Clinical trial NCT03109873
Conditions: Larynx Lip Oral Cavity Pharynx
Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
Start date: 2017-01-05; Completion date: 2020-07-31
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot clinical trial studies how well metformin hydrochloride works in affecting cytokines and exosomes in patients with head and neck cancer. Metformin hydrochloride may reduce the metabolic activity of cancer cells and of surrounding supportive tissues.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the capacity of metformin hydrochloride (metformin) to alter the cytokine and exosome profiles.

II. To assess the capacity of metformin to mitigate known side effects of external beam radiation therapy including inflammation, mucositis, dysphagia, xerostomia, and fatigue.

SECONDARY OBJECTIVES:

I. Assess safety and tolerability of metformin treatment in subjects undergoing external beam radiation treatment for head and neck cancer.

II. To determine the effect of metformin treatment on symptoms of xerostomia as assessed by the Xerostomia Questionnaire (XQ).

III. To determine the effect of metformin treatment on symptoms of mucositis as assessed by World Health Organization (WHO) classification.

IV. To determine the effect of metformin treatment on symptoms of dysphagia as assessed by the MD Anderson Dysphagia Inventory.

V. To determine the effect of metformin treatment on symptoms of fatigue as assess by the Multidimensional Fatigue Inventory (MFI).

Arms: arm 1: Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive metformin hydrochloride PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT. arm 2: Patients undergo External Beam Radiation Therapy (EBRT). Beginning 1 week prior to start of EBRT, patients receive placebo PO QD for 3 days and BID thereafter until 2 weeks after completion of EBRT.
Interventions: intervention 1: External Beam Radiation Therapy intervention 2: Metformin Hydrochloride intervention 3: Placebo
Intervention descriptions: intervention 1: Undergo External Beam Radiation Therapy intervention 2: Given orally intervention 3: Given orally

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 THOMAS JEFFERSON UNIVERSITY 
Kimmel Cancer Center 
 
Pilot study of metformin in head and neck cancer and its effect on 
proinflammatory cytokines and exosomes implicated in acute and 
chronic toxicity 
 
 
Principal Investigator: 
Adam Luginbuhl, MD,  
Department of Otolaryngology  
925 Chestnut Street, 6th floor 
Philadelphia, Pennsylvania 19107 United States 
Phone: 215-240-0748 
 
Co-Investigator(s): 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 


 
 
 
 
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Funding Sponsor: 
Departmentally funded 
Regulatory Sponsor: 
Thomas Jefferson University 
IND Number: 
N/A 
Study Product: 
Metformin 
Protocol Number: 
IRB#16D.639 /JT#9410 
 
 
Version: 
Date: 
V1 
5/15/2016 
V1.1 
1/3/2017 
V2.0 
3/1/2017 


 
 
 
 
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V3.0 
4/21/2017 
V4.0 
12/12/2017 
V5.0 
06/20/2019 
 
 
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 ................................................................................................................................................... 7 
1.0 INTRODUCTION ................................................................................................................................................. 9 
1.1 
SPECIFIC AIMS AND HYPOTHESIS .................................................................................................................. 9 
1.2 
BACKGROUND AND RATIONALE: .................................................................................................................. 9 
1.3 
PRECLINICAL DATA: ................................................................................................................................... 11 
1.4 
CLINICAL DATA .......................................................................................................................................... 13 
1.5 
STUDY THERAPY......................................................................................................................................... 15 
1.6 DOSE RATIONALE AND RISK/BENEFITS ............................................................................................................. 15 
2.0 STUDY OBJECTIVES ....................................................................................................................................... 18 
2.1 PRIMARY OBJECTIVE: ........................................................................................................................................ 18 
2.2 SECONDARY OBJECTIVE: ................................................................................................................................... 18 
2.3 PRIMARY STUDY ENDPOINTS ............................................................................................................................. 19 
2.4 SECONDARY STUDY ENDPOINTS ........................................................................................................................ 19 
2.5 PRIMARY SAFETY ENDPOINTS ........................................................................................................................... 19 
3.0 STUDY DESIGN ................................................................................................................................................. 19 
3.1 GENERAL DESIGN .............................................................................................................................................. 19 
4.0 SUBJECT SELECTION AND WITHDRAWAL ............................................................................................. 20 
4.1 INCLUSION CRITERIA ......................................................................................................................................... 20 
4.2 EXCLUSION CRITERIA ........................................................................................................................................ 20 
4.3 GENDER/MINORITY/PEDIATRIC INCLUSION FOR RESEARCH .............................................................................. 22 
4.4 SUBJECT RECRUITMENT AND SCREENING .......................................................................................................... 22 
4.5 EARLY WITHDRAWAL OF SUBJECTS .................................................................................................................. 22 
4.5.1 When and How to Withdraw Subjects ....................................................................................................... 22 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects ........................................................................ 23 
5.0 STUDY DRUG/THERAPY ................................................................................................................................ 23 
5.1 DESCRIPTION ..................................................................................................................................................... 23 
5.2 TREATMENT REGIMEN ....................................................................................................................................... 23 
5.3 RISKS ................................................................................................................................................................. 23 
5.4 METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................................... 25 
5.5 PREPARATION AND ADMINISTRATION OF STUDY DRUG/THERAPY .................................................................... 25 
5.6 SUBJECT COMPLIANCE MONITORING ................................................................................................................. 25 
5.7 PRIOR AND CONCOMITANT THERAPY ................................................................................................................ 25 
5.8 PACKAGING ....................................................................................................................................................... 25 
5.9 BLINDING OF STUDY DRUG................................................................................................................................ 25 
5.11 
PLACEBO ..................................................................................................................................................... 26 
5.12 RECEIVING, STORAGE, DISPENSING AND RETURN ........................................................................................... 26 
5.12.1 Receipt of Drug Supplies ......................................................................................................................... 26 
5.12.2 Storage .................................................................................................................................................... 26 
5.12.3 Dispensing of Study Drug ....................................................................................................................... 26 
5.12.4 Return or Destruction of Study Drug ...................................................................................................... 27 
6.0 STUDY PROCEDURES ..................................................................................................................................... 27 
6.1 STUDY VISIT SCHEDULE .................................................................................................................................... 27 
6.2 DEFINITION OF DOSE-LIMITING TOXICITIES AND EARLY STOPPING RULES: ....................................................... 28 
6.3 DOSE DELAYS AND DOSE MODIFICATIONS ........................................................................................................ 28 
6.4 LABORATORY PROCEDURES/EVALUATIONS ...................................................................................................... 29 
6.4.1 Clinical Laboratory Evaluations ............................................................................................................... 29 


 
 
 
 
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6.4.2 Special Assays or Procedures ................................................................................................................... 29 
6.4.3 Specimen Preparation, Handling, and Storage ......................................................................................... 29 
7.0 STATISTICAL PLAN ...................................................................................................................................... 29 
7.1 ANALYSIS FOR PRIMARY OUTCOME .................................................................................................................. 29 
7.2  ANALYSIS FOR SECONDARY OUTCOMES ........................................................................................................... 30 
7.3 SUBJECT POPULATION(S) FOR ANALYSIS: .......................................................................................................... 30 
7.4  SAMPLE SIZE JUSTIFICATION............................................................................................................................. 30 
8.0 SAFETY AND ADVERSE EVENTS ................................................................................................................. 31 
8.1 DEFINITIONS ...................................................................................................................................................... 31 
8.2 RECORDING OF ADVERSE EVENTS ..................................................................................................................... 33 
8.3 UNBLINDING PROCEDURES: ............................................................................................................................... 33 
8.4 STOPPING RULES: .............................................................................................................................................. 33 
8.5 DATA AND SAFETY MONITORING PLAN ............................................................................................................. 33 
8.5.1 Medical Monitoring and AE/SAE Reporting ............................................................................................. 34 
8.5.2 Data and Safety Monitoring Committee .................................................................................................... 34 
9.0 DATA HANDLING AND RECORD KEEPING .............................................................................................. 35 
9.1 CONFIDENTIALITY ............................................................................................................................................. 35 
9.2 SOURCE DOCUMENTS ........................................................................................................................................ 36 
9.3 CASE REPORT FORMS ........................................................................................................................................ 36 
9.4 RECORDS RETENTION ........................................................................................................................................ 36 
10.0 STUDY MONITORING, AUDITING, AND INSPECTING ......................................................................... 36 
10.1 STUDY MONITORING PLAN .............................................................................................................................. 36 
10.2 AUDITING AND INSPECTING ............................................................................................................................. 36 
10.2.1 Independent External and Internal Audits .............................................................................................. 37 
11.0 ETHICAL CONSIDERATIONS...................................................................................................................... 37 
12.0 STUDY FINANCES .......................................................................................................................................... 38 
12.1 FUNDING SOURCE ............................................................................................................................................ 38 
12.2 CONFLICT OF INTEREST ................................................................................................................................... 38 
13. REFERENCES .................................................................................................................................................... 38 
APPENDIX A: SCHEDULE OF EVENTS ............................................................................................................. 42 
APPENDIX A: SCHEDULE OF EVENTS ....................................................................................................................... 43 
 


 
 
 
 
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List of Abbreviations 
 
AKT: also named protein kinase B  
AMPK: adenosine monophosphate protein kinase  
ATP: adenosine triphosphate 
CAFs: cancer associated fibroblasts  
COX: cytochrome c oxidase 
ERK: extracellular regulated kinase 
FDG: fluoro deoxy-glucose 
GPCR: G protein-coupled protein receptor  
HOMA: homeostatic model assessment 
HNSCC: head and neck squamous cell carcinoma 
IGF-1: insulin growth factor 1 
IHC: immunohistochemistry  
IL-6: interleukin 6 
IL-1 Beta: interleukin 1 beta 
Ki67: Kiehl-67 antibody 
LKB1: liver kinase B1 
mTOR: mammalian target of rapamycin 
mTORC1: mTOR complex 1 
OXPHOS: oxidative phosphorylation 
PDE3B: phosphodiesterase 3B  
PET: positron emission tomography  
PI3K: phoshoinositide 3 =kinase 
PTEN: phosphatase and tensin homolog 
RAS: rat sarcoma oncogene 
RAF: rapidly accelerated fibrosarcoma 
ROS: reactive oxygen species 
TNF-a: tumor necrosis factor alpha 
TSC2: tuberous sclerosis 2 
 
 
 
 
 
 
 


 
 
 
 
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Study Summary 
Title 
Pilot study of metformin in head and neck cancer and its 
effect on proinflammatory cytokines and exosomes 
implicated in acute and chronic toxicity 
 
Short Title 
Metformin in radiation treatment of head and neck cancer 
Protocol Number 
IRB# 16D.639/JT#9410 
Phase 
Pilot 
Methodology/Study 
Design 
Pilot Feasibility trial 
Study Duration 
24 months 
Study Center(s) 
Single Center- Jefferson 
Objectives 
To assess the effect of metformin on radioprotection in normal 
tissue for subjects undergoing head and neck radiation.  We will 
evaluate metformin’s ability to decrease proinflammatory 
cytokines and decrease mucositis, xerostomia, fatigue and 
dysphagia. 
 
Number of 
Subjects 
50  
Diagnosis and 
Main Inclusion 
Criteria 
Subjects with a biopsy proven diagnosis of head and neck 
cancer, and who have a scheduled appointment for either 
postoperative adjuvant radiation or definitive radiation. 
Study Therapy, 
Dose, Route, 
Regimen 
Metformin is the therapeutic agent in the protocol. The initial 
starting dose will be 500mg orally daily for 3 (+2 days) days 
which then will be increased to 500 mg twice daily and, if 
tolerated, further increased to 1000mg twice daily after day 6 
(+2 days). Subjects will maintain 1000 mg twice a day dosing 
until two weeks post radiation.   
Subjects will be randomized to 1:1 to take metformin or placebo.  
Duration of 
administration and 
follow-up 
The initial starting dose will be 500mg orally daily for 3 (+2 days) 
days which then will be increased to 500 mg twice daily and, if 
tolerated, further increased to 1000mg twice daily after day 6 
(+2 days). Subjects will maintain 1000 mg twice a day dosing 
until two weeks post radiation.  The participant’s medical 
records will be reviewed every 3 months for 12 months.  2 vials 
of Blood and 5cc of saliva samples will be obtained before, 
during and immediately after treatment and every three months 
thereafter for one year    
Reference therapy 
None 


 
 
 
 
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Statistical 
Methodology 
The primary objective of the study is to assess the impact of 
metformin on cytokine and exosome profiles.  All subjects from 
whom blood and saliva samples are obtained both pre-, during 
and post-treatment will be included in the primary analyses. 
Change in cytokine profiles will be evaluated using mixed 
effects linear regression. 
Analysis of secondary outcomes will be primarily descriptive.  
The distribution of swallowing function and mucositis scores will 
be summarized.  The objective response rate will be estimated 
along with an exact 95% binomial confidence interval.  
Schema 
50 HNSCC patient candidates for adjuvant or neoadjuvant 
radiation 
 
Pre-metformin blood and saliva samples     
 
Randomized Metformin Treatment* 
(n=25) vs Placebo** Treatment (n=25) 
 
 
 
 
 
  
 
external beam 
radiation (sample collected halfway through) 
 
 
Post-
metformin 
blood and 
saliva 
sample 
 
 *Metformin (500 mg/day for 3 (+ 2 days) days followed by 500 mg twice 
daily for 3 days followed by 1000mg twice daily from day 6 (+2 days).  
Subjects will maintain 1000 mg twice a day dosing until two weeks post 
radiation.  ) 
** Placebo (1 tab  taken BID) No ramp up phase 
 


 
 
 
 
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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 
Purpose of the study: To assess the effect of metformin on inflammatory 
pathways in subjects with cancer of the head and neck undergoing external 
beam radiation.  We will use analysis of cytokines/chemokine profiles expression 
and exosome profiles in subjects that receive metformin during their radiation 
treatment.   
 
• Primary objective: Assess the impact of metformin on 
cytokine/chemokine and exosomes on blood and saliva during and after 
radiation.  
 
• Secondary objectives: Assess safety and tolerability of metformin 
treatment in subjects with head and neck cancer. Also, to assess the 
potential impact of metformin on the following: xerostomia, dysphagia, 
mucositis, fatigue as measured by EORTC QLQ – H&N35, Xerostomia 
Score, mucositis score and Multidimensional Fatigue Inventory (MFI) (See 
appendix).   
 
1.2 Background and Rationale:   
Effects of Radiation on Normal Tissue and Systemic Effects 
 
Treatment for Head and Neck Cancer has used radiation as one of the 
foundational components to achieve expected cure rates.  Protocols have been 
well established to maximize tumor kill rate and minimize collateral damage to 
surrounding tissue, yet the effects of radiation on normal tissue remains profound 
in the head and neck region.  Oral mucositis, swallowing, xerostomia and fatigue 
are the main drivers that affect quality of life status post treatment.   
 
Oral mucositis is a common, problematic, and painful complication of cancer 
therapy, in the regimens that include radiation therapy for the head and neck 
cancer1. Oral mucositis is a treatment-induced morbidity that has substantial 
impact on day-to-day functioning. In addition to the common need for, and 
inadequate pain control with, narcotics, the profound clinical impact of oral 
mucositis also includes weight loss, difficulty eating and swallowing, dehydration, 
need for nutritional support, and reduced performance status2, as well as 
secondary infections and diminished quality of life (QOL)3.  


 
 
 
 
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A majority of patients receiving combined chemoradiotherapy for head and neck 
cancer (HNC) can be expected to develop severe (WHO Grade 3-4) oral 
mucositis4 and nearly all HNC patients receiving RT with concurrent cisplatin are 
expected to develop oral mucositis (WHO Grade 2 or higher) 5. 
Standard chemoradiotherapy for locally advanced head and neck (HNC), 
whether in the post-operative or definitive setting, currently consists of intensity-
modulated radiation therapy (IMRT) plus/minus systemic therapy. The 
monoclonal antibody cetuximab has also been shown to increase the efficacy of 
radiotherapy for locally advanced head and neck cancer 6, and the combination 
of IMRT plus either single-agent cisplatin or single-agent cetuximab is currently 
being tested head-to-head for patients with human papilloma virus (HPV)-related 
oropharyngeal cancer in the ongoing RTOG 1016 trial. In addition, two recently 
published Phase 3 studies of palifermin in patients receiving RT plus single-agent 
cisplatin for HNC reported an overall incidence of severe (WHO Grade 3-4) oral 
mucositis among placebo patients of 67% in one study and 69% in the other7,8. 
Oral mucositis prevention and management remains a substantial unmet need. 
 
Patients with HNC may also suffer the additional complications of short- and long 
term xerostomia, taste change, and trismus related to post-radiation fibrosis. 
McBride et al. demonstrated a significant improvement in rates of xerostomia, 
shorter durations of PEG tube dependence when comparing intensity-modulated 
radiation therapy (IMRT) vs conventional radiation therapy 9.  Even though they 
found a significant early benefit, late stage dysphagia persisted in 7-10% of 
patients at 2-4 years out had grade 2 dysphage or higher with IMRT patients 
having a significantly higher rate of cervical esophageal strictures9.   
Fatigue is a well-known side effect of radiation with some indication that 
circulating cytokines and chemokines are responsible for this phenomena.  
Increase in interleukin (IL-1), tumor necrosis factor (TNF) and C-reacitve protein 
(CRP) have been found in patients with profound fatigue10.  Others have not 
been able to make association with inflammatory markers.  Xiao et al. found a 
strong correlation to fatigue and inflammatory markers with gene transcripts 
related to NFkB.  We propose in this study to look at an entire panel of 
inflammatory markers, utilizing Luminex technology with the Milliplex MAP 
Human Cytokine/chemokine Magnetic kit I (41 analytes) (sCD40L, EGF, Eotaxin, 
FGF-2, Flt-3 ligand, Fractalkine, G-CSF, GM-CSF, GRO, IFN-α2, IFN-γ, IL-1α, 
IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 
(p70), IL-13, IL-15, IL-17A, IP-10, MCP-1, MCP-3, MDC (CCL22), MIP-1α, MIP-
1β, PDGF-AA, PDGF-AB/BB, RANTES, TGF-α, TNF-α, TNF-β, VEGF).  Another 
possible mechanism that has not been described is exosomes/microvesicle 
communication that can be found systemically released by tissue under stress.   
Exosomes are small extra-cellular vesicles produced by all cells11 and present in 
almost all biological fluids including blood, urine, ascites, CSF, serum and 
plasma, and in the culture medium of cell cultures12. Currently exosomes are 


 
 
 
 
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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/mL12. 
Exosomes have recently emerged as important mediators in cell communication 
due to their enriched content in genetic material like mRNAs and non-coding 
RNAs12.  The biogenesis of exosomes which involves the endosomal 
compartment sets them apart from other extracellular vesicles11.  Their molecular 
profile partly, but not completely, resembles that of the parental cell. The precise 
function of exosomes remains unknown13.  The leading theory is that exosomes 
are an integral part of a complex, well-organized, form of information delivery that 
operates at short and long distances11. The content and number of exosomes 
generated likely change depending on whether cells are experiencing different 
stressors or stimuli13. Tumor-derived exosomes transfer signals and convey 
information locally within the tumor microenvironment as well as to distant tissues 
and organs to facilitate tumor growth and metastasis. They are present in the 
circulation and have ready access to all parts of the body11. 
Cytokines/chemokines are well established as molecules that convey a 
phenotype of tissue behavior or biologic mechanism.  They likewise are found in 
all bodily fluids and are secreted in times of stress.   
 
1.3 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 patients14.  Metformin specifically inhibits 
the complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial electron 
transport chain decreasing cellular respiration and the rate of ATP formation15,16. 
This triggers the activation of the energy sensor AMP-activated protein kinase 
(AMPK) that regulates cell metabolism and shifts it towards an energy-sparing 
state17. 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 agent18.   
  
Epidemiologic Data for Metformin’s Efficacy for Radioprotection and Cancer 
Prevention: 


 
 
 
 
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Retrospective studies have shown that diabetics treated with metformin have a 
cancer risk reduction of approximately 40% compared to diabetics not treated 
with metformin19,20.  Evans et al 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)21.  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 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)22.  Similarly, Niraula et al 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 
cells23.  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.   
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 cancer24.  Metformin in conjunction with N-acetyl-cysteine or 
captopril resulted in a 2.4-2.6 fold enhanced survival in mice exposed to 7Gy of 
radiation as well as survival of cell cultures.  Miller argues that the wide use and 
tolerability of metformin with an animal model that demonstrates enhanced 
survival should be considered 1st line in radiation countermeasures in the event 
of a radiation exposure.   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 and that patients treated concomitantly with metformin 
returned to their baseline values sooner25.  
 
Our current animal model looking at ameliorating the effects of radiation utilizes a 
thiol modifying agent RTA 408 and metformin.  In unpublished data the group 
drinking metformin dissolved in water is healing wounds at a significantly faster 
rate then the control animals.   
  
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-


 
 
 
 
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activated protein kinase (AMPK) by metformin. 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 glycolysis26. 
AMPK activation potentially promotes survival after radiation, especially in a low 
nutrient environment found in human tumors27. By inhibiting the formation of 
ROS, metformin may further protect tissues or cells against DNA damage and 
mutations28.  
  
Preclinical studies and clinical trials support the view that metformin has 
anticancer properties29-32 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 
signaling14,22,23,33. Several groups have shown that metformin’s ability to limit 
tumor growth in vivo is dependent on mitochondrial complex I34. Complex I 
inhibition blocks mitochondrial-dependent production of reactive oxygen species 
(ROS) and adenosine triphosphase (ATP)35,36.  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 glucose29 . Metformin sensitivity is 
further determined by glucose availability and overall oxidative phosphorylation 
(OXPHOS) capacity30. The decrease in ATP production results in the activation 
of the liver kinase B1 (LKB1) – adenosine monophosphate-activated protein 
kinase (AMPK) signaling pathway26-28.  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 regulators metabolism in an attempt to maintain energy 
homeostasis31.  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 
glycolysis32.  Metformin may also have activity that is independent of LKB1.  In 
LKB1 deficient cells, metformin is still able to affect the intracellular energy 
state33.  Metformin also alters the mitochondrial redox state by inhibiting 
glycerophosphate dehydrogenase34. Metformin reduces the mitochondrial citric 
acid cycle and induces aerobic glycolysis as well35. 
 
Collectively these considerations highlight that metformin may have utility as a 
selective radiation protector of normal but tumor cells.   
 
1.4 Clinical Data 
Summary of results from clinical studies:  
 


 
 
 
 
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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 cells29.  Also, 
there is high MCT4 expression in HNSCC cancer associated fibroblasts (CAFs) 
and in carcinoma cells with low proliferation rates29. 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 fibroblasts29. 
 
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 quickly25. 
 
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 metformin30,31.  Other studies have also shown a reduction in the frequency 
of cancer with metformin use32.  Evans et al 33 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 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 al22 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 al23 showed short-


 
 
 
 
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15 
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. 
 
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 cancer14,22,23.  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.  
 
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 EORTC QLQ 
– H&N35, mucositis score, the Multidimensional fatigue inventory  and the 
Xerostomia Questionnaire (XQ) all of which have been validated and used in 
multiple clinical studies to-date (Appendix).   
 
1.5 Study Therapy 
Description of the experimental product: 
 
Metformin is a biguanide oral antidiabetic drug. It inhibits 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. Metformin’s main effect on cells is to 
decrease mitochondrial oxidative phosphorylation (OXPHOS) complex I activity. 
Metformin treatment does not induce hypoglycemia. Metformin may represent a 
novel radioprotectant therapy.  
1.6 Dose Rationale and Risk/Benefits 
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. However, 


 
 
 
 
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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 normal 
tissue protection during radiation.   
 
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-two weeks prior to planned 
external beam radiation 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. If 
tolerated, metformin will be further increased to 1000mg twice daily after day 6. 
Subjects will maintain 1000 mg twice a day dosing until two weeks post radiation.   
 
There are currently multiple studies on-going using doses from between 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 8-10 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 12 weeks.  
 
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 500mg/day for 3 days.  From day 4, 500mg twice daily and then in 3 days 
(Day 6) dose escalation to 1000mg 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 study31.   
 
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 held 48 hours 
in advance of administration of IV dye, as is the standard practice among 
patients taking metformin.  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 


 
 
 
 
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American College of Radiology guidelines37. Metformin will be resumed 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 HNSCC and 
this study is not designed to evaluate efficacy of metformin in HNSCC, but this 
study is designed to evaluate whether the sequelae of treatment from external 
beam radiation are mitigated by use of metformin. Hence, the potential direct 
benefits to subjects in this study include the possibility of decreased, xerostomia, 
dysphagia, fatigue and other sequelae of RAI. Further, the possible societal 
benefits are large since this will allow us to learn about the pharmacodynamic 
effects of metformin in radiation 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 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 


 
 
 
 
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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 section 0. 
 
Potential benefits:  
 
Metformin may provide a radioprotective effect and mitigate the sequelae of 
external beam radiation.  Furthermore, metformin may alter tumor metabolism 
and improve outcomes in various cancers. This study is designed to evaluate 
whether the sequelae of radiation 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.  
2.0 STUDY OBJECTIVES 
1. To assess the capacity of metformin to alter the cytokine and exosome 
profiles.  
2. To assess the capacity of metformin to mitigate known side effects of 
external beam radiation therapy including inflammation, mucositis, 
dysphagia, xerostomia, and fatigue. 
 
2.1 Primary Objective: 
 
We have chosen a cytokine/chemokine profile analysis as a surrogate marker of 
trending inflammatory reaction.  This response drives the severity of 
mucositis/xerostomia and acute radiation toxicity. The blood and saliva counts will 
be compared in the pre-treatment sample, during treatment samples and post 
treatment samples. Luminex technology with 40 cytokines markers will be used 
(Luminex technology with the Milliplex MAP Human Cytokine/chemokine 
Magnetic kit I (41 analytes) (sCD40L, EGF, Eotaxin, FGF-2, Flt-3 ligand, 
Fractalkine, G-CSF, GM-CSF, GRO, IFN-α2, IFN-γ, IL-1α, IL-1β, IL-1ra, IL-2, IL-
3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-
17A, IP-10, MCP-1, MCP-3, MDC (CCL22), MIP-1α, MIP-1β, PDGF-AA, PDGF-
AB/BB, RANTES, TGF-α, TNF-α, TNF-β, VEGF).  Blood and saliva samples will 
be drawn before, during and immediately after treatment and every three months 
thereafter for one year. All blood samples will be taken by a phlebotomist who will 
be blinded as to whether the patient is in the experimental (radiation + metformin) 
or control (radiation + placebo) groups.  
 
2.2 Secondary Objective: 
• 
Assess safety and tolerability of metformin treatment in subjects 
undergoing external beam radiation treatment for head and neck cancer.  


 
 
 
 
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• 
To determine the effect of metformin treatment on symptoms of 
xerostomia as assessed by the Xerostomia Questionnaire (XQ) 
• 
To determine the effect of metformin treatment on symptoms of mucositis 
as assessed by WHO classification 
• 
To determine the effect of metformin treatment on symptoms of 
dysphagia as assessed by the MD Anderson Dysphagia Inventory 
• 
To determine the effect of metformin treatment on symptoms of Fatigue 
as assess by the Multidimensional fatigue inventory (MFI).  
2.3 Primary Study Endpoints 
a) Cytokine/chemokine profile  
b) Exosome profile.  
2.4 Secondary Study Endpoints 
Measures of  
a) Mucositis 
b) Dysphagia 
c) Xerostomia 
d) Fatigue.  
2.5 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.  
3.0 STUDY DESIGN 
Purpose of the study: To assess the radioprotective effect of metformin in 
subjects with head and neck cancer by evaluating both the ability of metformin to 
mitigate known side effects of radiation  therapy as well as alter the exosome 
profile in the serum. 
3.1 General Design 
Type of trial: Pilot Feasibility trial 
 
Planned accrual period: 24 months 
 
Planned follow-up period: 12 months  
 
Planned enrollment: Total of 50 patients  
 
Schema of the trial design, procedures, and stages: 


 
 
 
 
TJU v5.0 (2019-06-2) 
20 
  
Patients with a head and neck region biopsy and diagnosis of HNSCC cancer 
who are planned to undergo definitive treatment by definitive radiation or up front 
surgery followed by adjuvant radiation.  After informed consent is signed, patients 
will be administered metformin with dose escalation as tolerated* until time of 
radiation.  
 
 
  50 HNSCC patient candidates for adjuvant or neoadjuvant radiation 
 
Pre-metformin Blood and Saliva samples 
 
Randomized to Metformin Treatment* (N=25) vs  
Placebo** Treatment (n = 25) 
 
 
 
 
 
  
 
External beam radiation (sample 
collected half way through) 
 
 
Post-metformin blood and 
saliva sample 
 
 *Metformin (500 mg/day for 3 (+2 days) days followed by 500 mg twice daily for 3 days followed 
by 1000mg twice daily from day 6 (+2 days). Subjects will maintain 1000 mg twice a day dosing 
until two weeks post radiation.  ) 
** Placebo (1 tab  taken BID) No ramp up phase 
 
Participant’s Follow-up. The participant’s medical records will be reviewed every 
3 months for 12 months to assess:  Mucositis, xerostomia, fatigue and dysphagia  
4.0 SUBJECT SELECTION AND WITHDRAWAL 
 
4.1 Inclusion Criteria 
1. Diagnosis: Subjects with a diagnosis of head and neck cancer biopsy     
proven, and who are candidates for radiation therapy 
2. Age:  Subjects must be ≥ 18 years of age and ≤90 years old. 
3. Informed Consent:  All subjects must be able to comprehend and sign a 
written informed consent document.  
 
4.2 Exclusion Criteria 
1. Subjects who are pregnant or may become pregnant during metformin 
administration.  Pregnancy testing will be done in conjunction with 
preradiation protocols.   
2. Subjects on metformin for any reason during the preceding 4 weeks. 
3. Diabetic subjects are eligible if they are not taking metformin or insulin    


 
 
 
 
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21 
4. Subjects who have received iodinated contrast dye must wait 12 hours 
prior to starting Metformin.  If a CT scan with contrast is scheduled after 
screening and consent, the metformin cannot be taken until after the CT 
with contrast has been completed and they have waited 12 hours.   
5. Patients with plasma creatinine level greater than 1.3 mg/dL. 
6. Patients with plasma bicarbonate less than 22 mEq/L or history of lactic or 
any other metabolic acidosis.  
7. Patients with history of congestive heart failure. 
8. Patients with myocardial ischemia or peripheral muscle ischemia. 
9. Patients with sepsis or severe infection. 
10. Patients with history of lung disease currently requiring any supplemental 
oxygen treatment. 
11. Patients scheduled for radiation less than 6 days from enrollment  
12. Patients with history of hepatic dysfunction or hepatic disease and 
abnormal liver function tests.  Patients who have a history of hepatic 
dysfunction or hepatic disease and normal liver function tests will be 
eligible to participate. 
13. Patients with a current history (in the past 30 days) of heaving 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 
 
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. 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: 
Class C: 
 
 
 
 
 
 Class D: 
Carbonic anhydrase inhibitors 
 
 
Cimetidine 
Cephalexin  
 
 
 
 
Iodinated contrast 
agents 
Corticosteroids (orally inhaled) 
 
 
Somatropin 
Corticosteroids (systemic) 
Dalfampridine 
Dofetilide 
Glycopyrrolate 
Lamotrigine 
Luteinizing hormone-releasing hormone analogs 


 
 
 
 
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Pegvisomant 
Trospium 
 
4.3 Gender/Minority/Pediatric Inclusion for Research 
This protocol will include women, minorities and pediatric cases (participants 
between 18 and 21 years). African Americans have a higher incidence of head 
and neck cancer and hence minority subjects are expected to be accrued at a 
higher rate than white subjects as compared to the population that Thomas 
Jefferson University Hospital serves. There is nearly a 3:1 predominance of 
males to females in this diagnosis.  We will review accruals to this trial quarterly 
in the Head and Neck MDG and review the number of males and females 
accrued.  If this deviates from the expected ratio we will review our actual patient 
ratio for that time and determine a remediation plan within the MDG to ensure 
accrual of women. 
4.4 Subject Recruitment and Screening 
50 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, aspartate aminotransferase, alanine aminotransferase and alkaline 
phosphatase. 
 
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 
from the subject to record survival and progression for 2 years 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: 


 
 
 
 
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23 
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 from the subject to record survival and 
progression for 1 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 (+2 days) days which then will be increased to 500 mg 
twice daily and, if tolerated, further increased to 1000mg twice daily after day 6 (+ 
2 days). 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. 
 
The placebo will be dosed as 1 tab BID and will not have a dose escalation.   
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 


 
 
 
 
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24 
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 study is designed to assess as the primary end-point the effects of 
metformin on cytokines with short term administration and not to assess if 
metformin improves outcomes in head and neck cancer and hence it is unlikely 
to improve the clinical outcome of the subjects enrolled in this study.  
 
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 500mg/day for 3 days (+2 days).  From day 4, 500mg twice daily and then in 
3 days (+2 days) dose escalation to 1000mg twice daily will be achieved.  This 
will be taken until the day before surgery after dinner.  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 study31.   
 
Metformin will not be started if CT scan with intravenous contrast is scheduled.  
After the scan they will be instructed to start the metformin the following day. 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 trial37.   
 
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. 
 
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. 


 
 
 
 
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25 
5.4 Method for Assigning Subjects to Treatment Groups 
Randomization of 1:1 will be assigned at the time of accrual.  A randomization 
schedule will be developed by the study statistician using the method of random 
permuted blocks.  Randomization assignments will be loaded into REDCap and 
subjects will be randomized by accessing assignments through 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. An 8 week supply of metformin 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 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. Upon arrival for post-radiation follow-up, the bottle 
will be collected by our 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. See section 4.2 for more information.  
5.8 Packaging 
The 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. The study drug will be packaged in 
1 bottle containing 500mg tablets for a maximum of 8 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 two weeks after 
radiation therapy ends”.    
 
5.9 Blinding of Study Drug 
The bottle will be non-descript and contain either metformin or placebo depending 
on randomization.  Patients will be blinded to which pill (metformin or placebo) 
they will receive. Pill distribution will be completed by the pharmacist who will not 
be blinded. Principal Investigator and care providers making assessments will not 
be blinded. 


 
 
 
 
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26 
 
 5.11 Placebo 
 
Placebo will be given as 500mg 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 500mg capsules. The bottle 
will be labeled “take one tablet twice daily until two weeks after radiation therapy 
ends”.    
 
5.12 Receiving, Storage, Dispensing and Return 
5.12.1 Receipt of Drug Supplies 
The study drug will be provided by the Department of Otorhinolaryngology and 
will be coordinated through the Thomas Jefferson University Hospital Service 
(IDS) Pharmacy. Upon receipt of the study treatment supplies,  
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 the study sponsor of any damaged or unusable study 
treatments that are 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.  
 
5.12.2 Storage 
Drug 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 Investigator 
Brochure.  Clinical supplies may not be used for any purpose other than that 
stated in the protocol. 
 
5.12.3 Dispensing of Study Drug 


 
 
 
 
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27 
The study drug will be dispensed to the participants in 1 bottle containing 500mg 
tablets for a maximum of 8 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 two weeks after radiation therapy ends” for metformin or bottle will be 
labeled “take one tablet twice daily until two weeks after radiation therapy 
ends”.  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 the visit two weeks after 
the completion of radiation. Regular study drug reconciliation will be performed 
only at the end of the study.  
 
5.12.4 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, resolved, and documented prior to destruction of 
unused study drug.  Drug destroyed on site will be documented in the study files. 
6.0 STUDY PROCEDURES 
A schedule of events can be found in Appendix A.  
 
6.1 Study Visit Schedule 
Screening: 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.  
 
Visit 1: Subjects that meet the 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, blood and saliva will be collected, and participant will be randomized.   
 
Metformin/placebo 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 start of 
radiation.  Subject will be instructed to start taking the metformin/placebo at any 
point from 1 to 7 days from the start of radiation.   


 
 
 
 
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28 
 
Quality of life measures including the EORTC QLQ – H&N35, mucositis score, 
Multidimensional fatigue inventory and the Xerostomia Questionnaire (XQ) will be 
administered on an IPad through the website 
(https://az1.qualtrics.com/jfe6/preview/SV_87y9IyJ0sFo8oJv). Patients will be 
identified only by an ID number.  
 
Visit 2: Subjects will come in during the 3rd week of their radiation for blood draw, 
saliva collection, physical exam, quality of life questionnaires and tolerability 
assessment.  An inventory of medication will also be taken to assess compliance.  
Location of radiation is not dictated by this protocol.   
 
Visit 3: Two weeks after completion of radiation.  Subjects will be approached for 
bottle and pill reconciliation as well as follow up of side effects and adverse 
events.  Blood and saliva will be collected, and MD Anderson Dysphagia 
Inventory, Multidimensional fatigue inventory (MFI-20) and the Xerostomia 
Questionnaire (XQ) will be administered will be administered on an IPad through 
the website (https://az1.qualtrics.com/jfe6/preview/SV_87y9IyJ0sFo8oJv). 
Patients will be identified only by an ID number. 
 
Follow-up: Every 3 months during the 1st year post treatment subjects will have 
their regularly schedule appointments at which we will draw blood and saliva and 
administer quality of life surveys.  The participant’s medical records will be 
reviewed every 3 months for 12 months.  
 
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 
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. 


 
 
 
 
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Grade 2 toxicity: Dose will be reduced by 50% until grade 1 or lower. If symptoms 
are not resolved within 3 days of toxicity development the treatment will be 
interrupted definitively.  
 
Grade 3 toxicity (probably or definitely drug related): Treatment will be 
interrupted. Toxicity will be evaluated daily and if toxicity improves to grade 1 or 
lower dose will be reduced by 50%. If toxicity is not improved or resolved or 
reduced to grade 1, treatment will be interrupted definitively. 
 
Grade 4 toxicity (probably or definitely drug related): Treatment will be 
permanently discontinued. 
 
In case of grade 1 or 2 diarrhea (the most frequent side effect) a concomitant 
administration of loperamide will be provided. 
 
6.4 Laboratory Procedures/Evaluations  
 
6.4.1 Clinical Laboratory Evaluations 
To assess changes in cytokines and exosomes, patients will have two 7ml purple 
top tubes drawn in the office as well as collection of 5ml of saliva.  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. 
 
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 Analysis for Primary Outcome 
 
Mixed effects linear regression will be used to model longitudinal measurements 
of each cytokine.  Measurement time will be treated as a categorical variable and 
fixed effects in the model will include randomization assignment, time, and 
randomization by time interaction.  A linear contrast will be used to estimate the 
difference in randomization groups with respect to mean change from baseline to 


 
 
 
 
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post-treatment.  Significance of this difference will be calculated for each cytokine 
and p-values will be adjusted using the Benjamini and Hochberg procedure to 
control the false discovery rate at 5%.  Cytokine levels will likely need to be log-
transformed prior to analysis to meet model assumptions.     
 
Longitudinal measurements of exosomes will also be modeled using mixed 
effects linear regression in the same fashion.  This analysis is treated as 
separate from the cytokine questions and the p-value will not be adjusted.   
 
7.2  Analysis for Secondary Outcomes 
 
Analysis of secondary outcomes will be primarily descriptive.  The distribution of 
swallowing function and mucositis scores will be summarized by arm using 
means, medians, standard deviations, and ranges.  The objective response rate 
will be estimated by arm along with an exact 95% binomial confidence interval.   
 
7.3 Subject Population(s) for Analysis: 
All randomized participants with any data will be included in the analysis.    
 
7.4  Sample Size Justification 
50 subjects will be randomized 1:1 to either metformin or placebo resulting in 25 
subjects per group. The standardized difference in means between groups (effect 
size) that can be detected with 80% power was calculated for various 
assumptions of the number of cytokines with true differences above the 
detectable difference using the method of Jung (2005).  With at least 5 cytokines 
out of 40 being different, we have 80% power of detecting a difference for each 
test if the true difference is at least 1.1 standard deviations. 
 
Detectable difference (D) by number of cytokines with true difference>D 
assuming 80% power for each test. 
Number of 
cytokines with 
true difference >D 
(K) 
Detectable 
difference in 
means (D) 
Single test alpha 
Probability of 
detecting all K  
5 
1.1 
0.0060 
0.33 
10 
1.0 
0.014 
0.11 
15 
0.9 
0.025 
0.035 
20 
0.8 
0.042 
0.012 
25 
0.8 
0.070 
0.0038 
 
For the exosome analysis, we have 80% power to detect an effect size of 0.81 
(difference in means of 0.81 standard deviations) or greater using a two-sided 
test with alpha=0.05.   
 


 
 
 
 
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31 
 
Ref:  Jung, S.-H. 2005. Sample size for FDR-control in microarray data analysis. Bioinformatics: 
Vol. 21 no. 14, pp. 3097-3104. Oxford University Press. 
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 30 days following the last administration of study treatment.  


 
 
 
 
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Preexisting Condition 
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: 
• Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not be 


 
 
 
 
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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.    
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 
The safety monitoring will include careful assessment and appropriate reporting 
of adverse events as noted above, as well as the compliance and implementation 
of the SKCC data and safety-monitoring plan.  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events by both 
the PI and the SKCC DSMC. 
 


 
 
 
 
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8.5.1 Medical Monitoring and AE/SAE Reporting 
Every SKCC investigator initiated protocol includes requirements for reporting of 
adverse events based on CTC 4.0. All events are reported to the IRB and 
Medical Monitor using a password protected web-site. In addition all unexpected 
and serious adverse events (SAEs) are reported to the TJU IRB and to the Food 
and Drug Administration (FDA) if applicable. The investigator is required to 
submit all unexpected and serious adverse events to the TJU IRB and the 
Medical Monitor within the timeframes outlined in the below table. All AE/SAEs 
will be reported to the DSMC at the quarterly DSMC review meetings. Fatal 
adverse events related to treatment which are unexpected must be 
reported within 24 hours to the TJU IRB and the DSMC. Fatalities not 
related to the study drug/device must be reported within 5 days 
 
A summary of the reporting requirements for SKCC investigator-initiated studies are 
presented below. 
 
**NOTE: This table is based on the NCI AE/SAE reporting Guidelines 
and the TJU IRB Policy and Procedures. Please follow the individual 
protocol AE/SAE reporting guidelines if more stringent reporting 
procedures are specified** 
 
 
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 


 
 
 
 
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quarterly to review the progress and safety of all 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.  


 
 
 
 
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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 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 


 
 
 
 
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investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
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). 
 
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Appendix A: Schedule of Events 


 
 
 
 
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43 
Appendix A: Schedule of Events 
Study Procedures 
Screening 
Visit 1 
 
Visit 2 (During 3rd week 
of RT) 
End of  
Treatment 
(Visit 3)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 
X 
XC 
Pathology Report 
histologic confirmation 
of disease if available 
X 
 
 
 
 
Concomitant meds 
X 
X 
 
 
 
Toxicity and AE 
Assessment 
 
X 
X 
X 
X 
Treatment/ 
Intervention 
 
MetforminG 
 
X 
X 
 
 
PlaceboH 
 
X 
X 
 
 


 
 
 
 
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44 
Radiation Treatment 
 
X 
X 
 
 
Correlative Studies 
 
 
Blood sample 
collectionA 
 
X 
X 
X 
XC 
Saliva sample 
collectionB 
 
X 
X 
X 
XC 
A. A 
Two 7ml purple top tubes are to be drawn at each time point and transported directly to Dr. Rodeck’s laboratory.  
 
B. B 
5ml of saliva is to be collected at each time point and transported directly to Dr. Rodeck’s laboratory.  
 
C. 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. D 
Quality of life surveys include: EORTC QLQ – H&N35, mucositis score, Multidimensional fatigue inventory and the 
Xerostomia Questionnaire (XQ). All questionnaires will be administered online via an IPad provided at the visit.  
 
E. E 
Visit will be 2 weeks after the completion of radiation therapy.  
 
F. 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 12 months 
 
G. G 
The initial starting dose of metformin will be 500mg orally daily for 3 (+2 days) days which then will be increased to 
500mg twice daily and, if tolerated, further increased to 1000mg twice daily after day 6 (+2 days). 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. H 
Placebo will be given as 500mg tablets twice daily with no dose escalation