starting dose will be 500 mg orally daily for 3 days which then will be 
increased to 500 mg twice daily and, if tolerated, further increased to 1000 mg 
twice daily after day 6. Subjects will maintain 1000 mg twice a day dosing until 
two weeks post radioactive iodine treatment.  The participant’s medical records 
will be reviewed every three months, surveys administered, and CBC repeated 
over the course of one year according to the schedule outlined below 
Reference 
therapy 
None 

 
 
 
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Statistical 
Methodology 
The primary objective of the study is to estimate the impact of metformin on 
complete blood count and serum exosome profile following radioactive iodine 
treatment. All patients from whom samples are obtained both pre- and post-
treatment will be included in the primary analyses. Blood counts will be 
compared between the RAI/Metformin group (N=16) and the placebo control 
RAI group (N=16).  The estimated mean difference and associated 95% 
confidence interval will be calculated.   
Analysis of secondary outcomes will be primarily descriptive and related to taste 
disturbance, xerostomia, and xerophthalmia.  
Schema 
32 patients with thyroid cancer who undergo primary surgical resection and 
subsequently require RAI treatment. 
Preoperative blood and saliva 
 
Thyroidectomy 
 
       Recovery for approx 6-8 weeks 
 
Postoperative Pretreatment Metformin Blood and Saliva 
 
 
      Randomized Metformin treatment* (n=30) or placebo treatment (n=30) 1 wk 
 
                           Post-metformin or placebo Pre-RAI Tx blood and saliva 
 
 
 
                  RAI Tx 
 
 
                                                     Post RAI blood and saliva 
                                                          
 
                                                     Metformin or placebo Treatment** 2 wks 
                                                                        
 
                                                          Post-RAI Tx blood sample q 3mo x 12 mos 
 
 *Metformin (500 mg/day for 3 days followed by 500 mg twice daily for 3 days followed by 1000 
mg twice daily from day 6 until RAI tx) 
**Metformin (1000 mg twice daily for two weeks following RAI tx) 
 
 
 
 

 
 
 
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1.0 INTRODUCTION 
This document is a protocol for a human research study. This study will be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures.  
1.1 Specific Aims and Hypothesis  
Primary: 
● To estimate the impact of metformin on radiation-induced myelosuppression in 
patients treated with RAI after surgery for differentiated thyroid cancer. 
● To estimate the effects of metformin on serum and salivary exosome profile in 
patients with well-differentiated thyroid cancer treated with total thyroidectomy 
and radioactive iodine. 
 
Secondary:  
● To assess safety and tolerability of metformin treatment in subjects with thyroid 
cancer. 
● To assess the effect of metformin therapy on RAI-induced xerostomia, 
xerophthalmia, and dygeusia as measured by Xerostomia Questoinnaire (XC), 
the modified Vanderbilt Head and Neck Cancer Symposium Survey (version 2.0), 
University of Washington Quality of Life Questionnaire, and EORTCQLQ-H&N35   
 
Correlatives: 
● To assess the results of the radioactive iodine treatment in patients treated with 
metformin compared those not treated based on the outcomes of the radioactive 
iodine scan. 
1.2 Background and Rationale  
  Differentiated thyroid cancer (DTC) is the most frequently diagnosed primary 
endocrine-related malignancy, accounting for 3.8% of all new cancer cases in US. The 
majority of cases are papillary and follicular and 10-year overall survival is excellent, 
exceeding 90%. (Clement 2015) Treatment for DTC consists of total or near-total 
thyroidectomy, followed by administration of radioactive iodine (I-131) for remnant 
ablation or residual disease. (Clement 2015) 
  I-131 has been used in therapy for well-differentiated thyroid cancer for over 50 
years. The use of RAI is an essential adjuvant treatment strategy after thyroidectomy in 
patients with DTC.  The 2009 ATA guidelines recommend I-131 ablation in high-risk 
patients and selected low-risk patients (1-4 cm thyroid cancer confined to thyroid and 
high-risk features predicting an intermediate to high-risk of recurrence or death from 
thyroid cancer) (Cooper 2009).  The primary objectives of RAI treatment include 
eliminating residual normal and tumoral thyroid cells as the absence of normal residual 

 
 
 
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thyroid tissue improves the sensitivity of subsequent serum thyroglobulin levels as a 
tumor marker during follow-up for recurrence (Van Nostrand 2009). The eliminated 
normal residual thyroid tissue can no longer compete to take up a portion of 
administered RAI thus increasing sensitivity of detection of locoregional and/or 
metastatic disease on follow-up RAI whole body scans.  Additionally, the absence of 
intense uptake in the thyroid bed that would otherwise obscure other foci of adjacent 
uptake allows post-treatment scans to reveal additional disease that was not previously 
identified. 
  RAI therapy is usually carried out with high doses of iodine-131, and, in cases of 
recurrent or progressive iodine-avid metastatic disease, is often repeated to get 
favorable response.  RAI therapy is performed following either thyroid hormone 
withdrawal or preparation with recombinant human thyroid stimulating hormone (rhTSH) 
using whole-body and blood clearance studies.  For successful remnant ablation in low-
risk and high-risk patients, a minimum activity of 30-100 mCi/1.1-3.7GBq and 100-
200mCi/3.7-74 GBq is recommended (Clement 2015, Cooper 2009) 
  RAI is generally well tolerated. Complications are rarely life-threatening but can 
negatively affect patients’ quality of life. (Fard-Esfahani 2014)  Side effects of I-131 occur 
in many areas and organs systems. They are most often categorized by time of 
occurrence after therapy. Early effects are those that begin immediately after therapy 
until around 10 days post-treatment. Intermediate effects occur during the remainder of 
the first year after therapy and late effects can be experienced any time during the long-
term follow-up period. (Van Nostrand, 2009)  
  Within the head and neck, salivary gland dysfunction is the most frequently described 
complication after I-131 therapy. (Clement 2015) Usually salivary gland dysfunction 
occurs early and is transient, but it may also persist or appear late.  Xerostomia, occuring 
in 2-55% of patients, is generally the result of radiation-induced sialoadenitis. (Van 
Nostrand) Obstruction of Stensen’s and/or Wharton’s duct due to inflammation also 
leads to pain and swelling and can ultimately result in ductal narrowing secondary to 
fibrosis.  Ensuing hyposalivatoin can become chronic and leads to problems with oral 
hygiene, dental caries, and candidiasis. 
     Salivary glands concentrate iodide by a factor of 30-40 compared to blood and, as a 
result, the dose to salivary gland during first 12 hours after administration could be as 
high as 6Gy. (Fard-Esfahani 2014) Effect on salivary gland function is dose-related and 
more prominent in the parotid glands. Evaluation of volume in salivary glands using 
sonography shows significantly increased volume in the parotid glands after RAI 
dependent on received activity and time from irradiation. Occasionally radiation 

 
 
 
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sialoadenitis will result in facial nerve paralysis secondary to compression by a swollen 
parotid gland. 
     A review by Clement et al of 683 pts found that the prevalence of objective salivary 
gland dysfunction after I-131 ranged from 37-72%. In general, higher cumulative 
activities of I-131 are associated with increased risk of salivary gland dysfunction. 
Symptomatic salivary gland dysfunction correlated well with cumulative I-131 activity. 
(Clement 2015) 
     Treatment with I-131 can also result in disturbed nasolacrimal gland function and 
xerophthalmia resulting from inflammation of lacrimal gland. Recent studies have shown 
evidence of xerophthalmia in 16-33% of patients lasting for up to 2 years. (Van 
Nostrand 2009) A recent review reported that an abnormal Shirmer’s test was found 
significantly more frequently in patients exposed to I-131 compared to unexposed 
patients.(Clement 2015) RAI uptake by nasolacrimal duct mucosa leads to subsequent 
inflammation, edema, and fibrosis and can be responsible for lacrimal duct obstruction 
and resulting chronic epiphora. (Fard-Esfahani 2014). Conjunctivitis has also been 
reported in 23% of patients. (Van Nostrand 2009) 
     Leukopenia, thrombocytopenia, and anemia are major risks of I-131 therapy. (Van 
Nostrand 2009) Of the known potential adverse events of I-131 therapies, bone marrow 
suppression has been considered the most important. (Bikas 2016) More than 20 
publications have described bone marrow suppression secondary to I-131 therapy, 
though most are underpowered. Bone marrow suppression is mostly transient and 
results in a decreased in white blood cell and platelet count for up to 6-10 weeks. Total 
incidence is about 25% with leukocyte and platelet count nadirs 1-2 months after RAI 
administration (Fard-Esfahani 2014) Occasionally it results in increased susceptibility to 
infection or bleeding if the marrow dose exceeds about 200 cGy. (Fard-Esfahani 2014) 
     Of those patients receiving high-activity therapies, 38% have grade 1 bone marrow 
suppression as defined by the World Health Organization (WHO). Previous research 
has shown that even a single dose of RAI can cause changes in the peripheral CBC. 
(Padovani 2014) The degree to which an individual is affected is influenced by many 
factors including the patient’s clearance rate, the total cumulative prescribed activity of I-
131, the frequency of therapy and interval between treatments, the patient’s bone 
marrow reserve and the degree to which bone metastases are present. Interpretation of 
the hematologic effects of RAI therapy is complicated by the fact that many patients 
who require high cumulative activities of RAI also receive external beam radiation 
therapy (EBRT) to treat metastatic lesions to the bone, which carries its own 
hematopoietic toxicity (Padovani 2014) 
  First reported in 1963 by Haynie et al, transient leukopenia, anemia, and 
thrombocytopenia and occasional persistent anemia were noted after repeated RAI 
doses administered at 3-month intervals with traditional thyroid hormone (TH) 

 
 
 
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withdrawal. (Padovani 2014, Haynie 1963) More recent studies confirm what appear to 
be transient effects on blood counts measured in the first few weeks after RAI therapy, 
which some studies have shown to be less evident with an rhTSH preparation as 
compared to traditional TH withdrawal. To minimize BM suppression, Benua et al 
suggested not exceeding 200 cGy. (Van Nostrand 2009) 
Tumor Derived Exosomes 
     Exosomes are small extra-cellular vesicles produced by all cells and present in 
almost all biological fluids including blood, urine, ascites, CSF, serum and plasma, and 
in the culture medium of cell cultures. (Whiteside 2016, Silva 2015) Currently exosomes 
are defined as 40-150 nm diameter vesicles of endocytic origin, similar in size to 
viruses, with a bilayered lipid membrane, a cup shaped morphology, and densities 
ranging between 1.13-1.19 g/mL (Silva 2015). 
  Exosomes have recently emerged as important mediators in cell communication due 
to their enriched content in genetic material like DNA, mRNA, and non-coding RNAs 
such as microRNAs (miRNA). (Silva 2015) MicroRNAs are small (19-24bp) endogenous 
RNAs that regulate gene expression at the posttranscriptional level by targeting mRNA 
transcripts. (Silva 2015) 
    The biogenesis of exosomes, which involves the endosomal compartment, sets them 
apart from other extracellular vesicles (EV). (Whiteside 2016) Their molecular profile 
partly, but not completely, resembles that of the parental cell. Exosomes are composed 
of a lipid bilayer and at any given point can contain all known molecular constituents of 
a cell. (Kalluri 2016) Similarities in the molecular and genetic profile of the parent cell 
are usually present, and this has given rise to the concept of exosomes as putative 
tumor biomarkers. (Whiteside 2016) 
    The precise function of exosomes remains unknown. (Kalluri 2016) The leading 
theory is that exosomes are an integral part of a complex, well-organized, and 
evolutionarily conserved (present in bacteriea, plants, animals, man) form of information 
delivery that operates at short and long distances. (Whiteside 2016) They carry 
proteins, lipids, and nucleic acids in functionally active form and can regulate gene 
expression in recipient cells, thus determining their behavior. (Whiteside 2016) The 
discovery that their contents can be transferred to a recipient cell via fusion to mediate 
phenotypic alterations supports this notion that exosomes are dynamic mediators of 
intercellular communication (Kalluri 2016) Although some models of exosome uptake in 
target cells have been proposed, there is no consensus regarding the definition of the 
mechanisms. (Silva 2015) 
     The content and number of exosomes generated likely change depending on 
different stressors or stimuli cells experience. (Kalluri 2016) Exosome levels in plasma 
and other body fluids of patients with cancer are frequently elevated compared to 

 
 
 
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normal proliferating cells. (Whiteside 2016) Developing tumors become the main driver 
of cellular interactions and enhanced exosome biogenesis likely plays a particularly 
important role. (Whiteside 2016) Exosomes produced and secreted by tumor cells have 
been largely described as promotors of tumor progression.  They manipulate the local 
and distant biological environment by converting normal physiological processes to 
those favoring tumor growth and dissemination in part by silencing antitumor responses, 
supporting new vessel growth, and promoting survival of tumor cells. (Silva 2015, 
Whiteside 2016) Exosome-mediated transfer of oncogenes and oncogenic signals from 
one tumor cell to another or from tumor cells to normal cells is well documented in the 
literature (Whiteside 2016) Intercellular transfer of molecules containing oncogenic 
mutations to normal or malignant recipient cells includes activated oncoproteins, their 
transcripts, oncogenic DNA sequences and oncogenic mRNAs, and leads to 
reprogramming of cellular pathways, especially those responsible for growth factor 
production (Whiteside 2016) The ability of oncosomes to carry and deliver oncogenic 
signals to target cells, sustain autocrine growth-promoting pathways in parent tumor 
cells, and modify functions of stromal cells in the TME supports the conclusion that 
tumor-derived exosomes may play a critical role in oncogenic transformation (Whiteside 
2016) Tumor-derived exosomes have been shown to play a role in promoting 
angiogenesis. They are present in the circulation and have ready access to all parts of 
the body. (Whiteside 2016) Thus, tumor-derived exosomes have been dubbed 
“oncosomes” because of evidence for the presence in their cargo of oncogenes and 
factors promoting tumor growth (Whiteside 2016) 
     It has been suggested that stress, including hypoxia prevalent in the TME accounts 
for this copious exosome secretion by tumor cells (Whiteside 2016) Hypoxic conditions 
in the growing tumor induce malignant cells to increase production of exosomes 
(Whiteside 2016) In more advanced cancers, expanding tumor cells which have 
escaped immune surveillance produce exosomes which carry an immunosuppressive 
cargo and become active participants in the tumor escape from the host immune 
system (Whiteside 2016) One of the clinically undesirable effects of tumor-derived 
exosomes that merits attention is their ability to horizontally transfer drug resistance 
(Whiteside 2016) Recent studies indicate that this drug-resistance is, in part, attributable 
to packaged miRNAs transferred intercellularly transfer by exosomes from drug-
resistant to sensitive cancer cells. (Whiteside 2016) 
     On the other hand exosomes can also program the immune system in order to evoke 
an anti-tumor response by the organism (Silva 2015) It has been shown that exosomes 
possess antitumor function and can act to restrain disease progression.  (Kalluri 2016) 
The duality of roles makes clear that the network of interactions created by exosomes is 
complex and of utmost importance for a better understanding of the carcinogenic 
process (Silva 2015) 
     Exosomes and their contents have emerged as a potential source to detect cancer 
and provide information on potential regulatory drivers of tumor progression and 

 
 
 
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metastasis (Kalluri 2016) Cancer cells secrete millions of exosomes in order reprogram 
their surroundings to a tumor-promoting microenvironment. (Whiteside 2016) Tumor-
derived exosomes represent only a fraction of total exosomes present in the plasma, 
however, and this fraction may change depending on tumor progression. (Whiteside 
2016) Tumor-derived exosomes represent a substantial part of the plasma vesicular 
content, and their molecular and genetic profiles change in the course of disease or 
therapy (Whiteside 2016) As they are readily accessible in nearly all body fluids, it has 
been suggested that cancer exosomes may in fact serve as a “liquid biopsy” to aid in 
the diagnosis of malignancies, including prostate, pancreas, breast, and ovarian 
cancers, glioblastoma and melanoma. (Kalluri 2016) Exosomes may also serve to 
unravel new therapeutic targets and predict therapeutic responses. (Silva 2015)  
     Lipids and metabolites in cancer exosomes may offer insights into cancer detection 
and biology, however more precise knowledge is evolving with respect to the utility of 
proteins and nucleic acids. (Kalluri 2016) DNA in exosomes may provide information 
about cancer-specific mutations. (Kalluri 2016) Various RNAs including mRNA and 
noncoding RNAs such as microRNAs (miRNA) and long non-coding RNA (lncRNA) in 
exosomes are functional and can be transferred to recipient cells and translated into 
functional proteins thereby impacting the transcriptome of recipient cells. (Kalluri 2016) 
mRNAs carried by exosomes are known to be involved in critical cellular activities such 
as cell cycle regulation, chromosome segregation, proliferation, and migration. 
(Whiteside 2016) MicroRNAs are estimated to regulate the translation of nearly 60% of 
protein coding genes as they are involved in the regulation of many processes including 
differentiation, apoptosis, and development (Silva 2015) Deregulation of the 
expressions of certain miRNAs in the cell has been consistently observed during 
various pathologies including cancer. Studies report that transfer of exosomes 
associated with miRNAs to recipient cells occurs, which results in altered gene 
expression and functional effects. (Silva 2015) 
     Thus far, cancer-derived exosomes have been shown to induce changes in the 
morphology, protein expression, patterns of growth, and cytokine profile. Examination of 
stromal fibroblasts in the TME of various tumors suggests that they increase production 
of collagen and hyaluronic acid. (Whiteside 2016) Exosomes released by tumor cells 
also directly affect molecular and genetic programs in endothelial cells thus promoting 
the process of neovascularization. (Whiteside 2016) Within bone marrow, exosome-
mediated alterations have been shown to interfere with the hematopoietic cell 
development, differentiation, and function. (Whiteside 2016) Peinado et al have 
demonstrated in mice that exosomes from metastatic melanoma cells can enhance 
tumorigenesis by recruiting bone marrow-derived cells to initiate a pre-metastatic niche. 
(Silva 2015) In ovarian cancers, studies of the levels cancer-specific exosomal miRNAs 
have indicated that malignant tumors could be distinguished from benign disease. 

 
 
 
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Exosomes have also been shown to participate in the formation of the pre-metastatic 
niche in an in vivo pancreas cancer model. (Silva 2015) 
     The microRNAs nearly universally present in exosomes have been recently 
described as good biomarkers easily accessible in circulation of cancer patients (Silva 
2015) Enriched and specific miRNAs within exosomes may inform diagnosis and serve 
to monitor the progression of cancer (Kalluri 2016) The properties of tumor-derived 
exosomes place them in an ideal position to serve as promising surrogates of tumor-
derived proteins and transcripts (Whiteside 2016) They represent an enriched source of 
carefully packaged biomarkers, proteins, lipids, and nucleic acids. Transcripts carried in 
exosomes from cancer patients’ plasma could serve as biomarkers for non-invasive 
detection of malignant cells (Whiteside 2016) Measurements of mRNA expression 
levels in plasma exosomes may also be useful as surrogates of responses to immune 
therapies in patients with cancer (Whiteside 2016) Clinical efficacy of immune therapies 
may be influenced by tumor-derived exosomes (Whiteside 2016) 
   To date, the mechanisms tumor cells employ to regulate exosome secretion remain 
unknown, although emerging insights suggest that several distinct mechanisms may be 
involved and may depend on the cancer type and its aggressiveness. Accumulating 
data indicate that miRNA signatures for extracellular vesicles derived from plasma of 
patients with different cancers are distinct (Whiteside 2016) Multiple studies have shown 
that exosomes isolated from plasma of patients with different cancers, including 
glioblastoma, lung ca, and breast carcinoma, have distinct miRNA profiles (Whiteside 
2016) 
     MicroRNA in the circulation has been demonstrated as potential biomarkers of 
recurrence in papillary thyroid cancer (PTC). (Lee 2015) Currently, measuring serum 
thyroglobulin (Tg) levels provides the simplest long-term surveillance method, however, 
this may not suitable for up to 25% of patients with PTC due to anti-Tg antibodies, non-
total thyroidectomy, or lack of RAI ablation (Lee 2015) Circulating miRNAs are being 
investigated as an adjunct or alternative (Lee 2015) Previous studies Lee et al have 
found higher circulating levels miR-146b and miR-222, miRNAS related to thyroid cell 
proliferation, in patients with PTC when compared with normal glands. Subsequently, in 
vitro studies by Lee et al have confirmed the presence of miR-146b and miR-222 in 
exosomes released by both normal and PTC cells. (Lee 2015) 
1.2.1  Preclinical Data: 
 Metformin and its potential as radioprotective agent 
Metformin (N, N-dimethylbiguanide) is a biguanide that is best known for its use as first 
line therapy for type II diabetes patients (1).  Metformin specifically inhibits the complex I 
(NADH:ubiquinone oxidoreductase) of the mitochondrial electron transport chain 
decreasing cellular respiration and the rate of ATP formation (2) (3) (4). This triggers the 

 
 
 
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activation of the energy sensor AMP-activated protein kinase (AMPK) that regulates cell 
metabolism and shifts it towards an energy-sparing state (5). This leads to reduced 
hepatic glucose production, decreases intestinal absorption of glucose, and improves 
insulin sensitivity thereby increasing peripheral glucose uptake and utilization without 
causing hypoglycemia.  It is an FDA approved medication for the management of type 2 
diabetes mellitus with extensive safety data. In general, clinically significant responses 
are not seen at doses <1500 mg daily; however, a lower recommended starting dose 
and gradual increased dosage is recommended to minimize gastrointestinal symptoms. 
Extensive preclinical data now also support the effectiveness of metformin as an 
antineoplastic and radioprotective agent (6).   
Epidemiologic Data for Metformin’s Efficacy for Radioprotection and Cancer Prevention: 
Retrospective studies have shown that diabetics treated with metformin have a cancer 
risk reduction of approximately 40% compared to diabetics not treated with metformin 
(7,8).  Evans et al (9) reported that the risk of subsequent cancer diagnosis was 
reduced in patients with type 2 diabetes who received metformin (with an odds ratio of 
0.85 for any metformin exposure versus no metformin exposure).  The protective effect 
increased with greater metformin exposure (measured as total dose prescribed or total 
duration of use). 
Current evidence from epidemiologic studies suggests that metformin has clinical 
activity in breast cancer.  Hadad et al (11) demonstrated biomarker evidence for anti-
proliferative effects of metformin in women with breast cancer by decreasing Ki67 and 
messenger RNA expression for PDE3B (critical regulator of cAMP levels that affect 
activation of AMPK).  Similarly, Niraula et al (12) showed short-term preoperative 
metformin with a dosing schedule of 500mg three times daily was well tolerated and 
resulted in clinical and cellular changes consistent with beneficial anti-cancer effects 
with increased insulin sensitivity by HOMA in subjects and decreased proliferation and 
increased apoptosis in carcinoma cells.  Multiple clinical trials are currently evaluating 
the effect of metformin in combination with standard treatment in a variety of 
malignancies including breast, colorectal, pancreatic, lung, gynecologic, and prostate 
cancer (13, 14, 15).   
Anti-tumor effects by metformin are contrasted by several reports supporting the 
hypothesis that metformin may serve as a radioprotectant that can help to protect 
normal tissues against the radiation toxicity.  At present, the only prophylactic 
radioprotector that has been approved by the FDA is amifostine, which is used for 
radioprotection against xerostomia by radiation exposure in the treatment of head and 
neck cancer (Miller 2014) Based on the observations of several preclinical studies, 
Bikas et al conducted a 2016 retrospective study that showed that metformin 
significantly attenuated the I-131-induced decrease in white blood cells post-treatment 

 
 
 
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and that patients treated concomitantly with metformin returned to their baseline values 
sooner. (Bikas 2016) 
Mechanism of Action for Metformin: 
Metformin inhibits oxidative phosphorylation by downmodulating the activity of the 
complex I enzyme NADH dehydrogenase.  The inhibition of mitochondrial complex 
activity may contribtue to ROS metabolism and the activation of AMP-activated protein 
kinase (AMPK) by metformin (DOI: 10.1111/jdi.12328). AMPK is a central cellular 
energy sensor, activation of which leads to suppression of many of the processes highly 
dependent on ample cellular adenosine triphosphate supply, including gluconeogenesis, 
protein and fatty acid synthesis and cholesterol biosynthesis, promoting catabolic 
processes such as fatty acid beta oxidation and glycolysis14. AMPK activation potentially 
promotes survival after radiation, especially in a low nutrient environment found in 
human tumors. (Muaddi 2013) By inhibiting the formation of ROS, metformin may 
further protect tissues or cells against DNA damage and mutations. (Xu 2015) 
Preclinical studies and clinical trials support the view that metformin has anticancer 
properties (17) (18) (19) (20) although the mechanism(s) underlying this effect are 
subject to debate. The purported mechanisms are numerous and include OXPHOS 
complex I inhibition, AMPK activation and insulin growth factor signaling (21) (22) (23) 
(24).  Several groups have shown that metformin’s ability to limit tumor growth in vivo is 
dependent on mitochondrial complex I (25). Complex I inhibition blocks mitochondrial-
dependent production of reactive oxygen species (ROS) and adenosine triphosphase 
(ATP) (26-28).  Catabolite access may determine susceptibility to metformin anti-tumor 
effects as some cancer cells grown in the absence of glucose and presence of 
glutamine are more affected by metformin treatment than cells grown in the presence of 
glucose (29). Metformin sensitivity is further determined by glucose availability and 
overall oxidative phosphorylation (OXPHOS) capacity (30). The decrease in ATP 
production results in the activation of the liver kinase B1 (LKB1) – adenosine 
monophosphate-activated protein kinase (AMPK) signaling pathway (26-28).  Activation 
of this pathway usually occurs during times of hypoxia and nutrient deprivation, and 
reciprocally, it can be suppressed in times of “over nutrition” and hyperglycemia.  AMPK 
is a key energy sensor that regulates metabolism in an attempt to maintain energy 
homeostasis (31).  The end result of blocking the LKB1-AMPK signaling pathway is a 
down-regulation of energy consuming biosynthetic processes including 
gluconeogenesis, protein and fatty acid synthesis and cholesterol biosynthesis, and 
promotion of catabolic processes such as fatty acid beta oxidation and glycolysis (32).  
Metformin may also have activity that is independent of LKB1.  In LKB1 deficient cells, 
metformin is still able to affect the intracellular energy state (33).  Metformin also alters 
the mitochondrial redox state by inhibiting glycerophosphate dehydrogenase (34). 

 
 
 
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Metformin reduces the mitochondrial citric acid cycle and induces aerobic glycolysis as 
well (35). 
Collectively these considerations highlight that metformin may have utility as a selective 
radiation protector of normal but not tumor cells.  
1.2.2 Clinical Data 
Summary of results from clinical studies:  
Studies with metformin in cancer patients are abundant including all tumor sites.  Our 
group has recently finished an investigator-run trial looking at evidence of OXPHOS 
metabolism pre- and post-metformin.  
We have shown that head and neck squamous cell carcinomas (HNSCC) have high 
mitochondrial OXPHOS metabolism in highly proliferative cells17.  Also, there is high 
MCT4 expression in HNSCC cancer associated fibroblasts (CAFs) and in carcinoma 
cells with low proliferation rates17. MCT4 expression is a marker of pseudohypoxia, 
oxidative stress and enhanced glycolytic metabolism. We have demonstrated that there 
is metabolic coupling between highly proliferative carcinoma cells with high OXPHOS 
metabolism and low proliferative carcinoma cells and fibroblasts17. 
Bikas et al. retrospectively studied the radioprotective effects of Metformin on RAI 
treatment in differentiated thyroid cancer (DTC) patients by looking at complete blood 
count (CBC). The study used two arms. The Metformin group consisted of 40 diabetic 
patients with DTC taking Metformin while the control group consisted of 39 patients with 
DTC, combination of diabetic or not diabetic, not taking Metformin at the time of RAI 
treatment. Blood parameters included hemoglobin, red blood cell count, white blood cell 
count, absolute neutrophil count, absolute lymphocyte count, and platelet count. CBC 
was recorded at one month, six months, and twelve months. Patients treated with 
Metformin post-RAI treatment showed less of a decrease in white blood cell (WBC) 
count. The differences in WBC count between the two groups was highly statistically 
significant at all time points (P< 0.0001, P<0.0027, and P< 0.0001, respectively). The 
most prominent decrease in WBC was in absolute neutrophil count. WBC levels of 
patient in the Metformin group were also shown to recover to baseline levels more 
quickly (Bikas 2016). 
Metformin not only likely has radioprotective effects but may also have anticancer 
effects as well which could impact effect of radioactive iodine treatment. Retrospective 
studies have shown that diabetics treated with metformin have a cancer risk reduction 
of approximately 40% compared to diabetics not treated with metformin18, 19.  Other 
studies have also shown a reduction in the frequency of cancer with metformin use 20.  
Evans et al 21 reported that the risk of subsequent cancer diagnosis was reduced in 
patients with type II diabetes who received metformin (with an odds ratio of 0.85 for any 

 
 
 
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metformin exposure versus no metformin exposure).  The protective effect increased 
with greater metformin exposure (measured as total dose prescribed or total duration of 
use). 
There are currently multiple completed and on-going clinical trials evaluating the effect 
of metformin in combination with standard treatment of a variety of malignancies 
including breast, colorectal, pancreatic, lung, gynecologic, and prostate cancer22, 24, 25.  
There is one phase II study accruing subjects using paclitaxel plus metformin up to 
2500 mg a day or placebo in recurrent or metastatic head and neck cancer 26 
Metformin reduces mitochondrial OXPHOS metabolism and hence we expect it to 
reduce mitochondrial metabolism in carcinoma cells.  We want to investigate 
metformin’s effects on epithelial-stroma metabolic coupling and its ability to revert the 
high OXPHOS metabolism in carcinoma cells and revert the stroma to a less tumor 
permissive state in various cancers. 
Secondary end points will look at quality of life metrics including the Vanderbilt Head 
and Neck Cancer Symptom Survey, University of Washington Quality of Life 
Questionnaire, EORTCQLQ-H&N35, and the Xerostomia Questionnaire (XQ) all of 
which have been validated and used in multiple clinical studies to-date.  
1.3 Study Therapy 
Description of the experimental product: 
 
Metformin (N, N-dimethylbiguanide) is a biguanide that is best known for its use as first 
line therapy for type II diabetes patients (1).  Metformin specifically inhibits the complex I 
(NADH:ubiquinone oxidoreductase) of the mitochondrial electron transport chain 
decreasing cellular respiration and the rate of ATP formation (2) (3) (4). This triggers the 
activation of the energy sensor AMP-activated protein kinase (AMPK) that regulates cell 
metabolism and shifts it towards an energy-sparing state (5). This leads to reduced 
hepatic glucose production, decreases intestinal absorption of glucose, and improves 
insulin sensitivity thereby increasing peripheral glucose uptake and utilization without 
causing hypoglycemia.  It is an FDA approved medication for the management of type 2 
diabetes mellitus with extensive safety data. In general, clinically significant responses 
are not seen at doses <1500 mg daily; however, a lower recommended starting dose 
and gradual increased dosage is recommended to minimize gastrointestinal symptoms. 
Extensive preclinical data now also support the effectiveness of metformin as an 
antineoplastic and radioprotective agent (6).   
 
1.4 Dose Rationale and Risk/Benefits 
Summary of known and potential risks and benefits, if any, to subjects: 
 

 
 
 
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Metformin’s most serious toxicity is lactic acidosis, occurring in three of 100,000 patient-
years of use. Risk is significantly reduced when metformin use is avoided in those 
patients with hepatic, cardiac, or renal compromise. However, metformin’s risk of lactic 
acidosis may be overstated since the recent evaluation of metformin associated lactic 
acidosis cases from 347 trials showed that the risk of lactic acidosis with metformin was 
not significantly increased compared with other antiglycemic agents27. Minor 
gastrointestinal upset is the most common toxicity, leading to cessation of therapy in 
less than 5% of individuals. Metformin does not induce hypoglycemia. The possible 
societal benefits are large since this will allow us to learn about the pharmacodynamic 
effects of metformin in RAI, allowing for radioprotection against myelosuppression, 
xerostomia, and other sequelae of radiatioactive iodine treatment. More broadly, this will 
allow us to gain new information on metformin’s effect on mitigation of side effects of 
radiation, tolerability, and safety profile in a population of subjects with various cancers.  
 
Description and justification for the route of administration, dosing regimen, and 
treatment period: 
 
Metformin will be administered orally since this is the route of administration currently 
approved by the FDA. Beginning one week prior to planned RAI therapy, the drug will 
be initiated at a dose of 500mg orally daily for 3 days and will then be increased to 500 
mg twice daily, and, if tolerated, further increased to 1000mg twice daily after day 6. 
Subjects will maintain 1000 mg twice a day dosing until their scheduled radioactive 
iodine treatment. Following radioactive iodine treatment, subjects will resume oral intake 
of metformin for two weeks at 1000 mg twice a day dosing 
 
There are currently multiple ongoing studies using doses from 500 mg twice daily up to 
2500 mg per day in the treatment arms.  There are also studies using the extended 
release form for a dose of 1500 mg daily. We have chosen our starting dose and 
escalation regimen to minimize side effects.  The chosen standing dose is based on 
metformin’s therapeutic range (minimal therapeutic dose in diabetic patients is 1500-
2000 mg a day)28, 29. The time of planned exposure to metformin will be 3 weeks. We 
will allow a window of an additional 2 weeks in the event that there are delays in the 
treatment scheduling but no patients will receive metformin for more than 35 days.  
 
Rules for dose modification: Toxicity monitoring, dose modification and 
treatment of complications: 
 
Particular attention will be paid in the first three days of treatment. Patients will take 500 
mg/day for 3 days.  From day 4, 500 mg twice daily and then in 3 days dose escalation 
to 1000 mg twice daily will be achieved.  A phone call on the day of each dose 
escalation will be made in order to evaluate the tolerability of the drug and also weekly 
thereafter.  Patients will be instructed to contact the clinical investigators should any 
side effects occur during the study19.    

 
 
 
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In the event that an iodinated IV contrast dye load for CT scanning is required at some 
point during the metformin treatment period, the drug will be stopped the day before  IV 
dye administration, as is the standard practice among patients taking metformin.  
However, IV contrast dye generally precludes treatment with RAI as the iodinated 
contrast competes with RAI and thus limits its effect. Therefore, it is extremely unlikely 
that any patient will be receiving iodinated contrast at the time of the study. 
Furthermore, this measure is generally considered to be conservative as the risk of 
lactic acidosis in patients taking metformin has not been shown to be higher than that of 
the general population after IV contrast dye in recent literature.  Nevertheless, this 
measure is in compliance with current American College of Radiology guidelines30, 31. 
Metformin will be resumed the day after RAI treatment  
completion at the last dose the subject was receiving prior to being held and if 
escalation was planned as previously described.  
 
Toxicity will be evaluated using the most recent version (version 4) of the NCI toxicity 
criteria, i.e. the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0. The CTCAE provides descriptive terminology and a grading scale for each adverse 
event listed. A copy of the CTCAE can be found at http://ctep.cancer.gov. 
 
Grade 1 toxicity: Patient will be maintained on full dose. 
Grade 2 toxicity: Dose will be reduced by 50% until grade 1 or lower. If symptoms are 
not resolved the treatment will be discontinued definitively.  
Grade 3 toxicity (probably or definitely drug related): Treatment will be interrupted and 
reassessment of toxicity will be performed daily. If toxicity is reduced to grade 1 or lower 
dose will be reduced by 50%. If toxicity is not resolved after 3 days the treatment will be 
discontinued definitively.  
Grade 4 toxicity (probably or definitely drug related): Treatment will be discontinued 
definitively. 
 
In case of grade 1 or 2 diarrhea (the most frequent side effect), concomitant loperamide 
will be provided and with grade 2 diarrhea the dose will be reduced by 50% until grade 1 
or lower. 
 
 
Risk benefit analysis 
The risks using metformin are small in this protocol with strict inclusion and exclusion 
criteria. It is unknown if metformin improves outcomes in cancer but this study is 
designed to evaluate whether the sequelae of treatment with RAI are mitigated by use 
of metformin. Hence, the potential direct benefits to subjects in this study include the 
possibility of decreased myelosuppression, xerostomia, and other sequelae of RAI. 
Further, the possible societal benefits are large since this will allow us to learn about the 

 
 
 
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pharmacodynamic effects of metformin in RAI treatment, tolerability and safety profile. 
Metformin is a widely used drug with an extensive safety record. In order to further 
minimize the risk of toxicity, strict exclusion criteria will be applied. This trial could also 
lead to a better understanding of the properties of the cancer microenvironment. The 
hypothetical risk of loss of confidentiality is minimized by the layers of security in place 
as detailed above. 
Potential risks:  
 
There is a potential risk of development of side effects related to metformin 
administration. Most commonly reported side effects in 1-5% of patients are diarrhea, 
nausea, vomiting, and abdominal pain. An extremely low risk of lactic acidosis is 
present (0.001%) which is minimized by excluding patients with renal dysfunction, 
hepatic dysfunction, cardiac impairment, pulmonary impairment, or excessive alcohol 
use. There is also a risk of loss of confidentiality which will be minimized as outlined in 
the Risk Management Procedures section. 
 
Potential benefits:  
 
Metformin may provide a radioprotective effect and mitigate known sequelae of RAI.  
Furthermore, metformin may alter tumor metabolism and improve outcomes in various 
cancers. This study is designed to evaluate whether the sequelae of RAI are mitigated 
by metformin and thus some patients may benefit from this study by taking metformin.  
With regards to cancer benefit, this study is not designed to evaluate efficacy in cancer 
treatment and it is unknown if metformin improves outcomes in cancer. The study may 
have societal benefits by allowing us to learn more about the properties of metformin 
which could help future cancer patients.  
2.0 STUDY OBJECTIVES  
1. To estimate the capacity of metformin to mitigate radioactive iodine therapy-
induced myelosuppression as assessed by CBC 
2. To assess the capacity of metformin to mitigate known side effects of radioactive 
iodine therapy including xerostomia, xerophthalmia, and dysgeusia as assessed 
by standardized questionnaire  
3. To analyze changes in serum and salivary exosome profiles following a trial of 
metformin administration in patients receiving radioactive iodine treatment 
 
2.1 Primary Objective: 
We have chosen complete blood count (CBC) as our primary endpoint and serum and 
salivary exosome profiles as secondary endpoints. To evaluate if treatment with 
metformin inhibits RAI-induced myelosuppression and induces faster recovery of white 
blood cell count to baseline values, the blood counts will be compared in the pre- and 
post-treatment samples. Blood parameters will include hemoglobin, red blood-cell 
count, white blood-cell count, absolute neutrophil count, absolute lymphocyte count, and 

 
 
 
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platelet count. Blood and salivary samples will be drawn before surgery, before and 
immediately after treatment with metformin and RAI, and every three months thereafter 
for one year.  
 
All blood samples will be taken by a phlebotomist or trained personnel. A baseline blood 
sample, consisting of two tubes of 1 cc of whole blood each, will be drawn before 
thyroidectomy as part of standard procedure at patients’ pre-operative testing 
appointment.  Patients will recover for a period of 6-8 weeks and identical samples will 
be drawn within 72 hours of starting metformin.  Then samples will be drawn within three 
days before and within three days after RAI treatment, at the conclusion of metformin 
treatment, and every three months thereafter for one year. Blood parameters will include 
hemoglobin, red blood-cell count (RBC), white blood-cell count (WBC), absolute 
neutrophil count (ANC), absolute lymphocyte count (ALC), and platelet count. Assays 
will also be conducted on samples to assess metformin-induced changes in serum and 
salivary cytokines and growth factors, erythrocyte sedimentation rate (ESR), exosome 
evaluation, and metabolomics profile. 5 cc samples of patient saliva will be collected in 
specimen cups. 
 
2.2 Secondary Objective: 
● Assess safety and tolerability of metformin treatment in subjects undergoing RAI 
treatment for differentiated thyroid cancer 
● To estimate the effect of metformin treatment on symptoms of xerostomia, 
xeropthalmia and dysgeusia as assessed by the Xerostomia Questionnaire (XQ), the 
modified Vanderbilt Head and Neck Cancer Symposium Survey (version 2.0), 
University of Washington Quality of Life Questionnaire, and EORTCQLQ-H&N35  

 
 
 
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3.0 STUDY DESIGN 
3.1 General Design 
Type of trial: Pilot Efficacy trial 
 
Planned accrual period: 48 months 
 
Planned follow-up period: 12 months 
 
Planned enrollment: Total of 32 patients 
 
Schema of the trial design, procedures, and stages: 
  
Patients with a diagnosis of well-differentiated thyroid cancer who have undergone 
tumor resection and have indications for RAI treatment that meet our inclusion and 
exclusion criteria will be offered participation in this clinical trial. Patients who present to 
TJUH with a known diagnosis of differentiated thyroid cancer who plan to undergo 
surgical resection followed by radioactive iodine will be offered enrollment in the trial at 
the time of surgical scheduling.  Patients who undergo lobectomy for atypia of 
undetermined significance/follicular lesion of undetermined significance or follicular 
neoplasm/suspicious for follicular neoplasm who are subsequently found to a 
malignancy will be offered enrollment at their first follow-up visit.  After informed consent 
is signed and study subjects are randomized 1:1 to take metformin or placebo, patients 
will be administered metformin with dose escalation as tolerated until time of RAI 
treatment. There is no dose escalation for patients randomized to the placebo arm.  
Pre-operative and pre-RAI treatment CBC with differential will be compared to post-RAI 
treatment lab values. Standardized surveys assessing symptoms of xerostomia, 
sialadenitis, xerophthalmia and dysguesia will be completed. 
 
Participants’ Follow-up: Participants’ will have blood and saliva samples drawn post-
op before metformin administration, before and immediately following RAI treatment, 
after metformin, and then every three months for 12 months.  They will complete 
surveys at each post-op visit, and their medical records will be reviewed every 3 months 
for 12 months to assess for symptoms of myelosuppression, xerostomia, xerophthalmia, 
and dysgeusia. This will allow us to assess the radioprotective effects of metformin 
post-RAI treatment.  
 
Purpose of the study: To estimate the radioprotective effect of metformin in subjects 
with differentiated thyroid cancer by evaluating both the ability of metformin to mitigate 
known side effects of radioactive iodine therapy as well as alter the exosome profile in 
the serum. 

 
 
 
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3.2 Primary Study Endpoints 
● complete blood count 
● serum and salivary exosome profile 
 
3.3 Secondary Study Endpoints 
● Measures of 
a)    xerostomia 
b)    xerophthalmia 
c)    dysgeusia 
 
Correlative 
 
● To assess the results of the radioactive iodine treatment in patients treated with 
metformin compared those not treated based on the outcomes of the radioactive 
iodine scan. 
3.4 Primary Safety Endpoints 
 
Toxicity will be evaluated using the most recent version (version 3) of the NCI toxicity 
criteria, i.e. the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0. The CTCAE provides descriptive terminology and a grading scale for each adverse 
event listed. A copy of the CTCAE can be found at http://ctep.cancer.gov. Any grade 3 
or 4 SAE will require immediate notification to the DSMB and IRB. Metformin will be 
held for any grade 3 or 4 SAE.  
4.0 SUBJECT SELECTION AND WITHDRAWAL 
 
4.1 Inclusion Criteria 
1. 
Diagnosis: Subjects with a diagnosis of differentiated thyroid cancer who have 
undergone total or near-total thyroidectomy and are candidates for I-131 
treatment at TJUH are eligible to participate. 
2.      Age:  Subjects must be ≥ 18 years of age and ≤ 90 years old. 
3. 
Disease Status: Subjects must be diagnosed with differentiated thyroid 
cancer 
4. 
Prior Therapy:  Patients must have previously undergone or plan to undergo 
thyroidectomy. For those patients who have previously undergone surgery, 
pre-operative labs, including complete blood cell count with differential must 
be available. 
5. 
Patients who have a negative urine pregnancy test prior to enrollment. This 
should be done as part of pre-admission testing prior to surgery (within 14 
days of study enrollment).  
6. 
Informed Consent:  All subjects must be able to comprehend and sign a 
written informed consent document.  

 
 
 
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4.2 Exclusion Criteria 
1. Subjects who are pregnant or may become pregnant during metformin 
administration in accordance with radioactive iodine treatment guidelines. 
2. Subjects on metformin for any reason during the preceding 4 weeks. 
3. Diabetic subjects are eligible if they are not taking metformin, insulin or 
sulfonylureas. 
4. Subjects who have received iodinated contrast dye. Metformin treatment can be 
started the day after subjects complete iodinated contrast treatment.  If a CT 
scan with contrast is scheduled after screening and consent, the metformin 
treatment should be stopped the day before iodinated contrast administration. 
Metformin can be resumed on the day after last iodinated contrast was 
administered to the subject. 
5. Patients with history of hepatic dysfunction or hepatic disease and abnormal liver 
function tests (previously documented alanine aminotransferase greater than 40 
IU/dL and/or plasma aspartate aminotransferase greater than 45 IU/d).  Patients 
who have a history of hepatic dysfunction or hepatic disease but whose most 
recent liver function tests have been documented as normal will be eligible to 
participate. 
6. Patients with plasma creatinine level greater than 1.3 mg/dL. 
7. Patients with plasma alkaline phosphatase greater than 190 IU/dL. 
8. Patients with plasma bicarbonate less than 22 mEq/L or history of lactic or any 
other metabolic acidosis.  
9. Patients with history of congestive heart failure. 
10. Patients with myocardial ischemia or peripheral muscle ischemia. 
11. Patients with sepsis or severe infection. 
12. Patients with history of lung disease currently requiring any pharmacologic or 
supplemental oxygen treatment. 
13. Patients with a current history (in the past 30 days) of heavy drinking which is 
defined in accordance with CDC definition as more than 8 drinks per week for 
women and more than 15 drinks per week for men. A standard drink contains .6 
ounces of pure alcohol. Generally, this amount of pure alcohol is found in 12-
ounces of beer, 8-ounces of malt liquor, 5-ounces of wine, 1.5-ounces or a “shot” 
of 80-proof distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey). While on 
study, patients should limit their alcohol consumption to no more than 8 drinks 
per week for women and no more than 15 drinks per week for men. Patients who 
feel they cannot comply with this recommendation are not eligible.  
14. Patients with a systemic disease that could affect their bone marrow or peripheral 
blood cells (e.g. systemic lupus erythematosus, human immunodeficiency virus 
infection, rheumatoid arthritis) 
15. Patients who have received or will receive medication that could affect their 
hematologic state (tyrosine kinase inhibitors, cytotoxic chemotherapy) 
16. Patients who are Non-English speaking 

 
 
 
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*Note: This is due to the nature of the study and the process for full translations 
of the study documents.   
 
All medications other than those that may cause myelosuppression are permitted 
except those that are contraindicated with metformin under current FDA 
recommendations.  It is important to note that the medications that are 
contraindicated with metformin are contraindicated due to concern for theoretical 
interactions. The following is a list of medications identified as class C (monitor 
therapy) and class D (consider therapy modification) when treatment with 
metformin is considered (Patients taking class D medications who are 
unwilling/unable to switch to alternative therapy will be excluded): 
 
 
 
Class C 
Class D 
ACE Inhibitors, Alpha-lipoic acid, 
Androgens, BuPROPrion, Carbonic 
Anhydrase Inhibitors, Cephalexin, 
Dalfampridine, Dofetilide, Glycopyrrolate 
(Systemic), Hyperglycemia-Associated 
Agents, Hypoglycemia-Associated 
Agents, LamoTRIgine, MAO Inhibitors, 
Ondansetron, Pegvisomant, Quinolone 
Antibiotics, Salicylates, Selective 
Serotonin Reuptake Inhibitors, Thiazide 
and Thiazide-Like Diuretics, Topiramate, 
Trimethoprim, Trospium, Vandetanib, 
Verapamil 
Cimetidine, Dolutegravir, Iodinated 
Contrast Agents, Ranolazine 
 
 
4.3 Gender/Minority/Pediatric Inclusion for Research 
This protocol will include women, minorities and pediatric cases (participants between 
18 and 21 years). The incidence of thyroid cancer among women in the United States is 
20.3 per 100,000 compared to 6.8 per 100,000 among men making it almost three times 
as common among women. (Ryerson 2016) Thus, when enrolling patients, by the 
nature of this disease the study will include significantly more women than men. 
Differentiated thyroid cancer occurs less frequently in pediatric than in adult subjects. All 
women and pediatric patients between 18 and 21 who meet the inclusion criteria will be 
approached for inclusion in the trial.   
 
Inclusion of women plan: we will actively monitor the enrollment of women in the study 
continuously throughout the enrollment phase. We will ensure that women are actively 

 
 
 
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recruited and that their enrollment in the study during that time frame reflects the 3:1 
incidence ratio of the disease. 
 
4.4 Subject Recruitment and Screening 
32 subjects will be recruited and we expect to recruit subjects between the ages of 18 
and 90 with multiple comorbidities. Subjects will be recruited from the investigator or 
sub-investigator clinical practices. No advertisement will be conducted. Screening 
requirements include serum measurement of creatinine, bicarbonate, and in patients 
with known hepatic dysfunction, aspartate aminotransferase, alanine aminotransferase 
and alkaline phosphatase should be measured. 
4.5 Early Withdrawal of Subjects 
4.5.1 When and How to Withdraw Subjects 
Withdrawal criteria and procedures specifying when and how to withdraw 
subjects from the trial:  
 
Patients can withdraw at any time during the study if they no longer want to participate 
in the trial. If withdrawal occurs no further metformin administration will occur and 
patients will be required to return remaining metformin tablets which will be logged in to 
medication administration records and destroyed. If a subject withdraws consent to 
participate in the study, permission will be sought to use data pertaining to the subject in 
the analysis as far as they participate and they will be removed from subsequent 
analyses.  We will also attempt to obtain consent from the subject to record survival and 
progression for one year after enrollment. It is a high priority to try to obtain survival and 
progression free survival data on all subjects.  
 
Description of when a subject’s participation in the trial may be discontinued: 
 
Specific reasons for discontinuing a subject from this study are: 
1. Voluntary discontinuation by the subject who is at any time free to discontinue 
their participation in the study, without prejudice to further treatment. 
2. Safety reasons as judged by the investigator. 
3. Severe non-compliance to the protocol as judged by the investigator. 
4. Incorrect enrollment of the subject. 
5. Subject lost to follow-up 
6. Death 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
Survival data will be collected for subjects that withdraw prematurely as well as 
progression of disease information. If a subject withdraws consent to participate in the 
study, permission will be sought permission will be sought to use data pertaining to the 

 
 
 
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subject in the analysis as far as they participate and they will be removed from 
subsequent analyses. Consent will also be sought from the subject to record survival 
and progression for one year after enrollment. It is a high priority to try to obtain survival 
and progression free survival data on all subjects lost to follow-up. Subjects will be 
called by phone at least on three occasions, phone calls at least twice will be carried out 
to the next-of-kin and certified letters will be sent twice. If follow-up is not obtained after 
the previously listed attempts have been carried out the subject will be considered lost to 
follow-up. 
5.0 STUDY DRUG/THERAPY  
5.1 Description 
Metformin is a biguanide drug currently approved for the treatment of type 2 diabetes 
mellitus by the FDA. It is currently being investigated in multiple cancer treatment trials.  
5.2 Treatment Regimen 
Metformin is the therapeutic agent in the protocol. The initial starting dose will be 500mg 
orally daily for 3 days which then will be increased to 500 mg twice daily and, if 
tolerated, further increased to 1000mg twice daily after day 6. Patients will maintain 
1000 mg twice a day dosing until 2 weeks after completing their radiation. This dose 
schedule has been shown to be well tolerated. 
 
See Section 5.11 for information on the placebo. 
5.3 Risks 
Summary of known and potential risks and benefits, if any, to subjects:   
 
Metformin’s most serious toxicity is lactic acidosis, occurring in three of 100,000 patient-
years of use. Risk is significantly reduced when metformin use is avoided in those 
patients with hepatic, cardiac, or renal compromise and in those age 80 years or older. 
However, metformin’s risk of lactic acidosis may be overstated since the recent 
evaluation of metformin associated lactic acidosis cases from 347 trials showed that the 
risk of lactic acidosis with metformin was not significantly increased compared with 
other antiglycemic agents27. Minor gastrointestinal upset is the most common toxicity, 
leading to cessation of therapy in less than 5% of individuals. Metformin does not cause 
hypoglycemia. The possible societal benefits are large since this will allow us to learn 
about the pharmacodynamic effects of metformin in RAI, allowing for radioprotection 
against myelosuppression, xerostomia, and other sequelae of radiatioactive iodine 
treatment, as well metformin’s tolerability and safety profile in a cancer population. The 
study is designed to assess as the primary end-point the effects of metformin on 
radiation-induced bone-marrow suppression with short term administration and not to 
assess if metformin improves outcomes in cancer and hence it is unlikely to improve the 
clinical outcome of the subjects enrolled in this study.  

 
 
 
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Rules for dose modification: Toxicity monitoring, dose modification and 
treatment of complications: 
 
Particular attention will be paid in the first three days of treatment. Patients will take 500 
mg/day for 3 days.  From day 4, 500 mg twice daily and then in 3 days dose escalation 
to 1000 mg twice daily will be achieved.  This will be continued for two weeks following 
RAI treatment.  A phone call on the day of each dose escalation will be made in order to 
evaluate the tolerability of the drug and also weekly thereafter.  Patients will be 
instructed to contact the clinical investigators should any toxicity occur during the 
study19.   
 
Metformin will be started the following day if CAT scan with intravenous contrast is 
administered to decrease risk of lactic acidosis.  This further mitigates this risk. This 
approach is more stringent than the most recent recommendation of the American 
College of Radiology which does not recommend holding metformin in the absence of 
comorbidities (renal insufficiency, liver dysfunction, alcohol abuse, cardiac failure, 
myocardial or peripheral muscle ischemia, sepsis or severe infection) which are 
exclusion criteria for this clinical trial31.  CAT scan is not used routinely in patients with 
thyroid cancer as it is desirable to avoid iodinated contrast.  
 
Toxicity will be evaluated using the most recent version (version 4) of the NCI toxicity 
criteria, i.e. the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0. The CTCAE provides descriptive terminology and a grading scale for each adverse 
event listed. A copy of the CTCAE can be found at http://ctep.cancer.gov. 
 
Grade 1 toxicity: Patient will be maintained on full dose. 
Grade 2 toxicity: Dose will be reduced by 50% until grade 1 or lower. If symptoms are 
not resolved within 3 days the treatment will be discontinued definitively.  
Grade 3 toxicity (probably or definitely drug related): Treatment will be interrupted and 
toxicity reassessed daily. If toxicity improves to grade 2, dose will be reduced by 50%. 
Grade 4 toxicity (probably or definitely drug related): Treatment will be discontinued 
definitively. 
 
In case of grade 1 or 2 diarrhea (the most frequent side effect) a concomitant 
administration of loperamide will be provided. 
5.4 Method for Assigning Subjects to Treatment Groups 
Randomization of 1:1 will be assigned at the time of accrual. At the outpatient offices of 
the Department of Otolaryngology- Head and Neck Surgery, subjects will be randomly 
assigned to receive either a metformin or placebo. The Division of Biostatistics will 
generate the randomization schedule prior to the initiation of the study using the method 
of random permuted blocks. Randomization assignments will be loaded into a REDCap 

 
 
 
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database, and assignments will be accessed by the study coordinator using the 
REDCap randomization facility.   
5.5 Preparation and Administration of Study Drug/Therapy 
Metformin tablets will be provided by the Department of Otorhinolaryngology and will be 
coordinated through the Thomas Jefferson University Hospital Investigational Drug 
Service (IDS) Pharmacy. Drug will be stored in locked cabinet until given to the 
participants. A three week supply of metformin and placebo will be provided to subjects 
and the drug will be self-administered by the participants.   
5.6 Subject Compliance Monitoring 
There will be a pill bottle with the appropriate number of metformin or placebo tablets 
distributed to the patients upon enrollment into the trial.  The pill bottle will be 
accompanied with detailed instructions on the proper dosage/number of tablets to take 
daily as noted above.  At the first visit following completion of metformin administration 
(approximately 2 weeks after RAI), the bottle will be collected by the trial coordinator 
and the contents will be evaluated for compliance.  
5.7 Prior and Concomitant Therapy 
All medications are permitted except those that are contraindicated with metformin 
under current FDA recommendations.  It is important to note that the medications that 
are contraindicated with metformin are contraindicated due to concern for theoretical 
interactions.  
5.8 Packaging 
Metformin will be provided by the Department of Otorhinolaryngology and will be 
coordinated through the Thomas Jefferson University Hospital Investigational Drug 
Service (IDS) Pharmacy.  The study drug will be packaged in 1 bottle containing 500mg 
tablets for a maximum of 3 weeks. The bottle will be labeled “take one tablet daily for 
three days then one tablet twice daily for three days then two tablets twice daily until the 
day before the RAI treatment. Resume two tablets twice daily the day after RAI 
treatment until the end of the bottle”.  
5.9 Blinding of Study Drug 
The bottle will be non-descript and contain either metformin or placebo depending on 
randomization.  Patient will be blinded to which pill (metformin or placebo) they will 
receive.  Pill bottle distribution will be completed by the research coordinator who will 
not be blinded. Principal investigator and care providers making assessments will not be 
blinded.  
 
5.10 Receiving, Storage, Dispensing and Return 
 

 
 
 
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5.10.1 Receipt of Drug SuppliesThe study drug will be provided by the Department of 
Otorhinolaryngology and will be coordinated through the Thomas Jefferson University 
Hospital Investigational Drug Service (IDS) Pharmacy. Upon receipt of the study 
treatment supplies, an inventory must be performed and a drug receipt log will be filled 
out and signed by the person accepting the shipment. It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the 
shipment inventory. Any damaged or unusable study drug in a given shipment (active 
drug or comparator) will be documented in the study files. The investigator must notify 
study sponsor of any damaged or unusable study treatments that were supplied to the 
investigator’s site.   
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
5.10.2 StorageDrug will be stored in a locked cabinet until given to the participants at 
room temperature in the Thomas Jefferson University Hospital Investigational Drug 
Service (IDS) Pharmacy. The investigator must ensure that it is stored in accordance 
with the environmental conditions as defined in the package insert. Clinical supplies 
may not be used for any purpose other than that stated in the protocol.  
 
5.10.3 Dispensing of Study DrugThe study drug will be dispensed to the participants in 
1 bottle containing approximately 69 500mg tablets for a maximum of 3 weeks. The 
bottle will be labeled “The bottle will be labeled “take one tablet daily for three days then 
one tablet twice daily for three days then two tablets twice daily until the day before the 
RAI treatment. Resume two tablets twice daily the day after RAI treatment completion 
until the end of the bottle.” The amount of pills dispensed to every participant will be 
logged in the accountability logs by the pharmacist. The participant will be instructed to 
bring the bottle and all the pills that were not taken the day of his surgery. Regular study 
drug reconciliation will be performed only at the end of the study.  
5.10.4 Return or Destruction of Study Drug 
Regular study drug reconciliation will be performed at the end of the study. Drug that 
was assigned, drug consumed, and drug remaining will be logged in the drug 
accountability form and will be signed and dated.  
 
At the completion of the study, there will be a final reconciliation of drug purchased, 
drug consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be investigated, 

 
 
 
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resolved, and documented prior to destruction of unused study drug.  Drug destroyed 
on site will be documented in the study files. 
 
5.11 Placebo 
Placebo will be given as 500mg capsules twice daily. Placebo will be in capsule form. It 
will be stored in a locked cabinet until given to the participants at room temperature in 
the Thomas Jefferson University Hospital Investigational Drug Service (IDS) Pharmacy. 
 
The placebo will be packaged in bottles containing approximately forty-two (42) 500mg 
capsules. The bottle will be labeled “take one capsule twice daily until the day before 
the RAI treatment. The day after RIA treatment completion, resume one capsule twice 
daily until the end of bottle.”.    
 
6.0 STUDY PROCEDURES 
 
6.1 Study Visit ScheduleScreening: Trial Coordinator will screen the office charts for 
possible inclusion in the trial. Labs for the screening part will be available from pre-
admission testing that is standard of care for initial biopsy. Women of childbearing 
potential (WOCBP) should have a pregnancy test done as part of pre-admission testing 
prior to surgery (within 14 days of study enrollment). If a test was not done, it will be 
done at time of consent.  
Visit 1: Subjects who meet inclusion criteria after reviewing the initial biopsy, laboratory 
data, and clinical chart will be approached the day of their follow up after initial biopsy. 
The study coordinator will meet with the prospective candidates and go over the 
protocol, answer questions and obtain informed consent. If the subject is agreeable to 
the study, a physical exam will be performed, subject will be randomized and metformin 
or placebo will be dispensed. Instructions on how to take study drug will be given and 
times for follow up phone calls for tolerability and safety will be arranged with 
participants. Participants will be instructed to call with any side effects or adverse events 
that occur in the interim of the follow up phone calls.  
The exact date to start the metformin will be determined this visit based on the 
planned date of radioactive iodine (RAI) administration.  One week prior to the  
radioactive iodine treatment, the first dose of metformin can start.  Metformin or 
placebo will be stopped the day before RAI treatment is received.  
Per standard of care, a pregnancy test will be done within 72 hours of starting 
radioactive iodine administration.  
Quality of life measures will be assessed prior to start of metformin. 
 
 
Quality of life measures will be administered on an IPad through a website 
(https://az1.qualtrics.com/jfe1/preview/SV_57qgtgkjaexOy9f). Participants will be 

 
 
 
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identified only by study ID number. Paper questionnaires will be provided if the forms 
cannot be completed electronically.   
 
 
Metformin or placebo administration will resume the day after the last treatment 
with radioactive iodine and will be taken until the end of bottle (2 weeks after RAI 
treatment). 
Visit 2: At the first visit following completion of metformin administration for two weeks 
after RAI, patients will be approached for bottle and pill reconciliation, review of 
compliance with appropriate lab draws, as well as follow up of side effects and 
adverse events. 
 
Follow-up: A follow up phone call will be performed 2 weeks after the last dose of 
metformin for any other side effects or adverse events. Every 3 months during the first 
year post-treatment subjects will have their regularly scheduled appointments at which 
we will draw blood/saliva, administer quality of life surveys, and review medical records. 
 
Quality of life measures will be administered on an IPad through a website 
(https://az1.qualtrics.com/jfe1/preview/SV_57qgtgkjaexOy9f). Participants will be 
identified only by study ID number. Paper questionnaires will be provided if the forms 
cannot be completed electronically.   
 
 
6.2 Definition of Dose-Limiting Toxicities and early stopping rules:  
Toxicity will be evaluated using the most recent version (version 4) of the NCI toxicity 
criteria, i.e. the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0. The CTCAE provides descriptive terminology and a grading scale for each adverse 
event listed. A copy of the CTCAE can be found at http://ctep.cancer.gov. 
 
Grade 4 toxicity (probably or definitely drug related): Treatment will be permanently 
discontinued. 
 
6.3 Dose Delays and Dose Modifications 
Please see Section 5.3.  
6.4 Laboratory Procedures/Evaluations  
6.4.1 Clinical Laboratory Evaluations 
To assess changes in CBC, patients will be provided prescriptions for lab draws to be 
performed at previously specified time intervals and instructed to have their results 
forwarded to the Department of Otolaryngology.  To assess the effects of metformin on 
serum and salivary exosome profiles, samples will be collected in person by office 
nursing staff at follow-up visits to the Department of Otolaryngology and transported 
directly to Dr. Rodeck’s lab. 

 
 
 
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6.4.2 Special Assays or Procedures 
Exosome profiles of serum and saliva samples will be isolated and analyzed in the 
laboratories of Drs. Rodeck and Harshyne using previously established protocols.   
6.4.3 Specimen Preparation, Handling, and Storage 
Blood and saliva will be collected in the Department of Otolaryngology, de-identified and 
analyzed in the labs of Dr. Rodeck and Harshyne. 
7.0 STATISTICAL PLAN 
7.1 Sample Size Determination 
The sample size was chosen to have adequate precision for estimating the effect size 
comparing groups with respect to change from pre-resection to post-resection.  From 
data in Bikas et al, we estimate that the standardized effect size for comparing change 
from pre-resection to post-resection between groups will be at least 0.78 standard 
deviations.  For a 95% confidence interval to have half-width of 0.78 SDs, 14 patients 
per group are required.    Allowing for 10% attrition, we will recruit and randomize 32 
patients (16 per group).   
7.2 Statistical Methods 
The primary objective of the study is to estimate the impact of metformin on change in 
complete blood count.  Longitudinal measures of CBC will be modeled using mixed 
effects linear regression.  Outcomes will be transformed as necessary (e.g., log 
transformed) prior to analysis.  Fixed effects will include time (Pre-resection, Post-
resection, 3 months post-resection, 6 months post-resection, 12 months post-resection), 
treatment (metformin vs. control) and treatment by time interaction.  We will use a linear 
contrast to test the null hypothesis that change from pre-resection to post-resection is 
the same in the control and metformin groups.  Secondary analyses will compare 
groups with respect to change from pre-resection to each of the follow-up times.  
Components of complete blood count will be analyzed with similar models.   
 
Other longitudinally measured continuous outcomes will be modeled using mixed 
effects linear regression and longitudinally measured binomial and ordinal outcomes will 
be modeled using generalized linear mixed effects regression.     
7.3 Subject Population(s) for Analysis: 
All randomized participants with any data will be included in the analysis as randomized. 
Missing outcome data will not be imputed. 

 
 
 
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8.0 SAFETY AND ADVERSE EVENTS 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops 
or worsens in severity during the course of the study.  Intercurrent illnesses or 
injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
● results in study withdrawal 
● is associated with a serious adverse event 
● is associated with clinical signs or symptoms 
● leads to additional treatment or to further diagnostic tests 
● is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.   
 
A serious adverse event is any AE that is:  
● fatal 
● life-threatening 
● requires or prolongs hospital stay 
● results in persistent or significant disability or incapacity 
● a congenital anomaly or birth defect 
● an important medical event 
 
Important medical events are those that may not be immediately life threatening, 
but are clearly of major clinical significance. They may jeopardize the subject, and 
may require intervention to prevent one of the other serious outcomes noted 
above.  For example, drug overdose or abuse, a seizure that did not result in in-
patient hospitalization, or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be 
regarded as non-serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end of the 
study treatment follow-up.  For this study, the study treatment follow-up is defined 
as 15 days following the last administration of study treatment.  
Preexisting Condition 

 
 
 
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A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event will be recorded 
and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events 
are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the investigator will instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.  The 
investigator will notify the sponsor of any death or adverse event occurring at any 
time after a subject has discontinued or terminated study participation that may 
reasonably be related to this study.  The sponsor will also be notified if the 
investigator should become aware of the development of cancer or of a congenital 
anomaly in a subsequently conceived offspring of a subject that has participated in 
this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any 
one of the following conditions is met:  
● The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality 
● The abnormality suggests a disease and/or organ toxicity 
● The abnormality is of a degree that requires active management; e.g. 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization 
should be documented and reported as a serious adverse event unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should 
be documented as an adverse event if the condition meets the criteria for and 
adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 

 
 
 
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● Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
● Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
● Hospitalization or prolonged hospitalization for therapy of the target disease 
of the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all 
adverse events will be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should be recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period will be recorded.   
 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause.  Serious 
adverse events that are still ongoing at the end of the study period will be followed up to 
determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
8.3 Unblinding Procedures:  
At the completion of the accrual period subjects will remain blinded until after the 
primary and secondary endpoints have been collected.  Once study is complete, PI will 
unblind patients to their randomization upon request. 
8.4 Stopping Rules: 
Grade 4 toxicity (probably or definitely drug related): Treatment will be discontinued 
definitively. 
 
Participants will be discontinued from study drug as per physician discretion 
8.5 Data and Safety Monitoring Plan 
All AEs and SAEs, safety and toxicity data, and any corrective actions will be submitted 
to the DSMC per the frequency described in the SKCC DSMP. The report to the SKCC 

 
 
 
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DSMC will also include any unanticipated problems that in the opinion of the PI should 
be reported to the DSMC. 
For expedited reporting requirements, see table below:                                            
DSMC AE/SAE Reporting Requirements 
 
 
 
8.5.2 Data and Safety Monitoring Committee 
Data and Safety Monitoring Committee (DSMC) is the Data and Safety Monitoring Board 
(DSMB) for the SKCC. The DSMC is a multidisciplinary committee charged with 
overseeing the monitoring of safety of participants in clinical trials, and the conduct, 
progress, validity, and integrity of the data for all clinical trials at the Thomas Jefferson 
University SKCC. The committee meets quarterly to review the progress and safety of all 

 
 
 
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active research protocols that are not monitored by another safety and data monitoring 
committee or board. 
● The DSMC meets quarterly. Additional DSMC meetings are scheduled based 
on the nature and number of trials being monitored over a specified time 
period. The DSMC meets (by conference call) within 24 hours following the 
notification of an unexpected adverse event felt to be related to the study 
drug.  
● Prior to each DSMC meeting, each board member, is provided a printout of all 
reported AEs and SAEs occurring during the reporting period for this clinical 
trial. The principal investigator provides a detailed and comprehensive 
narrative assessment of current adverse events to date, indicating their 
possible significance and whether these toxicities have affected the conduct of 
the trial. DSMC members are provided with the principal investigator’s 
assessment, a written report summarizing adverse events, safety data, and 
activity data observed during the specified time period described in each 
protocol, as well as recommendations from the Medical Monitor. A review of 
outcome results (response, toxicity and adverse events) and factors external 
to the study (such as scientific or therapeutic developments) is discussed, and 
the Committee votes on the status of each study.  
● A summary of the board’s action is sent to each investigator, the PRC and 
TJU IRBs. The DSMC actions may include recommendations/requirements 
that will lead to improved patient safety and/or efficacy, significant benefits or 
risks that have developed, or other changes determined to be necessary. The 
DSMC may also take note of slow accrual or lack of scientific progress, and 
refer such issues to the PRC. The DSMC provides the investigator with the 
rationale for any decision made.  
 
9.0 DATA HANDLING AND RECORD KEEPING 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
● What protected health information (PHI) will be collected from subjects in this 
study 
● Who will have access to that information and why 
● Who will use or disclose that information 
● The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 

 
 
 
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subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents. The source documents for the trial will 
include: hospital records, clinical and office charts, laboratory notes, pharmacy 
dispensing records, pathology records, adverse events and SAE forms, phone interview 
logs. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  
If a space on the CRF is left blank because the procedure was not done or the question 
was not asked, write “N/D”.  If the item is not applicable to the individual case, write 
“N/A”.  All entries should be printed legibly in black ink.  If any entry error has been 
made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO 
NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 
9.4 Records Retention 
All study essential documents will be retained by the investigator for 2 years after the 
completion of the study.  
10.0 STUDY MONITORING, AUDITING, AND INSPECTING 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for monitoring activities.  The Investigator 
will also ensure that compliance or quality assurance reviewers are given access to all 
the above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.). 

 
 
 
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Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
10.2.1 Independent External and Internal Audits  
In addition to review by the DSMC, all studies initiated by SKCC investigators are 
audited by an independent auditor once they have achieved 10% of target accrual. 
However, a study can be audited at any time based on recommendations by the IRB, 
DSMC, PRC and/or the Director of Clinical Investigations, SKCC. Studies are re-audited 
once they have achieved 50% of target accrual. Special audits may be recommended 
by the IRB, DSMC or PRC based on prior findings, allegations of scientific misconduct 
and where significant irregularities are found through quality control procedures. Any 
irregularities identified as part of this process would result in a full audit of that study.  
 
In addition to the audits at 10 and 50%, the CRO randomly audits at least 10 percent of 
all patients entered into therapeutic SKCC trials and other trials as necessary, on at 
least a bi-annual basis, to verify that there is a signed and dated patient consent form, 
the patient has met the eligibility criteria, and that SAEs are documented and reported 
to the TJU IRB.  
 
All audit reports are submitted to the DSMC for review and action (when appropriate). A 
copy of this report and recommended DSMC action is sent to the PRC and TJU IRB. 
The committee regards the scientific review process as dynamic and constructive rather 
than punitive. The review process is designed to assist Principal Investigators in 
ensuring the safety of study subjects and the adequacy and accuracy of any data 
generated. The TJU IRB may, based on the DSMC and auditor’s recommendation, 
suspend or terminate the trial.  
 
11.0 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator before 
commencement of this study.   
 

 
 
 
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All subjects for this study will be provided a consent form that is compliant with local and 
federal regulations, describing this study and providing sufficient information for subjects 
to make an informed decision about their participation in this study. This consent form 
will be submitted with the protocol for review and approval by the IRB for the study.  The 
formal consent of a subject, using the IRB-approved consent form, must be obtained 
before that subject is submitted to any study procedure.  This consent form must be 
signed by the subject or legally acceptable surrogate, and the investigator-designated 
research professional obtaining the consent.  
12.0 STUDY FINANCES 
12.1 Funding Source 
The study is funded by the Department of Otorhinolaryngology. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
will have the conflict reviewed by a properly constituted Conflict of Interest Committee 
with a Committee-sanctioned conflict management plan that has been reviewed and 
approved by the study sponsor prior to participation in this study.  All Jefferson 
University Investigators will follow the TJU Conflicts of Interest Policy for Employees 
(107.03). 
13. REFERENCES 
1. 
Rizos CV, Elisaf MS. Metformin and cancer. Eur J Pharmacol. Mar 13 2013. 
2. 
Luo Q, Hu D, Hu S, et al. In vitro and in vivo anti-tumor effect of metformin as a 
novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer. 
2012;12:517. 
3. 
Vitale-Cross L, Molinolo AA, Martin D, et al. Metformin prevents the development 
of oral squamous cell carcinomas from carcinogen-induced premalignant lesions. 
Cancer Prev Res (Phila). Apr 2012;5(4):562-573. 
4. 
Patel H, Younis RH, Ord RA, et al. Differential expression of organic cation 
transporter OCT-3 in oral premalignant and malignant lesions: potential 
implications in the antineoplastic effects of metformin. J Oral Pathol Med. Mar 
2013;42(3):250-256. 
5. 
El-Mir MY, Nogueira V, Fontaine E, et al. Dimethylbiguanide inhibits cell 
respiration via an indirect effect targeted on the respiratory chain complex I. J 
Biol Chem. Jan 7 2000;275(1):223-228. 
6. 
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-
diabetic effects through inhibition of complex 1 of the mitochondrial respiratory 
chain. Biochem J. Jun 15 2000;348 Pt 3:607-614. 

 
 
 
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7. 
Algire C, Moiseeva O, Deschenes-Simard X, et al. Metformin reduces 
endogenous reactive oxygen species and associated DNA damage. Cancer Prev 
Res (Phila). Apr 2012;5(4):536-543. 
8. 
Hawley SA, Ross FA, Chevtzoff C, et al. Use of cells expressing gamma subunit 
variants to identify diverse mechanisms of AMPK activation. Cell Metab. Jun 9 
2010;11(6):554-565. 
9. 
Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth 
control in tumour suppression. Nat Rev Cancer. Aug 2009;9(8):563-575. 
10. 
Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose 
homeostasis in liver and therapeutic effects of metformin. Science. Dec 9 
2005;310(5754):1642-1646. 
11. 
Ben Sahra I, Laurent K, Giuliano S, et al. Targeting cancer cell metabolism: the 
combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis 
in prostate cancer cells. Cancer Res. Mar 15 2010;70(6):2465-2475. 
12. 
Pollak M. Metformin and other biguanides in oncology: advancing the research 
agenda. Cancer Prev Res (Phila). Sep 2010;3(9):1060-1065. 
13. 
Kahn BB, Alquier T, Carling D, et al. AMP-activated protein kinase: ancient 
energy gauge provides clues to modern understanding of metabolism. Cell 
Metab. Jan 2005;1(1):15-25. 
14. 
Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of 
metformin: an overview. Clin Sci (Lond). Mar 2013;122(6):253-270. 
15. 
Hirsch HA, Iliopoulos D, Tsichlis PN, et al. Metformin selectively targets cancer 
stem cells, and acts together with chemotherapy to block tumor growth and 
prolong remission. Cancer Res. Oct 1 2009;69(19):7507-7511. 
16. 
Rozengurt E, Sinnett-Smith J, Kisfalvi K. Crosstalk between insulin/insulin-like 
growth factor-1 receptors and G protein-coupled receptor signaling systems: a 
novel target for the antidiabetic drug metformin in pancreatic cancer. Clin Cancer 
Res. May 1 2010;16(9):2505-2511. 
17. 
Curry JM, Tuluc M, Whitaker-Menezes D, et al. Cancer metabolism, stemness 
and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic 
symbiosis in head and neck cancer. Cell Cycle. May 1 2013;12(9):1371-1384. 
18. 
Johnson JA, Pollak M. Insulin, glucose and the increased risk of cancer in 
patients with type 2 diabetes. Diabetologia. Oct 2010;53(10):2086-2088. 
19. 
Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus 
report. Diabetes Care. Jul 2010;33(7):1674-1685. 
20. 
Libby G, Donnelly LA, Donnan PT, et al. New users of metformin are at low risk 
of incident cancer: a cohort study among people with type 2 diabetes. Diabetes 
Care. Sep 2009;32(9):1620-1625. 
21. 
Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of 
cancer in diabetic patients. Bmj. Jun 4 2005;330(7503):1304-1305. 
22. 
Hadad S, Iwamoto T, Jordan L, et al. Evidence for biological effects of metformin 
in operable breast cancer: a pre-operative, window-of-opportunity, randomized 
trial. Breast Cancer Res Treat. Aug 2011;128(3):783-794. 

 
 
 
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23. 
Niraula S, Dowling RJ, Ennis M, et al. Metformin in early breast cancer: a 
prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat. 
Oct 2012;135(3):821-830. 
24. 
Rizos CV, Elisaf MS. Metformin and cancer. Eur J Pharmacol. Apr 5 2013;705(1-
3):96-108. 
25. 
Esteva FJ, Moulder SL, Gonzalez-Angulo AM, et al. Phase I trial of exemestane 
in combination with metformin and rosiglitazone in nondiabetic obese 
postmenopausal women with hormone receptor-positive metastatic breast 
cancer. Cancer Chemother Pharmacol. Jan 2013;71(1):63-72. 
26. 
Metformin plus paclitaxel for recurrent or metastatic head and neck cancer: a 
randomized phase II trial. NCT01333852. Clinicaltrials.gov 
 
27. 
Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic 
acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst 
Rev. 2010(4):CD002967. 
28. 
Garber AJ, Duncan TG, Goodman AM, et al. Efficacy of metformin in type II 
diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J 
Med. Dec 1997;103(6):491-497. 
29. 
Fujioka K, Brazg RL, Raz I, et al. Efficacy, dose-response relationship and safety 
of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic 
patients with inadequate glycaemic control despite prior treatment with diet and 
exercise: results from two double-blind, placebo-controlled studies. Diabetes 
Obes Metab. Jan 2005;7(1):28-39. 
30. 
Gupta R. Use of intravenous contrast agents in patients receiving metformin. 
Radiology. Oct 2002;225(1):311-312; author reply 312. 
31. 
Manual on Contrast Media, Version 8. 2012. American College of Radiology. 
Accessed May 6th at  
http://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/Contrast%2
0Manual/Metformin.pdf. 2012. 
 
 
Appendix A: Schedule of Events 

 
 
 
 
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Appendix A: Schedule of Events 
Study Procedures 
Screening 
Visit 1 
 
Visit 2 (End of 
Treatment)E 
Follow-upF 
Informed consent  
 
X 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
Demographics, 
Medical history  
X 
X 
 
 
 
 
Physical examination, 
vitals, weight, blood 
pressure 
 
X 
X 
 
Randomization 
 
X 
 
 
Quality of Life 
QuestionnairesD 
 
X 
X 
XC 
Pathology Report 
histologic confirmation 
of disease if available 
X 
 
 
 
Concomitant meds 
X 
X 
 
 
Toxicity and AE 
Assessment 
 
X 
X 
XI 
Pregnancy testJ 
X 
X 
 
 

 
 
 
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Treatment/ 
Intervention 
 
MetforminG 
 
X 
X 
 
PlaceboH 
 
X 
X 
 
Radiation Treatment 
 
X 
X 
 
Correlative Studies 
 
 
Blood sample 
collectionA 
 
X 
X 
XC 
Saliva sample 
collectionB 
 
X 
X 
XC 
A. Two 7ml purple top tubes are to be drawn at each time point and transported directly to Dr. Rodeck’s laboratory.  
B. 5ml of saliva is to be collected at each time point and transported directly to Dr. Rodeck’s laboratory.  
C. Blood samples, saliva samples, and quality of life questionnaires will be collected every 3 months for the first year post treatment. 
Collection will occur at participant’s regularly scheduled appointments.  
D. Quality of life surveys include: EORTC QLQ – H&N35, modified Vanderbilt Head and Neck Cancer Symposium Survey, University of 
Washington Quality of Life Questionnaire, and  Xerostomia Questionnaire (XQ). All questionnaires will be administered online via an IPad 
provided at the visit.  
E. Visit will occur following completion of metformin treatment for 2 weeks after RAI  
F. Patients will be seen at regularly scheduled appointments every 3 months for the 1st year post treatment. Participant’s medical records will 
be reviewed every 3 months for 24 months 
G. The initial starting dose of metformin will be 500mg orally daily for 3 days which then will be increased to 500mg twice daily and, if 
tolerated, further increased to 1000mg twice daily after day 6. Patients will maintain 1000mg twice daily dosing until 2 weeks after 
completion of radiation. If patient must have CT scan with intravenous contrast, metformin will be held and participant will be instructed to 
start metformin the day following the scan.  
H. Placebo will be given as 500mg tablets twice daily with no dose escalation. 
I. 
Assessment for AEs will occur as a phone call performed 2 weeks after the last dose of metformin. 
J. Pregnancy test to confirm eligibility should be done as part of pre-admission testing prior to surgery (within 14 days of enrollment) or done 
at time of consent. Pregnancy testing is done per standard of acre 72 hours prior to start of radioactive iodine administration.