Clinical trial NCT02946996
Conditions: Prostate Cancer
Sponsor: Medical University of South Carolina
Start date: 2016-12-28; Completion date: 2024-08-19
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to look at the effect that the study drug OPC has on AGE levels in patients with prostate cancer.

Detailed description:
AGEs are a type of metabolite, or substance, found in the food. The AGE content in food is determined by the types of food you eat and also how you prepare your food. The researchers helping conduct this study have found a potential link between AGE levels and cancer. The purpose of this study is to see if Oligomeric Procyanidin Complex (OPC) has an effect on the AGE levels in your blood and to see if those AGE levels have an effect on your cancer.

Arms: arm 1: Subjects will be supplied with metformin tablets850mg. During the ramp up phase subjects will take metformin in the morning. During weeks 2-12 the metformin tablet will be taken approximately 12 hours apart. arm 2: Subjects will take one OPC capsule at the same time each morning and evening, approximately 12 hours apart during weeks 1-12. arm 3: During week 1, subjects will take one metformin tablet in the morning and one OPC tablet in the morning and in the evening, about12 hours apart.

During weeks 2-12 the metformin tablet will betaken approximately 12 hours apart and one OPC about 12 hours apart, in the morning and in the evening.
Interventions: intervention 1: Metformin intervention 2: OPC
Intervention descriptions: intervention 1: None intervention 2: OPC is a derivative of grape seed extract

Protocol documents:
Prot_SAP_000.pdf: 
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Phase II Study of Pharmacologic Manipulation of AGE (Advanced 
Glycation Endproducts) Levels in Prostate Cancer Patients Receiving 
Androgen Deprivation Therapy 
 
 
Principal Investigator:   
          Michael Lilly, MD 
 
 
Professor of Medicine 
 
 
Division of Hematology-Oncology 
 
 
Medical University of South Carolina 
 
 
BSB102 
 
 
173 Ashley Street 
 
 
Charleston, SC  29425 
 
 
Telephone 843-792-0592 
 
 
e-mail:  lillym@musc.edu 
 
Co-Investigators: 
 
Todd Gourdin, MD 
 
 
Assistant Professor of Medicine 
 
 
Division of Hematology-Oncology 
 
 
Medical University of South Carolina 
 
 
BSB103  (MSC635) 
 
 
173 Ashley Street 
 
 
Charleston, SC  29425 
 
 
Telephone 843-792-4271 
 
 
FAX 843-792-0644 
 
 
e-mail:   gourdith@musc.edu 
 
 
 
David Turner, PhD 
 
 
Assistant Professor of Pathology 
 
 
Department of Pathology and Laboratory Medicine 
 
 
Medical University of South Carolina 
 
 
BE 407 (MSC 908) 
 
 
68 President Street 
 
 
Charleston, SC  29425 
 
 
Telephone 843-876-2309 
 
 
e-mail:  turnerda@musc.edu 
 
 
 
 


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Coordinating Center: 
 
Sponsor Investigator Support Unit 
 
 
Medical University of South Carolina 
 
 
86 Jonathan Lucas St, Suite 373 
 
 
Charleston, SC 29425 
 
 
Telephone:  843-792-2708 
 
 
Email:  anderton@musc.edu 
 
 
 
Version History: 
Version 12.0 dated May 8, 2023    
Version 11.0 dated April 30, 2019 
Version 10.0 dated February 25, 2019 
Version 9.0 dated August 15, 2018 
Version 8.0 dated May 8, 2018 
Version 7.0 dated December 19, 2017 
Version 6.0 dated August 10, 2017 
Version 5.0 dated June 12, 2017 
Version 4.0 dated March 17, 2017 
Version 3.0 dated January 17, 2017 
Version 2.0 dated November 29, 2016 
Version 1.3 dated October 24, 2016 
Version 1.2 dated September 9, 2016 
 


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TABLE OF CONTENTS 
Definition of Terms Used ............................................................................................................. 4 
1 
BACKGROUND ................................................................................................................... 5 
 
AGEs are Lifestyle-Associated Mediators of Degenerative Diseases. .......................... 5 
2 
STUDY OBJECTIVES........................................................................................................ 10 
 
Study Overview ......................................................................................................... 10 
 
Primary Objective. ..................................................................................................... 10 
 
Secondary Objectives. ............................................................................................... 10 
3 
Subject Selection ............................................................................................................... 10 
 
Inclusion Criteria ........................................................................................................ 10 
 
Exclusion Criteria ....................................................................................................... 11 
 
Study Registration ..................................................................................................... 11 
4 
Drug Administration ........................................................................................................... 11 
 
Arm 2:  OPC only. ...................................................................................................... 11 
 
Medication Compliance Assessment. ........................................................................ 11 
 
Dose Modifications. ................................................................................................... 11 
 
Discontinuation of Therapy ........................................................................................ 12 
 
Restricted Therapies During Study Therapy .............................................................. 12 
 
Supportive Care during Therapy ................................................................................ 12 
5 
SCHEDULE OF INTERVENTIONS AND ASSESSMENTS ................................................ 12 
 
General Considerations ............................................................................................. 12 
 
Assessments and Procedures ................................................................................... 12 
 
Disease assessment.................................................................................................. 12 
 
Correlative Research ................................................................................................. 13 
 
Schedule of Assessments ......................................................................................... 13 
6 
Study Drug Information ...................................................................................................... 13 
 
Oligomeric Procyanidin Complex (OPC) .................................................................... 13 
7 
Adverse events .................................................................................................................. 15 
 
Definitions .................................................................................................................. 15 
 
Reporting of SAEs ..................................................................................................... 16 
8 
data Safety Monitoring ....................................................................................................... 17 
 
Responsible Individuals and Organizations. .............................................................. 17 
 
Data Collection .......................................................................................................... 17 
9 
Statistical Methods and power analysis .............................................................................. 17 
 
Primary endpoint: ...................................................................................................... 18 
 
Secondary endpoints: ................................................................................................ 18 
 
Statistical considerations .............................................. Error! Bookmark not defined. 
REFERENCES ......................................................................................................................... 19 
APPENDIX A.  SCHEDULE OF PROCEDURES AND ASSESSMENTS................................... 24 
APPENDIX B:  Calculation of Creatinine Clearance .................................................................. 25 
 
 
 


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DEFINITION OF TERMS USED 
ADT 
 
 
androgen deprivation therapy 
AE 
 
 
adverse event 
AGE 
 
 
advanced glycation endproducts 
AGER  
 
receptor for AGE 
ALT 
 
 
alanine transaminase 
ANC 
 
 
absolute neutrophil count 
AST 
 
 
aspartate aminotransferase 
BID 
 
 
two times per day 
BMI 
 
 
body mass index 
BUN 
 
 
blood urea nitrogen 
CBCD  
 
complete blood count with differential 
CDC 
 
 
Center for Disease Control and Prevention 
CML 
 
 
carboxymethyllysine 
CMP 
 
 
comprehensive metabolic panel 
CRP 
 
 
c-reactive protein 
CTCAE  
 
Common Toxicity Criteria for Adverse Events 
DSMC  
 
Data Safety Monitoring Committee 
ECOG  
 
Eastern Cooperative Oncology Group 
eCRF  
 
electronic case report form 
FDA 
 
 
Food and Drug Administration 
GCP 
 
 
Good Clinical Practice 
GI 
 
 
gastrointestinal 
GRAS  
 
generally recognized as safe 
GSE 
 
 
grape seed extract 
HCC 
 
 
Hollings Cancer Center 
Hgb 
 
 
hemoglobin 
HMS 
 
 
hypogonadal metabolic syndrome 
ICH 
 
 
International Code of Harmonization 
ID 
 
 
identifier 
IDS 
 
 
Investigational Drug Services 
IIT  
 
 
Investigator Initiated Trial 
IRB 
 
 
Institutional Review Board 
LDL 
 
 
low density lipoprotein 
MG 
 
 
methylglyoxyl 
MTD 
 
 
maximum tolerated dose 
MUSC  
 
Medical University of South Carolina 
NADHP oxidase 
nicotinamide adenine dinucleotide phosphase-oxidase 
NYHA  
 
New York Heart Association 
OPC 
 
 
Oligomeric Procyanidin Complex 
OTC 
 
 
over the counter 
PCa 
 
 
prostate cancer 
PI 
 
 
Principal Investigator 
PO 
 
 
by mouth 
PSA 
 
 
prostate specific antigen 
RAGE  
 
receptor for AGE 
ROS 
 
 
reactive oxygen species 
SAE 
 
 
serious adverse event 
SIS  
 
 
Sponsor-Investigator Support Unit 
sRAGE  
 
soluble form of RAGE 
USP 
 
 
United States Pharmacopeia 
VAMC  
 
Ralph H. Johnson VA Medical Center 
VCAM-1 
 
vascular cell adhesion molecule-1 
VLDL 
 
 
very low density lipoprotein 
 
 
 
 


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1 
BACKGROUND 
 
AGEs are Lifestyle-Associated Mediators of Degenerative Diseases. 
Despite great progress in the treatment of many cancers, specific populations across the world 
still suffer disproportionately high levels of cancer incidence and mortality. Cancer disparity is 
most evident in our African American populations who bear the highest cancer burden for many 
tumor types. Poor diet, low income, obesity, and a lack of exercise are established lifestyle factors 
that are known to increase cancer burden and are often more prevalent in African American 
communities (1-3). As our understanding of tumor biology advances, it is becoming increasingly 
clear that these interrelated lifestyle factors have distinct molecular consequences on the biologic 
make up of tumors, altering cell signaling events and gene expression profiles to contribute to 
cancer disparity outcomes such as its earlier development or its progression to more aggressive 
disease. Sparse information exists about the genetic and biologic factors that contribute to 
differential cancer survival and mortality rates observed in minority populations. A greater 
understanding of the interplay between risk factors and the molecular mechanisms associated 
with cancer disparity will significantly affect minority health.  
We recently reported a potential mechanistic link between sugar-derived metabolites (collectively 
AGEs or advanced glycation endproducts) and cancer, which may provide a molecular 
mechanism to account for the consequence of our lifestyle choices that can directly affect tumor 
biology and contribute to cancer (and generalized health) disparity (4).  
1.2 
AGE Accumulation Is Inherently Linked to Lifestyle 
Systematic reviews and meta-analysis studies support the view that eating unhealthily, being 
overweight or obese and/or sustaining a sedentary lifestyle can increase risk of cancer, risk of 
cancer recurrence, and decrease overall survival rates (5,6). A recent statement from Cancer 
Research UK estimated that lifestyle accounts for around 40% of cancer cases, second only to 
smoking. This is racially significant as the highest rates of being overweight and obese (defined 
as a BMI >25) and the lowest adherence to CDC-recommended physical activity guidelines 
(defined as a minimum of 150 minutes per week) occur among the African American populations 
at highest risk of developing and dying of cancer (7). A family tradition of high-calorie “soul foods” 
with a heavy use of fat and sugar exists for many African American families. In addition, low 
income promotes the use of cheap, unhealthy, and highly processed foods, which can lead to 
weight gain, obesity, and increased cancer risk. Poverty rates within African Americans 
communities are among the highest in the country and they are also more likely to live in 
designated “food deserts” where people have limited access to healthy affordable food (8). All of 
these lifestyle factors not only contribute to health disparity and increase cancer risk but 
significantly contribute to the exogenous AGE accumulation pool in our bodies:  
The typical Western diet comprising red meat, refined grains, and high fat/high sugar foods are 
associated with systemic disease and are particularly AGE-laden, contributing as much as 30% 
of the AGEs accumulated within our bodies (9). The consumption of AGE-rich diets by mice 
increases circulating and tissue AGE content to promote conditions such as atherosclerosis, 
diabetes, and kidney disease, all of which are inhibited by dietary AGE restriction (9). Although 
human studies are limited, associations between elevated AGE and serum biomarkers of 
oxidative stress, endothelial dysfunction, inflammation, hyperlipidemia, and hyperglycemia have 
been identified in patients with impaired renal function and diabetes (9). Evidence supports dietary 
AGE restriction for the reduction of 8-isoprostanes and TNFα in healthy adults and reduced 
glucose and insulin resistance and AGE-modified low-density lipoprotein in type II diabetes 
patients (10).  
AGE content in foods is not only dependent on nutritional content but also on how the food is 
prepared. Cooking methods involving dry heat such as grilling, broiling, and searing, used to 
improve food flavor, aroma and appearance, accelerate the glycation reaction between sugars 


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and proteins to significantly increase overall AGE content (9). Frying meats, for example, can 
increase AGE content by as much as 10 fold. Thermal processing and/or irradiation by food 
manufacturers, used to improve food safety, preservation, and taste also rapidly accelerates the 
AGE-forming reaction (9). Due to beneficial effects on flavor, synthetic AGEs are now directly 
added into the manufacturing process for several food items. Processed foods are now one of 
the most common food items in groceries baskets across the country and due to their relatively 
low cost are often most heavily used by low-income families.  
Recent data from the European Prospective Investigation into Cancer and Nutrition Study 
conclude that a sedentary lifestyle poses twice the risk of premature death as being overweight 
or obese (11). Studies of the effects of physical activity on AGE levels are limited and are mainly 
carried out using animal models but indicate that regular physical activity can help maintain or 
even reduce AGE levels in our bodies. In obese rats, regular moderate exercise reduced 
advanced glycation early diabetic nephropathy, lowered plasma AGE-associated fluorescence as 
well as overall renal AGE content (12). Similarly, increased physical activity in middle-aged 
senescent rats reduced both cardiac fibrosis and circulating AGE levels (13). In nondiabetic 
middle-aged women, a 12-week lifestyle modification consisting of an initial educational session 
followed by encouragement showed that the number of daily walking steps significantly correlated 
with AGE levels. Decreases in AGEs correlated with reduced body weight and body fat content 
(14).  
In summary, AGEs are inherently linked with poor lifestyle and play a pathogenic role in multiple 
diseases associated with growing older. Approaches to define the molecular consequences of 
AGE accumulation may define novel therapeutic targets and potential biomarkers with which to 
reduce cancer incidence and mortality, particularly in minority populations.  
1.3 
AGE Accumulation, RAGE, and Stress Response 
Persistent, unchecked inflammation and a related increase in oxidative stress are major biologic 
consequences of poor lifestyle and an underlying factor behind most, if not all, systemic diseases.   
A healthy diet and regular exercise has been shown to reduce chronic inflammation associated 
with diabetes and cardiovascular disease in the absence of weight loss, and studies indicate that 
increased physical activity is associated with lower inflammatory marker levels (19, 20).   
A major pathogenic consequence of AGE accumulation is the perpetual activation of immune-
mediated chronic inflammation and the generation of ROS, which results in a perpetual 
inflammatory microenvironment susceptible to disease development. CRP is a marker of 
inflammation that is linked with increased risk of heart disease, diabetes, and some cancers. In 
diabetes, serum AGE levels are an independent determinant of CRP levels due to a chronic 
inflammatory response (15).  African Americans have an increased burden of chronic 
inflammation, which is independent of BMI and other potential confounding factors (16).  African 
Americans have higher CRP levels than Caucasian American, which correlates with obesity and 
other metabolic and disease risk factors (24).  Clinical and epidemiologic evidence also identifies 
African American race as an independent risk factor for elevated oxidative stress (17) and the 
increased expression and/or activity of critical oxidative stress markers (18) .  
AGEs contribute to immune-mediated chronic inflammation by functioning as ligand for the 
transmembrane receptor for AGE known as RAGE (or AGER; Fig 1). Mechanistically, AGE-
mediated activation of RAGE results in the increased activation of proinflammatory transcriptional 
regulators, including nuclear factor-kappa B (NF-κB), STAT3, and hypoxia inducible factor 1 
(HIF1). In diabetes, RAGE activation perpetuates NF-κB activation in a feedback loop involving 
de novo synthesis of NFκB-p65, which functions to maintain a persistent pool of this key 
proinflammatory regulator. Increased activation of these critical transcription factors increases the 
secretion of cytokines/chemokines such as IL1β, IL6, and TNFα, leading to the increased 
recruitment of lymphoid and myeloid immune cells into tissues, elevated ROS production, and an 


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inflammatory response (19). To perpetuate the cycle and add further fuel to the fire, reactive 
intermediates generated during AGE formation (i.e., Schiff's Bases and Amadori products) can 
directly increase ROS production and increased ROS presence can in turn further promote the 
formation of AGE precursors such as methylglyoxal to create a cyclic and persistent inflammatory 
response (20) . Significantly, antioxidants can inhibit AGE-induced changes in glucose 
consumption and lower ROS levels. AGE activation of RAGE increases heme oxygenase-1, 
nuclear translocation of NF-κB, and increased endothelial expression of vascular cell adhesion 
molecule-1 (VCAM-1), all of which function to increase oxidative stress and elevated levels of 
ROS (21). RAGE loss of function inhibits all of these AGE-mediated effects.  
1.4 
AGEs and Cancer 
It is now generally accepted that chronic inflammation, oxidative stress, and cancer are 
intrinsically linked, and an inflammatory microenvironment is an essential element for both the 
onset and growth of tumors.  In precancerous lesions, a constant state of inflammatory response 
and increased ROS production can cause both genetic and epigenetic alterations to alter gene 
expression and increase cancer risk (22).  In established tumors, inflammation is thought to 
mediate cross-talk between cancers cells and the stroma, resulting in the active recruitment of 
immune cells to the tumor microenvironment and increased oxidative stress (22).  The 
inflammatory milieu created contributes to tumor onset and progression by promoting genetic 
instability, cell survival, growth, and metastatic potential.  
Although the mechanistic links between AGEs and lifestyle have been identified in diseases such 
as diabetes and cardiovascular disease(9), a potential contribution to the development and 
progression of cancer is relatively understudied. AGE presence in human tumors was first 
demonstrated in larynx, breast, and colon tumors by immune-histochemical staining. Exogenous 
AGE treatment of breast (23) and prostate (24)  immortalized cancer cell lines promotes cell 
growth, migration, and invasion. In prostate cancer, AGE-modified basement membrane 
promotes the invasive properties of prostate epithelial cells and correlates with decreased survival 
(24). A recent article found that the dietary-derived AGE carboxymethyl-lysine was associated 
with modestly increased risk of pancreatic cancer and may partially explain the positive 
association between red meat and pancreatic cancer (25).  Increases in the exogenous AGE pool 
mediated by poor diet and a sedentary lifestyle may contribute to tumor development and growth 
through the perpetual activation of immune response. This would be particularly significant in 
population groups with the highest prevalence of poor lifestyle and cancer risk, such as our African 
American communities, which evidence suggests may have higher AGE accumulation levels (4). 
The receptor for AGEs, RAGE, is also overexpressed in a number of tumors and evidence 
suggests a direct link between RAGE activation with the proliferation, survival, migration, and 
invasion of tumor cells. Loss of RAGE in inflammatory mouse models confers resistance to skin 
carcinogenesis and suppresses tumor growth (19). In prostate cancer, RAGE preferentially 
interacts with AGE over other potential RAGE ligands and AGE treatment of prostate cancer cells 
induces both cell growth and invasion (26). 
Our group examined circulating and tumor AGE levels in clinical specimens of prostate cancer 
and identified a race specific, tumor-dependent pattern of accumulation (4) . AGE levels were 
significantly elevated in both serum and tumor, with highest accumulation occurring in more 
aggressive tumors. When examined in a matched cohort of patients, high AGE levels in the serum 
correlated with high AGE accumulation in cancer tissue (4). Significantly, when the data were 
stratified by race, AGE metabolite levels were significantly higher in serum from African American 
cancer patients compared with Caucasian. These initial data indicate that AGEs may represent a 
potential mechanistic link between cell metabolism and cancer, which may also provide a biologic 
consequence of the lifestyle risk factors that drive cancer health disparity.  


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Based on associations between active metabolism, lifestyle, and immune response, increases in 
exogenous AGE accumulation may represent a biologic mechanism contributing to cancer 
disparity and may represent a novel paradigm to explaining the increased cancer incidence and 
mortality figures observed within minority populations.  A series of recent articles has highlighted 
the tumor-associated immune response as a critical pathway contributing to cancer disparity in 
African Americans. An examination of expression differences based upon tumor composition 
shows that cytokine signaling associated with an increased immune response was found to be a 
predominant pathway increased in African American prostate cancer patients (2). Upon closer 
analysis, the majority of race-specific differential gene expression was found in the stromal 
compartment of the tumor (2). A similar race-specific increase in immune response gene copy 
number and gene expression was seen in matched radical prostatectomy tissues (27) and in 
Gleason 6 prostate tumors (1).  
An analysis of more than 500 genes previously associated with prostate cancer shows that African 
American prostate tumors have significant upregulation of NF-κB and inflammatory cytokine 
factors (IL6, IL8, IL1B, C-X-C chemokine receptor type 4, and fatty acid synthase) compared with 
European Americans (28). In breast cancer, race is an independent predictor of elevated IL6 
levels (29). Clinical and epidemiologic evidence also identifies African American race as an 
independent risk factor for elevated oxidative stress and ROS levels. For example, NADPH 
oxidase catalyzes the reduction of superoxide (O2·) radicals to ROS. Significantly, HUVEC cells 
from African Americans show higher levels of nitric oxide, lower superoxide dismutase activity, 
and increased expression of the NADPH oxidase subunit p47phox protein than their Caucasian 
counterparts (18). These combined data further indicate that the immune-mediated inflammatory 
response may be elevated in African American cancer patients and therefore may be more 
susceptible to the pathogenic effects of AGE accumulation. Such a heightened inflammatory 
response may be a major contributor to the development and progression of cancer and 
contribute to the dire cancer incidence and survival rates observed in this population.  
The existence of AGE metabolites, their connections with diet and lifestyle, and their contribution 
to systemic disease are relatively unfamiliar to the general public as well as the cancer research 
community. Although emerging research has identified increased levels of AGEs in the circulation 
and tumor of cancer patients and has identified a significant role in carcinogenesis for their 
cognate receptor RAGE, it is not known if the same AGE–RAGE–mediated biologic pathways 
established in other systemic diseases are at play in the tumor microenvironment and to what 
extent AGEs derived from poor diet and a sedentary lifestyle contribute. Overall, supporting 
evidence for dietary restriction and/or physical activity interventions to reduce AGE levels in 
humans is hampered by the need for long-term high-quality randomized control trials with larger 
cohorts and defined disease outcomes.  The difficulties of effecting these changes over long 
periods of time in a wide spectrum of patients are well known.  The development of pharmacologic 
methods to manipulate AGE levels could be a significant aid to defining the role of AGEs in cancer 
development and progression. 
1.5 
Prostate Cancer and the Hypogonadal Metabolic Syndrome:  Possible Role for 
AGEs.   
The primary treatment for advanced prostate cancer is ADT.  While highly effective at producing 
regression of prostate cancer, ADT is not curative.  Furthermore it has significant side effects due 
to the lack of testosterone.  Adverse effects of ADT include decreases in bone mineral density; 
metabolic changes such as weight gain, decreased muscle mass, and increased insulin 
resistance; decreased libido and sexual dysfunction; hot flashes; gynecomastia; reduced testicle 
size; anemia; and fatigue (30). Several observational studies suggest an increased risk of 
diabetes (31,32) and cardiovascular events (33), although most published studies report that ADT 
is not linked to greater cardiovascular mortality. Randomized trials have found value in treatments 
for some adverse effects including bone loss (bisphosphonates, denosumab, selective estrogen 
receptor modulators), markers of metabolic syndrome (exercise, diet, metformin), gynecomastia 


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(tamoxifen, prophylactic radiation), muscle loss (resistance and aerobic exercise), and hot flashes 
(venlafaxine, medroxyprogesterone, cyproterone acetate, gabapentin). 
A subset of ADT toxicities is referred to as the HMS because of its resemblance to the metabolic 
syndrome in the diabetes and cardiovascular literature.  The HMS consists of increased body fat 
(particularly subcutaneous fat), obesity, insulin resistance, sarcopenia, elevated triglycerides and 
VLDLs, and increased adiponectin.  Additional significant metabolic toxicities include loss of bone 
mass, and increased risk of an acute cardiac event.   The HMS differs from the standard metabolic 
syndrome by the absence of hypertension (present in standard metabolic syndrome), and the 
elevated levels of adiponectin (reduced in standard metabolic syndrome; (34)).   
Components of the metabolic syndrome (whether pre-existing or associated with ADT) are 
associated with poor outcomes from prostate cancer treatment (35).  Obesity is associated with 
shortened progression-free survival after active surveillance (36), prostatectomy (37) and 
radiation (38,39), and with shortened time to castration-resistant disease in subjects receiving 
androgen deprivation therapy (40).  Poor glycemic control is associated with biochemical 
recurrence after radical prostatectomy (44) and in more advanced patients (41), and with impaired 
overall survival (42)  
Since AGEs are implicated in the metabolic syndrome described from diabetic and cardiac 
subjects, it is likely that they will play a role in the metabolic syndrome associated with prostate 
cancer and androgen deprivation.  Thus, development of methods to modulate AGE levels may 
provide additional tools to improve cancer-specific outcomes in prostate cancer patients. 
1.6 
Pharmacologic Manipulation of AGE levels 
AGEs accumulate in our tissues and organs over time and contribute to the development and 
complications associated with diseases of advancing age, including diabetes, cardiovascular 
disease, renal failure, arthritis, and neurodegenerative disorders (43). The rate of AGE 
accumulation in our bodies results from a balance between (i) their endogenous accumulation 
during the breakdown of sugar via the non-enzymatic, spontaneous glycosylation of proteins, 
lipids, and DNA; (ii) their exogenous intake through the foods we consume and other lifestyle 
factors such as drinking alcohol, smoking, and a sedentary lifestyle; and (iii) their inefficient 
removal via renal and/or enzymatic clearance, around 10% to 30% of exogenous AGEs are 
absorbed intestinally but only a third of those are excreted in urine and feces (9). AGEs bind to 
several receptors proteins, most clearly the RAGE.  Receptor engagement then activates a variety 
of signaling pathways, including NFB.  These documented features of AGE production, 
accumulation, elimination, and signaling provide guidance for the development of pharmacologic 
approaches to AGE modification.  Agents with at least some activity in diabetic or chronic kidney 
disease populations (animal models or patients) include glucose regulators, antioxidants, RAGE 
regulators, and oral AGE-binding resins. 
1.6.1.  Glucose regulators.  Metformin has been widely studied as an agent to modulate AGE 
levels in diabetic populations and intact animal models(44,45).   Most studies demonstrate that 
metformin reduces the plasma levels of some AGE species, usually methyglyoxal metabolites.  In 
contrast metformin effects on the more abundant carboxymethyllysine species are less 
consistent.  Metformin has been used in prostate cancer patients to improve insulin sensitivity but 
direct effects on AGE levels in that population have not been assayed (45).  
1.6.2.  Antioxidants.  An extensive literature documents the effects of antioxidant grape seed 
extracts on AGE production and levels in animal models (46-52).  The polyphenol-rich fractions 
from grape seeds and skins consist predominately of multimers of catechins and epicatechins, 
their gallic acid esters, and (at times) other polyphenols such as resveratrol.  Administration of 
these materials (either as purified compounds or complex mixtures) reproducibly reduces AGE 
levels and AGE effects on end organs in animal models of diabetes, obesity, and cardiovascular 


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disease.  In patients (usually obese, diabetic, or chronic kidney disease subjects) AGE levels 
decrease and sRAGE increase.  End-organ damage may also improve (53,54). 
1.6.3.  RAGE regulators.  Down-regulation of RAGE or increased secretion of  sRAGE can 
reduce signaling through the AGE-RAGE axis.  Multiple agents have been described as down-
regulating RAGE levels in cultured cells, or increasing sRAGE in the plasma of treated animals.  
Pioglitazone, statins, ACE inhibitors, and AT-1 receptor antagonists have all been shown to have 
activity through these mechanisms (55,56). 
1.6.4.  AGE-binding resins.  The phosphate-binding resin sevelamer has been shown to bind 
AGEs in vitro, and to lower age levels in the plasma of patients with chronic kidney disease(57).   
2 STUDY OBJECTIVES 
 
Study Overview 
The overall goal of this Phase II study is to identify safe pharmaceutical agents that can reduce 
the plasma levels of AGEs in patients with prostate cancer. 
 Primary Objective.   
The primary objective is to determine if the test agent reduces AGE levels by 30% (or greater) in 
50% or more of test subjects. 
 Secondary Objectives.   
 
Identify correlations between AGE level changes and baseline, changes in clinical 
parameters (BMI, PSA, insulin resistance (HOMA-IR), A1C, testosterone, lipids, diet) and 
quality of life measures (AUA symptom index, FACT-P). 
 
Identify toxicities of the test agent in PCa subjects.  
 
Identify correlations between AGE level changes and baseline, changes in laboratory 
parameters of inflammation (plasma IL6, leptin, CRP), oxidative stress (MDA, oxLDLs), 
and sRAGE. Identify the spectrum of protein species that are modified by AGEs, and the 
changes in levels of these modified proteins to treatment. 
3 SUBJECT SELECTION 
 Inclusion Criteria 
1. Confirmation of adenocarcinoma of the prostate that is documented by one of the 
following:  pathology report or clinic note with documented history of prostate cancer.  
2. Subjects must be receiving ADT with a GnRH agonist or antagonist, with or without an 
anti-androgen, with a current testosterone level documented to be <50ng/dL at 
enrollment.  Subjects whose ADT is interrupted may enroll or continue on study as long 
as the testosterone is documented to remain <50ng/dL for the entire duration of study 
participation.  Subjects who have undergone orchiectomy are also eligible. 
3. Subjects must have adequate hematologic, renal, and hepatic function at baseline, as 
follows: 
 
Hematology parameters:  ANC >1000/mcL, platelets > 100,000/mcL, Hgb 
>8.0gm/dL 
 
Renal Function:  eGFR of > 45mls/min using Cockkroft and Gault formula (see 
appendix C).   
 
Liver Function:  Total bilirubin ≤ULN, AST and ALT <1.5xULN  


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4. Able to swallow and retain oral medication 
5. ECOG performance status of 0 – 2 
6. Ability to sign written informed consent 
7. Testosterone level <50ng/dL 
 
Exclusion Criteria 
1. Known allergy to grapes or grape seed 
2. History of receiving more than 2 classes of ADT. 
3. Prior cytotoxic chemotherapy for metastatic prostate cancer; prior treatment with 
genomically-targeted agents, or Provenge is allowed.     
 Study Registration  
The SIS Unit will provide patient registration services for this study.  The SIS unit will conduct a 
patient eligibility audit review of all redacted eligibility source documents prior to patient 
registration.  These procedures are outlined in the study’s Operations Manual.  After obtaining 
signed informed consent and completion of required baseline assessments, eligible subjects will 
be registered.  A unique subject number will be assigned to each patient.  The SIS Unit will issue 
a patient registration confirmation email to the enrolling study team at the time of registration.  
This confirmation will include the patient’s study ID number.  Patient registrations may occur 
between 8AM and 5PM EST, Monday through Friday.   
4 
DRUG ADMINISTRATION 
During the course of the study, subjects will continue to receive ADT therapy per subject’s 
primary oncologist.  Changes to ADT administration will be made at the discretion of the primary 
oncologist.   
 
Study drug capsules may be taken with or without food.  Capsules lost through vomiting will not 
be made up. 
 
  Arm 1:  OPC only.   
Subjects will take OPC at the same time each morning and evening, approximately 12 hours 
apart from day 1 to day 85 (12 weeks).   
 
Agent 
Duration 
Administration 
OPC 
Weeks 1-12 
500 mg  PO BID 
 
   Medication Compliance Assessment.   
Patients will be required to track daily doses of study drugs by maintaining a daily medication 
diary.   
   Dose Modifications.   
There will be no reduction or escalation of OPC dose.  The patient will either take 500mg BID or 
go off study.  Interruption of dosing for more than 14 consecutive days will result in the patient 
being taken off study. 
 


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       Discontinuation of Therapy 
Participation in this study should be discontinued for any of the following reasons: 
 
 
Change in anti-cancer therapy 
 
Procedures requiring general anesthesia.  
 
Development of any medical condition that, in the opinion of the treating physician, 
requires discontinuation of the study intervention 
 
Withdrawal of consent by the subject 
 
Evidence of allergic reaction to any component of the treatment regimen 
 
Any grade 3-4 hematologic or non-hematologic toxicity (other than diarrhea) that does not 
resolve to grade 1 or less in 14 days of treatment interruption.   
 
Interruption of study drug for more than 14 consecutive days.   
 
Restricted Therapies During Study Therapy  
 
None 
 Supportive Care during Therapy 
It is unlikely that specific supportive care interventions will be needed for the study interventions.  
General supportive care for the subjects will be at the discretion of the treating physician, except 
as limited as described in Section 4.2 Drug Administration. 
5 SCHEDULE OF INTERVENTIONS AND ASSESSMENTS 
 General Considerations 
 
Informed consent must be signed prior to any study-specific assessments being done 
 
Screening assessments may be done up to 28 days prior to registration.  Screening 
assessments completed within 28 days of day 1 do not have to be repeated. 
 
Day 85 or End of Study Assessments may be done +/- 7 days, but all efforts should be 
made to complete this visit within 24 hours of last dose of study drug 
 
All research blood samples must be collected while the subject is fasting. 
 Assessments and Procedures 
The following clinical assessments are made at the times designated in the study calendar. 
 
History and physical examination to review patient medical history, medication list, 
overall health and any side effects they may be experiencing.   
 
CBCD 
 
Fasting CMP (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
albumin, alkaline phosphatase, AST, ALT, calcium).  The CMP to confirm eligibility 
does not need to be fasting, but a fasting CMP does need to be collected prior to day 
1 drug administration. 
 
PSA, testosterone, A1C, and BMI 
 
While on study, documented testosterone level must be maintained during treatment <50ng/dL 
 Disease assessment 
Disease response will be obtained by the assessment of PSA at enrollment and at the time the 
patient comes off study.  Imaging studies will be done if clinically indicated and/or at the 
discretion of the subject’s primary oncologist. 


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 Correlative Research  
After consent and prior to drug administration on day 1 and at day 85 (or end of study) the 
following research procedures will be completed: 
 
 
Quality of Life Questionnaires (FACT-P, AUA). 
     
 
Fasting research blood will be taken to participating research labs for analysis of the 
correlative studies to look at AGE levels, CRP, insulin levels and other biomarkers.   
 
 Research samples for correlative studies will be linked using the study ID issued at 
registration.  
  
 
Food intake assessment using the NIH “Eating at America’s Table Study Quick Food 
Scan” and the NCI “Quick Food Scan.”   
 Schedule of Assessments 
See Appendix A.   
 
6 
STUDY DRUG INFORMATION 
 
There are no clinical studies describing interactions between commonly used prostate cancer 
therapy and OPC.    A search of the drug.com database for interactions reveals no citations.   
    Oligomeric Procyanidin Complex (OPC) 
6.1.1 Agent Description.  OPC is a form of plant-derived polyphenols. OPC may be also called 
oligomeric flavanols. The three richest OPC sources are grape seed, pine bark and red 
wine. Grape seeds contain lipid, protein, carbohydrates, and 5-8% polyphenols depending 
on the variety. Polyphenols include gallic acid, the monomeric flavan-3-ols catechin, 
epicatechin, gallocatechin, epigallocatechin, and epicatechin 3-O-gallate, and dimers, 
trimers, or higher order polymers of these monomers.  
Grape seeds and skins are obtained as by-products of wine production.  Grape seeds and 
skins are ground, then extracted with either hot water or a water:ethanol mixture, followed 
by spray drying to produce GSE.  GSEs typically contain 80% or more OPCs, with smaller 
amounts of procyanidin monomers and their gallic acid esters.  In this protocol, a 
characterized and standardized GSE will be used as a source of OPC for patient treatment.  
This material, manufactured by Polyphenolics Inc., as MegaNatural® Gold Grape Seed 
Extract, has been described extensively in patents and used in human clinical trials. 
6.1.2 Pharmacology.   In vitro studies have shown GSE or the more-purified OPC to have 
anticancer effects (see (58-61) for recent reviews) and synergistic effects with 
doxorubicin (59) in inhibiting cancer cell growth and chemotherapy drug cardiotoxicity.  
GSE was found to down-regulate the NF-kB and MAPK pathways, along with related 
downstream pathways such as cyclin D1, iNOS, and COX also linked to inflammation 
(Fig. 1). Procyanidins found in GSE also inhibit xanthine oxidase activity and non-
competitively inhibit the proteolytic enzymes collagenase and elastase and the 
glycosidases hyaluronidase and beta-glucuronidase.  
 


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Fig.1: Molecular targets of proanthocyanidins in prevention or therapy of 
cancers. (66) 
 
Multiple biologic effects have been ascribed to OPCs, as a result of their potent antioxidant 
effects.  The phenotypes potentially resulting from OPC administration to animals include 
altered capillary permeability, inhibition of cardiotoxicity from anthracyclines, improved 
glucose tolerance, prevention of weight gain, and atherosclerosis. In some cases these 
phenotypes were accompanied by a reduction in levels of proinflammatory cytokines such 
as TNF and IL-6.  Small human trials have shown possible efficacy in decreasing LDL 
and increasing total serum antioxidant activity. Additionally, topical application of GSE has 
been shown to accelerate wound contraction and closure. Orally administered GSE was 
not effective for reducing breast induration following radiotherapy in patients with breast 
cancer.  These   protective effects theoretically come from its ability to modulate anti-
apoptotic genes and modify molecular targets such as DNA damage and repair, lipid 
peroxidation and intracellular calcium homeostasis. 
The bioavailability of OPCs derived from GSE or other sources is variable and 
controversial. Higher molecular weight (polymeric) polyphenols tend to be very poorly 
bioavailable. Thus, preparations skewed toward lower molecular weight compositions are 
likely to be more efficacious.  A GSE used in previous studies has been molecularly 
profiled by LC-MS analysis, and shown to consist of catechin and epicatechin monomers 
(15%); epicatechin dimmers, trimers, tetramers and their gallates (80%); and higher-order 
polymers and their gallic acid esters (5%).   
Procyanidin multimers are cleaved in the gut and absorbed primarily as catechin and 
epicatechin monomers.  The detection of proanthocyanidin dimers B1 and B2 in human 
plasma was reported in 2 studies. The absorption of these dimers was ~100-fold lower 
than that of the monomeric flavanols. However, these compounds were found to have 
direct effects on the intestinal mucosa and protect it against oxidative stress or the actions 
of carcinogens.  70% of GSE is eliminated within the first 24 hours, most through the urine 
and feces although some through the bile.  
6.1.3 Adverse reactions and Toxicology.  GSE side effects have not been reported in the 
medical literature, but very few human studies have been done. In one study normal 
volunteers were given the particular GSE preparation proposed for this study at 100 mg 
three times a day orally for 6 months, no major side effects were reported (62).  A similar 
dose was used in a study of radiation-induced skin toxicity in breast cancer patients (63).  
According to a GSE summary document published by the U.S. Department of Health and 


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Human Services and National center for Complementary and Alternative Medicine, Grape 
Seed Extract side effects may include dry, itchy scalp, dizziness, headache, high blood 
pressure, hives, indigestion and nausea. 
GSE inhibits CYP3A4 and can affect the intracellular concentration of drugs metabolized 
by this enzyme. Due to its anticoagulant (antiplatelet) effects, GSE could possibly enhance 
the activity of warfarin. GSE modulates UGT enzymes in vitro and can increase the side 
effects of drugs metabolized by them. 
6.1.4 Sources.  We will use MegaNatural Gold® brand of OPC manufactured by Polyphenolics, 
Inc.  This is incorporated into capsules by Swanson Health Products (Fargo, ND) as 
“Characterized Grape Seed Extract”, 500mg (product SWH093).  Capsules will contain 
500mg of OPC.  MegaNatural Gold® brand of OPC has been extensively characterized 
in terms of the quantity of monomers, oligomers, and polymers of catechins and 
epicatechins, and is on the FDA’s GRASlist.  The dose of OPC has been shown to be safe 
from an unpublished Phase I study conducted at HCC/MUSC (M. Lilly, unpublished, 2015).  
The MTD was more than 3000mg daily.  MUSC IDS will supply OPC capsules to subjects 
at MUSC.  
7 ADVERSE EVENTS 
 Definitions 
 
Adverse Events (AE).  An AE is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and that does not necessarily 
have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the study drugs, whether or not is it causally related.  During clinical 
trials, adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more adverse events.) 
 
Serious Adverse Event (SAE).  An SAE is any untoward medical occurrence that at any dose:   
 
results in death,  
 
is life-threatening (defined as an event in which the patient was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe),  
 
requires inpatient hospitalization or causes prolongation of existing hospitalization,  
 
results in persistent or significant disability/incapacity,  
 
is a congenital anomaly/birth defect,  
 
results in the development of drug dependency or drug abuse,  
 
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the patient or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above.)  Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.  
 
Overdoses.  An overdose is defined as the accidental or intentional ingestion of any dose of a 
product that is considered both excessive and medically important.  Overdoses should be 
following the same reporting requirements as SAEs. 


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Reporting of SAEs 
Following the subject’s registration, all SAEs should be collected and reported, including those 
thought to be associated with clinical trial procedures. SAE terminology and severity grading will 
be based on CTCAEv4.  The following categories and definitions of causal relationship to study 
drug should be used: 
 
Definitely related: 
An adverse event occurring in a plausible time relationship to drug 
administration, and which cannot be explained by concurrent 
disease or other drugs or chemicals.  The response to withdrawal 
of the drug should be clinically plausible.  The event must be 
definite pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary and feasible. 
 
Possibly related: 
An adverse event with a reasonable time sequence to 
administration of the drug, but which could also be explained by 
concurrent disease or other drugs or chemicals.  Information on 
drug withdrawal may be lacking or unclear. 
 
Not related: 
An adverse event with a temporal relationship to drug 
administration which makes a causal relationship improbable, and 
in which other drugs, chemicals or underlying diseases provide 
plausible explanations. 
 
 
Adverse events classified as “serious” require expeditious handling and reporting to the 
coordinating center and Sponsor-Investigator.   SAEs must be reported to all of these entities 
within 24hrs of becoming aware of the event, whether or not the event is related to the study drugs 
or procedures.  If only limited information is initially available, follow-up reports are required.  The 
original SAE form must be kept on file at the study site. 
 
SAEs should be reported on the 102508 SAE eCRF via REDCap at redcap.musc.edu.  The 
coordinating center will be responsible for submission to the Sponsor-Investigator, HCC-DSMC 
and FDA as applicable.  SAEs should be reported to the site’s IRB per institutional standards.   
 
The site should receive confirmation from MUSC that the SAE report was received.  If not, please 
contact the SIS Unit immediately. 
 
Collection of complete information concerning SAEs is extremely important.  Thus, follow-up 
information which becomes available as the SAE evolves, as well as supporting documentation 
(e.g., hospital discharge summaries and autopsy reports), should be collected subsequently, if 
not available at the time of the initial report, and immediately sent using the same procedure as 
the initial SAE report. 
 
AEs should be followed to resolution or stabilization, and reported as SAEs if they become serious. 
This also applies to subjects experiencing AEs that cause interruption or discontinuation of study 
drugs, or those experiencing AEs that are present at the end of their participation in the study; 
such subjects should receive post-treatment follow-up as appropriate.  All SAEs must be collected 
which occur within 30 days of discontinuation of dosing or completion of the patient’s participation 
in the study if the last scheduled visit occurs at a later time. 


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8 DATA SAFETY MONITORING 
 Responsible Individuals and Organizations. 
The Principal Investigator will be responsible for monitoring the safety and efficacy of the trial, 
executing the DSM plan, and complying with all reporting requirements. This will be accomplished 
under the oversight of the HCC DSMC.    
 
The HCC DSMC is responsible for monitoring data quality and patient safety for all interventional 
IITs at HCC. The HCC DSMC will have oversight of this protocol. The HCC DSMC will meet at a 
minimum on an annual basis to discuss the investigator-initiated trial. Also, the IIT will be audited 
by the DSMC auditor or external agency at least once a year. 
 
The DSMC reviews all IRB reportable serious adverse events, monitoring/ auditing reports, and 
protocol deviations and has the authority to recommend closure and/or suspension for trials on 
which there are safety or trial conduct issues and may submit recommendations for corrective 
actions. The DSMC recommendations for modifications to the trial (if requested) are forwarded to 
the principal investigator. The principal investigator is notified of this recommendation in order 
that he/she may alert all investigators involved in the trial with regard to the potential action.  At 
this time the principal investigators may submit to the DSMC additional information that could 
affect the Committee's decision.  
 
All IRB reportable serious adverse events, monitoring/ auditing reports will be reviewed by the 
HCC DSMC for review during the DSMC monthly meetings. The SIS Unit will forward the event 
report to the HCC DSMC so that the information can be reviewed at the next available DSMB 
meeting. During the DSMB review, the DSMB can make recommendations for any further study 
action. The SIS Unit will maintain a copy of the DSMB approval letters for each event review within 
this study’s central file. 
   Data Collection 
Electronic CRF’s will be provided for the recording of data and reporting that requires expedited 
review, such as SAE submissions.  All data should be substantiated by clinical source 
documents organized within a patient research record. ICH Good Clinical Practices are to be 
followed.  Data submission guidelines are outlined in the 102508 Operations Manual. 
 
Electronic data for on study and follow-up patient data is submitted via the electronic system 
called REDCap.  REDCap is managed from MUSC as a consortium partner under their CTSA. 
REDCap CRF is a secure, Web-based application designed to capture and manage research 
study data. 
 
The system has been reviewed for 21CFR Part 11 compliance and has been deemed “21CFR 
11 Capable.” Users of the REDCap system are limited to members of the IRB approved 
research team who are delegated data management responsibilities, typically the study 
coordinator and data manager.  
9 STATISTICAL METHODS AND POWER ANALYSIS 
This is a non-randomized single arm Phase II study enrolling 20 patients. Patients will be 
considered evaluable for the primary objective if they have both a baseline and 12 week 
measure of AGEs. Patients who drop out of the study for any reason before the week 12 visit 
will be replaced. All patients who receive at least one dose of study treatments will be 
considered evaluable for toxicity.  
 


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    Primary endpoint:   
The primary endpoint will be a binary indicator of a 30% or greater decrease in plasma AGE level 
between baseline and week 12 specimens. An active agent for further study will be one that 
induces a 30% or greater decrease in total AGE levels in at least 50% of treated subjects.  Total 
AGEs, CML-AGEs (carboxymethyllysine (CML)), and the AGE precursor methylglyoxyl (MG) will 
be measured using a 96-well competitive ELISA (Cell Biolabs).  
 Secondary endpoints:   
Secondary clinical endpoints will include a description of the toxicity profile of the test agent in 
prostate cancer patients, and recording changes in BMI, fasting glucose, insulin resistance 
(HOMA-IR), anthropomorphic measurements as well as testosterone and PSA levels. Changes 
in the analytes will be assessed with respect to age (in years), duration of ADT, extent of cancer, 
personal or family history of diabetes mellitus, race, and BMI.    
 
 Statistical analysis and sample size justification for Primary Objective 
The primary endpoint will be a binary indicator of a 30% or greater decrease in plasma age level 
between baseline and week 12 specimens. With a sample size of 20 patients, we can estimate 
the percentage of patients with a 30% or greater decrease in AGE levels based on a 90% 
confidence interval with a half-width of no greater than 0.19 (e.g., if the observed proportion is 
0.20 or 0.50, then the 90% CI would (0.05, 0.35) or (0.31,0.69), respectively). If at least 8 of 20 
subjects in a cohort achieve this degree of AGE reduction we will conclude that the agent has 
interesting activity for AGE suppression based on the lower limit of the 90% confidence interval 
exceeding 0.20.  This analysis assumes that an agent in which only 20% of patients demonstrate 
30% or greater decrease in plasma AGE would not be sufficiently active for further study. An exact 
binomial test will be performed based on a null hypothesized true proportion of 0.20 (i.e., only 
20% of patients have a 30% or greater reduction in AGE levels).  With an alternative of 0.50 and 
a sample size of 20 patients, assuming a one-sided test with a significance level of 0.05, the 
power to detect this difference is 0.87. 
 Statistical analyses for Secondary Objectives 
Toxicities will be tabulated per arm by type and grade, and the proportion of patients with grade 
3 or grade 4 toxicities, or an SAE will be estimated with a 90% confidence interval. Changes in 
continuous secondary endpoints will be graphically displayed and summarized per treatment arm 
with summary statistics.  Associations between AGE level changes and other clinical and 
demographic characteristics and laboratory parameters will be explored using graphical displays 
(e.g. scatterplots, boxplots) and evaluated using linear regression with change in AGE as the 
outcome, and clinical/demographic characteristic as the independent variable. 


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REFERENCES 
(1) Reams RR, Agrawal D, Davis MB, Yoder S, Odedina FT, Kumar N, et al. Microarray 
comparison of prostate tumor gene expression in African-American and Caucasian American 
males: a pilot project study. Infect Agent Cancer 2009 Feb 10;4 Suppl 1:S3-9378-4-S1-S3.  
 
(2) Kinseth MA, Jia Z, Rahmatpanah F, Sawyers A, Sutton M, Wang-Rodriguez J, et al. 
Expression differences between African American and Caucasian prostate cancer tissue 
reveals that stroma is the site of aggressive changes. Int J Cancer 2014 Jan 1;134(1):81-91.  
 
(3) Martin DN, Starks AM, Ambs S. Biological determinants of health disparities in prostate 
cancer. Curr Opin Oncol 2013 May;25(3):235-241.  
 
(4) Foster D, Spruill L, Walter KR, Nogueira LM, Fedarovich H, Turner RY, et al. AGE 
metabolites: a biomarker linked to cancer disparity? Cancer Epidemiol Biomarkers Prev 2014 
Oct;23(10):2186-2191.  
 
(5) Parkin DM. 9. Cancers attributable to inadequate physical exercise in the UK in 2010. Br J 
Cancer 2011 Dec 6;105 Suppl 2:S38-41.  
 
(6) Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC. Diet, nutrition and the 
prevention of cancer. Public Health Nutr 2004 Feb;7(1A):187-200.  
 
(7) Sauaia A, Byers T. Obesity in US Children in Adults. The Journal of the American Medical 
Association, JAMA 2012;307(20):2145-2146.  
 
(8) Zenk SN, Lachance LL, Schulz AJ, Mentz G, Kannan S, Ridella W. Neighborhood retail food 
environment and fruit and vegetable intake in a multiethnic urban population. Am J Health 
Promot 2009 Mar-Apr;23(4):255-264.  
 
(9) Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, et al. Advanced glycation end 
products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc 2010 
Jun;110(6):911-16.e12.  
 
(10) Kellow NJ, Savige GS. Dietary advanced glycation end-product restriction for the 
attenuation of insulin resistance, oxidative stress and endothelial dysfunction: a systematic 
review. Eur J Clin Nutr 2013 Mar;67(3):239-248.  
 
(11) Ekelund U, Ward HA, Norat T, Luan J, May AM, Weiderpass E, et al. Physical activity and 
all-cause mortality across levels of overall and abdominal adiposity in European men and 
women: the European Prospective Investigation into Cancer and Nutrition Study (EPIC). Am J 
Clin Nutr 2015 Mar;101(3):613-621.  
 
(12) Boor P, Celec P, Behuliak M, Grancic P, Kebis A, Kukan M, et al. Regular moderate 
exercise reduces advanced glycation and ameliorates early diabetic nephropathy in obese 
Zucker rats. Metabolism 2009 Nov;58(11):1669-1677.  
 
(13) Wright KJ, Thomas MM, Betik AC, Belke D, Hepple RT. Exercise training initiated in late 
middle age attenuates cardiac fibrosis and advanced glycation end-product accumulation in 
senescent rats. Exp Gerontol 2014 Feb;50:9-18.  
 
(14) Yoshikawa T, Miyazaki A, Fujimoto S. Decrease in serum levels of advanced glycation end-
products by short-term lifestyle modification in non-diabetic middle-aged females. Med Sci Monit 
2009 Jun;15(6):PH65-73.  
 


NCT # NCT02946996 
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20 
 
(15) Tan KC, Chow WS, Tam S, Bucala R, Betteridge J. Association between acute-phase 
reactants and advanced glycation end products in type 2 diabetes. Diabetes Care 2004 
Jan;27(1):223-228.  
 
(16) Chandler PD, Scott JB, Drake BF, Ng K, Manson JE, Rifai N, et al. Impact of vitamin D 
supplementation on inflammatory markers in African Americans: results of a four-arm, 
randomized, placebo-controlled trial. Cancer Prev Res (Phila) 2014 Feb;7(2):218-225.  
 
(17) Morris AA, Zhao L, Patel RS, Jones DP, Ahmed Y, Stoyanova N, et al. Differences in 
systemic oxidative stress based on race and the metabolic syndrome: the Morehouse and 
Emory Team up to Eliminate Health Disparities (META-Health) study. Metab Syndr Relat Disord 
2012 Aug;10(4):252-259.  
 
(18) Feairheller DL, Park JY, Sturgeon KM, Williamson ST, Diaz KM, Veerabhadrappa P, et al. 
Racial differences in oxidative stress and inflammation: in vitro and in vivo. Clin Transl Sci 2011 
Feb;4(1):32-37.  
 
(19) Riehl A, Nemeth J, Angel P, Hess J. The receptor RAGE: Bridging inflammation and 
cancer. Cell Commun Signal 2009 May 8;7:12-811X-7-12.  
 
(20) Rojas A, Mercadal E, Figueroa H, Morales MA. Advanced Glycation and ROS: a link 
between diabetes and heart failure. Curr Vasc Pharmacol 2008 Jan;6(1):44-51.  
 
(21) Guimaraes EL, Empsen C, Geerts A, van Grunsven LA. Advanced glycation end products 
induce production of reactive oxygen species via the activation of NADPH oxidase in murine 
hepatic stellate cells. J Hepatol 2010 Mar;52(3):389-397.  
 
(22) Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the 
seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009 Jul;30(7):1073-
1081.  
 
(23) Sharaf H, Matou-Nasri S, Wang Q, Rabhan Z, Al-Eidi H, Al Abdulrahman A, et al. 
Advanced glycation endproducts increase proliferation, migration and invasion of the breast 
cancer cell line MDA-MB-231. Biochim Biophys Acta 2015 Mar;1852(3):429-441.  
 
(24) Rodriguez-Teja M, Gronau JH, Breit C, Zhang YZ, Minamidate A, Caley MP, et al. AGE-
modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness 
and decrease prostate cancer survival. J Pathol 2015 Mar;235(4):581-592.  
 
(25) Jiao L, Stolzenberg-Solomon R, Zimmerman TP, Duan Z, Chen L, Kahle L, et al. Dietary 
consumption of advanced glycation end products and pancreatic cancer in the prospective NIH-
AARP Diet and Health Study. Am J Clin Nutr 2015 Jan;101(1):126-134.  
 
(26) Ishiguro H, Nakaigawa N, Miyoshi Y, Fujinami K, Kubota Y, Uemura H. Receptor for 
advanced glycation end products (RAGE) and its ligand, amphoterin are overexpressed and 
associated with prostate cancer development. Prostate 2005 Jun 15;64(1):92-100.  
(27) Rose AE, Satagopan JM, Oddoux C, Zhou Q, Xu R, Olshen AB, et al. Copy number and 
gene expression differences between African American and Caucasian American prostate 
cancer. J Transl Med 2010 Jul 22;8:70-5876-8-70.  
 
(28) Powell IJ, Dyson G, Land S, Ruterbusch J, Bock CH, Lenk S, et al. Genes associated with 
prostate cancer are differentially expressed in African American and European American men. 
Cancer Epidemiol Biomarkers Prev 2013 May;22(5):891-897.  
 


NCT # NCT02946996 
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(29) Park NJ, Kang DH. Inflammatory cytokine levels and breast cancer risk factors: racial 
differences of healthy Caucasian and African American women. Oncol Nurs Forum 2013 
Sep;40(5):490-500.  
 
(30) Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate 
cancer. J Urol 2013 Jan;189(1 Suppl):S34-42; discussion S43-4.  
 
(31) Lage MJ, Barber BL, Markus RA. Association between androgen-deprivation therapy and 
incidence of diabetes among males with prostate cancer. Urology 2007 Dec;70(6):1104-1108.  
 
(32) Derweesh IH, Diblasio CJ, Kincade MC, Malcolm JB, Lamar KD, Patterson AL, et al. Risk 
of new-onset diabetes mellitus and worsening glycaemic variables for established diabetes in 
men undergoing androgen-deprivation therapy for prostate cancer. BJU Int 2007 
Nov;100(5):1060-1065.  
 
(33) Kintzel PE, Chase SL, Schultz LM, O'Rourke TJ. Increased risk of metabolic syndrome, 
diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for 
prostate cancer. Pharmacotherapy 2008 Dec;28(12):1511-1522.  
 
(34) Smith MR, Lee H, Fallon MA, Nathan DM. Adipocytokines, obesity, and insulin resistance 
during combined androgen blockade for prostate cancer. Urology 2008 Feb;71(2):318-322.  
 
(35) Flanagan J, Gray PK, Hahn N, Hayes J, Myers LJ, Carney-Doebbeling C, et al. Presence 
of the metabolic syndrome is associated with shorter time to castration-resistant prostate 
cancer. Ann Oncol 2011 Apr;22(4):801-807.  
 
(36) Bhindi B, Kulkarni GS, Finelli A, Alibhai SM, Hamilton RJ, Toi A, et al. Obesity is associated 
with risk of progression for low-risk prostate cancers managed expectantly. Eur Urol 2014 
Nov;66(5):841-848.  
 
(37) Chalfin HJ, Lee SB, Jeong BC, Freedland SJ, Alai H, Feng Z, et al. Obesity and long-term 
survival after radical prostatectomy. J Urol 2014 Oct;192(4):1100-1104.  
 
(38) Chandra RA, Chen MH, Zhang D, Loffredo M, D'Amico AV. Evidence suggesting that 
obesity prevention measures may improve prostate cancer outcomes using data from a 
prospective randomized trial. Prostate Cancer 2014;2014:478983.  
 
(39) Wang LS, Murphy CT, Ruth K, Zaorsky NG, Smaldone MC, Sobczak ML, et al. Impact of 
obesity on outcomes after definitive dose-escalated intensity-modulated radiotherapy for 
localized prostate cancer. Cancer 2015 Sep 1;121(17):3010-3017.  
 
(40) Keto CJ, Aronson WJ, Terris MK, Presti JC, Kane CJ, Amling CL, et al. Obesity is 
associated with castration-resistant disease and metastasis in men treated with androgen 
deprivation therapy after radical prostatectomy: results from the SEARCH database. BJU Int 
2012 Aug;110(4):492-498.  
 
(41) Shevach J, Gallagher EJ, Kochukoshy T, Gresia V, Brar M, Galsky MD, et al. Concurrent 
Diabetes Mellitus may Negatively Influence Clinical Progression and Response to Androgen 
Deprivation Therapy in Patients with Advanced Prostate Cancer. Front Oncol 2015 Jun 
15;5:129.  
 
(42) Xu H, Zhang LM, Liu J, Ding GX, Ding Q, Jiang HW. The association between overall 
survival of prostate cancer patients and hypertension, hyperglycemia, and overweight in 
Southern China: a prospective cohort study. J Cancer Res Clin Oncol 2013 Jun;139(6):943-951.  


NCT # NCT02946996 
CTO # 102508 
Version Date: 05/08/2023 
 
22 
 
 
(43) Cho SJ, Roman G, Yeboah F, Konishi Y. The road to advanced glycation end products: a 
mechanistic perspective. Curr Med Chem 2007;14(15):1653-1671.  
 
(44) Tanaka Y, Uchino H, Shimizu T, Yoshii H, Niwa M, Ohmura C, et al. Effect of metformin on 
advanced glycation endproduct formation and peripheral nerve function in streptozotocin-
induced diabetic rats. Eur J Pharmacol 1999 Jul 2;376(1-2):17-22.  
 
(45) Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bartschi D, et al. 
Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 
trial (SAKK 08/09). Eur Urol 2014 Sep;66(3):468-474.  
 
(46) Xu L, Li B, Cheng M, Zhang W, Pan J, Zhang C, et al. Oral administration of grape seed 
proanthocyanidin extracts downregulate RAGE dependant nuclear factor- kappa BP65 
expression in the hippocampus of streptozotocin induced diabetic rats. Exp Clin Endocrinol 
Diabetes 2008 Apr;116(4):215-224.  
 
(47) Lu M, Xu L, Li B, Zhang W, Zhang C, Feng H, et al. Protective effects of grape seed 
proanthocyanidin extracts on cerebral cortex of streptozotocin-induced diabetic rats through 
modulating AGEs/RAGE/NF-kappaB pathway. J Nutr Sci Vitaminol (Tokyo) 2010;56(2):87-97.  
 
(48) Li X, Xu L, Gao H, Li B, Cheng M. Effects of grape seed proanthocyanidins extracts on 
AGEs and expression of bone morphogenetic protein-7 in diabetic rats. J Nephrol 2008 Sep-
Oct;21(5):722-733.  
 
(49) Li X, Xiao Y, Gao H, Li B, Xu L, Cheng M, et al. Grape seed proanthocyanidins ameliorate 
diabetic nephropathy via modulation of levels of AGE, RAGE and CTGF. Nephron Exp Nephrol 
2009;111(2):e31-41.  
 
(50) Cui XP, Li BY, Gao HQ, Wei N, Wang WL, Lu M. Effects of grape seed proanthocyanidin 
extracts on peripheral nerves in streptozocin-induced diabetic rats. J Nutr Sci Vitaminol (Tokyo) 
2008 Aug;54(4):321-328.  
 
(51) Cai Q, Li BY, Gao HQ, Zhang JH, Wang JF, Yu F, et al. Grape seed procyanidin b2 inhibits 
human aortic smooth muscle cell proliferation and migration induced by advanced glycation end 
products. Biosci Biotechnol Biochem 2011;75(9):1692-1697.  
 
(52) Yin W, Li B, Li X, Yu F, Cai Q, Zhang Z, et al. Anti-inflammatory effects of grape seed 
procyanidin B2 on a diabetic pancreas. Food Funct 2015 Sep;6(9):3065-3071.  
 
(53) Huang SM, Chang YH, Chao YC, Lin JA, Wu CH, Lai CY, et al. EGCG-rich green tea 
extract stimulates sRAGE secretion to inhibit S100A12-RAGE axis through ADAM10-mediated 
ectodomain shedding of extracellular RAGE in type 2 diabetes. Mol Nutr Food Res 2013 
Dec;57(12):2264-2268.  
 
(54) Leu JG, Lin CY, Jian JH, Shih CY, Liang YJ. Epigallocatechin-3-gallate combined with 
alpha lipoic acid attenuates high glucose-induced receptor for advanced glycation end products 
(RAGE) expression in human embryonic kidney cells. An Acad Bras Cienc 2013 Apr-
Jun;85(2):745-752.  
 
(55) Lanati N, Emanuele E, Brondino N, Geroldi D. Soluble RAGE-modulating drugs: state-of-
the-art and future perspectives for targeting vascular inflammation. Curr Vasc Pharmacol 2010 
Jan;8(1):86-92.  
 


NCT # NCT02946996 
CTO # 102508 
Version Date: 05/08/2023 
 
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(56) Di BB, Li HW, Li WP, Shen XH, Sun ZJ, Wu X. Pioglitazone inhibits high glucose-induced 
expression of receptor for advanced glycation end products in coronary artery smooth muscle 
cells. Mol Med Rep 2015 Apr;11(4):2601-2607.  
 
(57) Yubero-Serrano EM, Woodward M, Poretsky L, Vlassara H, Striker GE, AGE-less Study 
Group. Effects of sevelamer carbonate on advanced glycation end products and antioxidant/pro-
oxidant status in patients with diabetic kidney disease. Clin J Am Soc Nephrol 2015 May 
7;10(5):759-766.  
 
(58) Kaur M, Agarwal C, Agarwal R. Anticancer and cancer chemopreventive potential of grape 
seed extract and other grape-based products. J Nutr 2009 Sep;139(9):1806S-12S.  
(59) Olaku OO, Ojukwu MO, Zia FZ, White JD. The Role of Grape Seed Extract in the 
Treatment of Chemo/Radiotherapy Induced Toxicity: A Systematic Review of Preclinical 
Studies. Nutr Cancer 2015;67(5):730-740.  
 
(60) Bagchi D, Swaroop A, Preuss HG, Bagchi M. Free radical scavenging, antioxidant and 
cancer chemoprevention by grape seed proanthocyanidin: an overview. Mutat Res 2014 
Oct;768:69-73.  
 
(61) Nandakumar V, Singh T, Katiyar SK. Multi-targeted prevention and therapy of cancer by 
proanthocyanidins. Cancer Lett 2008 Oct 8;269(2):378-387.  
 
(62) Vinson JA, Proch J, Bose P. MegaNatural((R)) Gold Grapeseed Extract: In Vitro 
Antioxidant and In Vivo Human Supplementation Studies. J Med Food 2001 Spring;4(1):17-26.  
 
(63) Brooker S, Martin S, Pearson A, Bagchi D, Earl J, Gothard L, et al. Double-blind, placebo-
controlled, randomised phase II trial of IH636 grape seed proanthocyanidin extract (GSPE) in 
patients with radiation-induced breast induration. Radiother Oncol 2006 Apr;79(1):45-51.  
 
(64) Heckman-Stoddard BM, Gandini S, Puntoni M, Dunn BK, DeCensi A, Szabo E. 
Repurposing old drugs to chemoprevention: the case of metformin. Semin Oncol 2016 
Feb;43(1):123-133.  
 
(65) Gong J, Kelekar G, Shen J, Shen J, Kaur S, Mita M. The expanding role of metformin in 
cancer: an update on antitumor mechanisms and clinical development. Target Oncol 2016 Feb 
11.  
 
(66) Provinciali N, Lazzeroni M, Cazzaniga M, Gorlero F, Dunn BK, DeCensi A. Metformin: risk-
benefit profile with a focus on cancer. Expert Opin Drug Saf 2015 Oct;14(10):1573-1585.  
 


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APPENDIX A.  SCHEDULE OF PROCEDURES AND ASSESSMENTS 
 
Timepoint 
Procedure
Screeninga
Day 1a
Day 85/                
End of studyc
Study Procedures 
H & P
X 
X 
X 
AE assessment
X 
CBCD
X 
X 
X 
CMP (fasting)a
X 
X 
X 
PSA
X 
Xf 
X 
Testosterone
X 
X 
X 
BMI
X 
X 
X 
RX 
OPC 
X-------------------------------X
Drug diary reviewd
 
 
X 
Correlative 
Research 
Informed consent
X 
FACT-P Quality of Life 
Questionnaires
Xe 
X 
Research Blood (fasting)b
Xe 
X 
a. Screening assessments may be used for the Day 1 assessments if they were completed within 28 days of day 1. The CMP 
used for eligibility confirmation does not have to be fasting, but a fasting CMP will need to be collected prior to day 1 
drug administration.  Fasting is defined as nothing containing calories since the previous midnight. 
b. Recommended tubes:  1x7mL sodium heparin, 1x7mL lithium heparin, 1x7mL EDTA, 1x7mL serum (Clot).  Fasting 
research blood will be taken to participating research labs for analysis for of the for correlative studies to look at AGE 
levels, CRP, insulin levels and other biomarkers. 
c. Day 85 visit may be done +/- 7 days.  If the subject goes off-study less than 2 weeks after start of dosing, “end of study” 
labs and questionnaires will not be done. 
d. The drug diary will be given to each subject on day 1 to be completed during the study.  The subject should return the 
drug diary and pill bottle at the end of study visit to review study compliance.   
e. Research blood and FACT-P QOL Questionnaires may be done at any point after consent and prior to day 1 drug 
administration.  
f. If clinically indicated 
   
 
  
 
 


NCT # NCT02946996 
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Version Date: 05/08/2023 
 
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APPENDIX B:  CALCULATION OF CREATININE CLEARANCE 
 
Estimation of creatinine clearance using Cockroft and Gault method:  
 
ClCR for males (mL/min) = 
 
[140 - age (years)] X [weight (kg)] 
 
 
 
                                    (72) X [Serum creatinine (mg/dL)] 
 
For SI units: 
ClCR for males (mL/min) =  
 
[140 - age (years)] X [weight(kg)] X (1.23) 
 
 
 
 
                                  [Serum creatinine (µmol/L)]