Phase 1b/2 Study of Chitosan for Pharmacologic Manipulation of AGE (Advanced Glycation Endproducts) Levels in Prostate Cancer Patients
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: Medical University of South Carolina

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Phase 1b/2 study of Chitosan for Pharmacologic Manipulation of AGE (Advanced 
Glycation Endproducts) Levels in Prostate Cancer Patients  
 
 
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 
 
Chris Brunson, MD 
Medical Director 
Mabry Cancer Center 
1161 Cook Road 
Orangeburg, SC 29115 
(803) 395-4600 
 
 
 
 

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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:  843-792-0275 
 
 
Email:  gibsond@musc.edu 
 
 
 
Version History:    
Version 6.1 dated September 9, 2020 
Version 5.0 dated March 13, 2020 
Version 4.0 dated December 13, 2019 
Version 3.0 dated July 30, 2019 
Version 2.1 dated April 22, 2019 
Version 1.6 dated November 27, 2018 
Version 1.5 dated October 8, 2018 
Version 1.4 dated September 18, 2018 
Version 1.3 dated August 31, 2018  
 

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Table of Contents 
Definition of Terms Used ................................................................................................................5 
1 
Background ...............................................................................................................................6 
1.1 
AGEs are Lifestyle-Associated Mediators of Degenerative Diseases. ............................6 
1.2 
AGE Accumulation Is Inherently Linked to Lifestyle .....................................................6 
1.3 
AGE Accumulation, RAGE, and Stress Response ..........................................................8 
1.4 
AGEs and Cancer .............................................................................................................8 
1.5 
Prostate Cancer and the Hypogonadal Metabolic Syndrome:  Role for AGEs? ............10 
1.6 
Pharmacologic Manipulation of AGE levels .................................................................11 
2 
Study Objectives .....................................................................................................................15 
2.1 
Study Overview .............................................................................................................15 
2.2 
Primary Objective ..........................................................................................................15 
2.3 
Secondary Objectives.....................................................................................................15 
3 
Subject Selection ....................................................................................................................15 
3.1 
Inclusion Criteria ...........................................................................................................15 
3.2 
Exclusion Criteria ..........................................................................................................16 
3.3 
Study Registration ..........................................................................................................16 
4 
Treatment Administration .......................................................................................................16 
4.1 
Androgen deprivation therapy .......................................................................................16 
4.2 
Chitosan administration .................................................................................................17 
Table 2.  Dose escalation cohorts ....................................................................................... 17 
4.3 
Medication Compliance Assessment .............................................................................17 
4.4 
Discontinuation of Therapy ...........................................................................................17 
4.5 
Restricted Therapies During Study Therapy ..................................................................17 
4.6 
Supportive Care during Therapy ....................................................................................19 
5 
Schedule of Interventions and Assessments ...........................................................................19 
5.1 
General Considerations ..................................................................................................19 
5.2 
Assessments and Procedures..........................................................................................19 
5.3 
Subject Recruitment .......................................................................................................20 
5.4 
Informed Consent Process .............................................................................................20 
5.5 
Disease Assessment .......................................................................................................20 
5.6 
Toxicity Assessment ......................................................................................................21 
5.7 
Schedule of Assessments ...............................................................................................21 
5.8 
Correlative Studies .........................................................................................................21 
6 
Study Drug Information - Chitosan ........................................................................................21 
6.1 
Agent Description. .........................................................................................................21 
6.1.1 Supply....................................................................................................................... 21 
6.1.2 Storage. .................................................................................................................... 21 
6.1.3 Administration. ....................................................................................................... 21 
6.1.4 Known Potential Toxicities. ................................................................................... 22 
7 
Risks and Benefits ..................................................................................................................22 

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7.1 
Potential Risks ...............................................................................................................22 
7.2 
Protection Against Risk .................................................................................................22 
7.3 
Potential benefits of the proposed research to the subjects and others ..........................22 
7.4 
Withdrawal of subjects ..................................................................................................22 
8 
Adverse events ........................................................................................................................23 
8.1 
Definitions......................................................................................................................23 
8.2 
Reporting of SAEs .........................................................................................................23 
8.3 
Unanticipated Adverse Device Effects ..........................................................................25 
9 
Data Safety Monitoring ..........................................................................................................25 
9.1 
Responsible Individuals and Organizations. ..................................................................25 
9.2 
Data Collection ..............................................................................................................26 
9.3 
Food and Drug Administration Review .........................................................................26 
10 Statistical Methods and Power Analysis ................................................................................26 
10.1 
Escalation Design...........................................................................................................26 
10.2 
Expansion Cohort Design and Statistical Analysis. .......................................................27 
References ......................................................................................................................................28 
Appendix A.  Schedule of Procedures and Assessments ...............................................................33 
Appendix B:  FACT-P Quality of Life Questionnaire ...................................................................34 
 

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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 
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 

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SAE 
 
 
serious adverse event 
SIS  
 
 
Sponsor-Investigator Support Unit 
sRAGE  
 
soluble form of RAGE 
USP 
 
 
United States Pharmacopeia 
VCAM-1 
 
vascular cell adhesion molecule-1 
VLDL  
 
very low density lipoprotein 
 
1 
BACKGROUND 
1.1 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 

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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 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.  

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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 
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 

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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.  
 
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 

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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:  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; 

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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 (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 NFkB.  These documented features of AGE production, 

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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  AGE-binding resins.   
Sevelamer consists of polyallylamine that is crosslinked with epichlorohydrin.  In overall 
structure it is a polymer with free amino groups.  The marketed form sevelamer hydrochloride is 
a partial hydrochloride salt being present as approximately 40% amine hydrochloride and 60% 
sevelamer base.  Sevelamer is normally used to lower phosphorus levels, and is given chronically 
to patients on dialysis.  The amine groups of sevelamer become partially protonated in the 
intestine and interact with phosphate ions through ionic and hydrogen bonding.  Sevelamer has 
also been shown to bind AGEs in vitro, and to lower AGE levels in the plasma of patients with 
chronic kidney disease (44).  While having little toxicity, sevalamer is extremely expensive, with 
current wholesale costs of $1200/month. 
 
1.6.2  Chitosan as an AGE sequestering agent.   
Chitosan is a linear polysaccharide composed of randomly distributed β(1→4)-linked D-
glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is made by 
treating the chitin shells of shrimp and other crustaceans with an alkaline substance such as 
sodium hydroxide.  Chitosan can also be recovered commercially from the stems of mushrooms.  
Like sevelamer, chitosan is also a polymer decorated with free amino groups that become 
partially protonated at the intestinal pH.  It can bind phosphorus and other anions, as well as 
AGEs.  In contrast to sevelamer, chitosan is derived from food sources and is safe and 
inexpensive.  These parallels suggest that chitosan could be a clinically useful AGE-lowering 
agent. 
 
Several studies in mice and humans implicate carbonyl stress from methylgloxal (MG)-derived 
AGEs in diabetic nephropathy (45,46). Chitosan directly binds MG-derived AGEs in vitro and 
lowers serum and tissue levels of AGEs in mouse models (46).  Furthermore chitosan treatment 
reduced AGE-related nephropathy in mice, both histologically and clinically.  A small clinical 
trial of chitosan administration to chronic dialysis patients demonstrated an improvement in 
several biochemical parameters of nephropathy with the treatment (47).  However no studies to 
date have demonstrated that chitosan can reduce either serum or tissue levels of AGEs in humans 
with AGE-related diseases.  Similarly there are no clear data as to the in vivo mechanism by 
which chitosan reduces AGEs in animal models. 
 
1.6.3   Biodistribution of oral chitosan.   
The systemic absorption and distribution of chitosan following oral exposure are likely 
influenced by the molecular weight of the polymer. The effect of molecular weight on chitosan 
absorption has been evaluated in male Sprague Dawley rats (48). Oral gavage administration of 
chitosan with molecular weights of 3.8, 7.5, 13, 22, or 230kDa resulted in maximum plasma 

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chitosan concentrations (Cmax) of 20.23, 9.30, 5.86, 4.32, or less than 0.5μg/mL, respectively. 
The results of this study suggest that the absorption of chitosan from the gastrointestinal tract 
following oral exposure is inversely related to chitosan molecular weight, as there is likely low 
bioavalability associated with the higher molecular weight chitosan polymers.  
 
The biodegradation of chitosan influences absorption and distribution because both are 
dependent on molecular weight.  The biodegradation of chitosan invivo is dependent on the 
degree of deacetylation (49).   Enzymatic degradation of chitosan depends on the ability to 
hydrolyze glucosamine -glucosamine, glucosamine-N-acetyl-glucosamine and N-acetyl-
glucosamine-N-acetyl-glucosamine linkages (50).   Degradation of chitosan in vertebrates is 
thought to occur predominantly by lysozymes and bacterial .  While eight human chitinases have 
been identified with three showing enzymatic activity, their capacity to degrade chitosan has not 
been investigated (50,51).   
 
1.6.4  Toxicity of oral chitosan. 
Under the auspices of the National Toxicology Program, chronic oral dosing of chitosan (Mw 
82KD, 86% deacetylated) for 6 months, was studied in rats (52).  Serum levels of cholesterol, 
triglycerides, and phosphorous were significantly decreased in rats exposed to 9% chitosan 
(equivalent to 5.2gm/kg/day), as were serum levels of vitamin A and vitamin E; serum levels of 
1,25(OH) vitamin D were increased.   Vitamin E concentrations in the livers of exposed rats 
were significantly lower than those in control rats.  Exposure to chitosan also had digestive 
effects, including increases in fecal weight and moisture, and decreases in percent fat digested.  
There was a decrease in thymus and liver weights, along with decreased fatty tissue in the livers 
of exposed rats.  There was no effect of any dose of chitosan on longevity. 
 
Chitosan is widely regarded as being a non-toxic, biologically compatible polymer (53). It is 
approved for dietary applications in Japan, Italy and Finland (54).  In the United States it is 
widely marketed (without FDA approval) as a weight loss agent that binds fats and prevents their 
absorption (55)(56)(57).  In a study on fat chelation, 4.5 g/day chitosan (Mw and DD not noted) 
in humans was not reported toxic, although no significant reduction in fat was found (58).  
Additional, no significant effects were reported following oral administration of chitosan at up to 
6.75 g per day for 8 weeks in male and female volunteers (59).  It has been approved by the FDA 
for use in wound dressings (60).   Wound contraction and increased healing were found using 
chitosan (61). 
 
Chitosan has been extensively tested in human for indications related to obesity, glucose control, 
hypertension, renal failure, and the metabolic syndrome.  Table 1 is a partial selection of trials 
that can be found in the published literature.  These studies include 371 patients treated with oral 
chitosan, in doses up to 5,250mg daily, and for periods of up to 1 year.  These doses include the 
range of proposed dosing in our study.  A variety of benefits were claimed.  No study reported 
SAEs or significant (grade 3,4) AEs.  When reported, compliance was generally high, and in 
randomized studies, was similar between the chitosan and placebo arms.  Described AEs 

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predominately included GI complaints (constipation, bloating, full feeling, gas) but these were 
also described in the placebo arms.  Where attribution was made, constipation was described as 
“not related” to the study drug.  Three studies made no comment on chitosan toxicity.  While the 
toxicity in these studies may be unclear, it is unlikely that the chitosan intervention was highly 
toxic. (58,62-72) 
 
 
Because of the broad use of chitosan for many different studies, plus its use as a pharmacologic 
excipient and a topical agent, the FDA has had many occasions to review chitosan.  The FDA 
has not made any proscription for use of this agent.  It is freely available in every health food 
store in the country, as well as multiple on-line locations.  The manufacturer of our proposed 
chitosan preparation (Primex EHF, Iceland) reports that they have sold over 400,000,000 doses 
of chitosan in the past few years.   This broad use of chitosan, in the community and in peer-
reviewed clinical trials, gives confidence that the agent is safe. 
Table 1.  Toxicity of Chitosan in Humans  

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2 STUDY OBJECTIVES 
 
2.1 Study Overview 
The overall goal of this Phase Ib/2 study is to identify a safe dose of chitosan for pharmacologic 
reduction of AGE levels in PCa subjects. 
 
2.2 Primary Objective   
The primary objective is to determine the maximum tolerated dose (MTD) of chitosan in subjects 
with PCa on ADT.  The MTD will be defined as the dose that produces no more than 1 dose-
limiting toxicity (DLT) in 6 subjects.   
 
2.3 Secondary Objectives 
The mechanistic studies under this section are to document any systemic effects from the 
chitosan treatment, related magnitude and timing of AGE depletion to chitosan effects, and 
determine if chitosan can reduce tissue, as well as serum, AGE levels.  
• 
Identify systemic effects of chitosan on redox status (RedoxSys, serum oxidized glutathione), 
inflammation (plasma cytokines, Toll-like receptor signaling), and insulin resistance 
(HOMA-IR). 
• 
Determine if chitosan modifies bowel permeability (plasma endotoxin) and microbiome 
diversity (16s rDNA sequencing). 
• 
Correlate changes in serum AGE levels (pan-AGE, carboxymethyllysine, methylglyoxal, 
pentosidine adducts) with changes in tissue AGE levels as determine by skin autofluorescence. 
• 
Define the frequency of a > 30% reduction in total AGE levels from the pretreatment level.  
A frequency of 50% will be considered “interesting” for further study. 
 
3 SUBJECT SELECTION 
 
3.1 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 or testosterone sythesis inhibitor.  The current testosterone level must be 
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 
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• Renal Function:  eGFR of ≥ 45mls/min using Cockkroft and Gault formula  
• Liver Function:  Total bilirubin ≤ULN, AST and ALT <1.5x ULN  
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 at time of enrollment.   
8. Age 18 or older. 
9. May have had prior radiation therapy, surgery, or cryoablation for primary prostate 
cancer 
10. May have had prior cytotoxic chemotherapy for metastatic prostate cancer, prior 
treatment with genomically-targeted agents, or Provenge    
3.2 Exclusion Criteria 
1. Known allergy to chitosan or shellfish. 
2. History of receiving more than 2 classes of ADT.   
3. Chronic constipation (BM < 3x weekly), history of malabsorption or history of daily 
laxative use. 
4. Patients requiring medication administration with lunch or dinner or at a frequency of 
three or more times per day are not eligible.  
5. Current use of chitosan, sevelamer, and/or glucosamine. 
6. Patients currently on diclofenac or any of the restricted therapies listed in section 4.5 
3.3 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.  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 assigned cohort dose 
level and study ID number.  
 
4 
TREATMENT ADMINISTRATION 
4.1 Androgen deprivation therapy   
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 their discretion, but the 
testosterone level should remain <50ng/dL during the entire study..   

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4.2 Chitosan administration 
Subjects will be enrolled sequentially into four cohorts; the starting dose level is cohort 1.  These 
cohorts will take chitosan as described in Table 2.  Three patients will be enrolled into cohort 1, 
and no patients will be enrolled into the next cohort until the final patient in cohort 1 will have 
completed 28 days of treatment. 
 
Chitosan will be taken up to 30 minutes before, or during, the middle and evening meals (BID 
dosing) or the largest meal of the day (Q day dosing).  Chitosan will not be taken with breakfast, 
and the subjects should endeavor to take any chronic medicines before or with breakfast to 
minimize the chance of absorption of pharmaceuticals to chitosan.  Any pharmaceuticals should 
be taken at least 1 hour before or 2 hours after chitosan.  Any chitosan doses lost through 
vomiting will not be made up. 
 
      
Table 2.  Dose escalation cohorts 
Cohort 
Chitosan 
-1 
500mg Q day 
1 
500mg BID 
2 
1000mg BID 
3 
1500mg BID 
4 
2000mg BID 
4.3 Medication Compliance Assessment   
Patients will be required to track daily doses of study drugs by maintaining a daily medication 
diary.  The subject will be asked to bring his drug diary and pill bottle back for each clinic visit 
to assess drug compliance. 
4.4 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 in 4.5) that does not 
resolve, with drug discontinuation, to grade 1 or less in 14 days. 
4.5 Restricted Therapies During Study Therapy  
Current use of chitosan, sevelamer, and/or glucosamine. 
 
Drugs Eliminated by Biliary Excretion (defined as greater than 4% excretion in bile): 

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• Chemotherapeutic Agents 
o Irinotecan 
o Paclitaxel 
o Vincristine 
• Anti-Hyperlipidemics 
o Ezetimibe 
o Fluvastatin 
o Pravastatin 
o Rousvastatin  
o Simvastatin 
• Anti-Hypertensives  
o Ramipril 
o Spironolactone 
o Valsartan 
• Analgesics 
o Acetaminophen 
• NSAIDS 
o Diclofenac 
o Indomethacin 
• Anti-histamines  
o Desloratadine 
o Fexofenadine 
o Levocetrizine 
• Anti-diabetics 
o Rosiglitazone 
• Immunosuppressants 
o Mycophenolic acid 
• Anti-Psychotics 
o Quetiapine 
• Anti-retrovirals 
o Lopinavir 
o Ritonavir 
• Antibiotics  
o Ceftriaxone 
o Trovafloxacin 
• Others 
o Cyclobenzaprine 
o Ketoconazole 
o Montelukast 
 

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4.6 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. 
5 SCHEDULE OF INTERVENTIONS AND ASSESSMENTS 
5.1 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 +/- 3 days.   
• All research and clinical blood samples must be collected while the subject is fasting. 
5.2 Assessments and Procedures 
The following clinical assessments are made at the time subjects are screened for the trial.  Some 
of these may need to be repeated prior to day 1; see Appendix A for more details regarding the 
schedule of procedures and assessments. 
• 
A full medical history and physical examination to review patient medical history, 
medication list, overall health and any side effects they may be experiencing.  Medical 
history will include: 
o Extent of cancer to include metastatic disease 
o Concomitant medications 
o current ADT therapy 
• 
Height, weight  
• 
CBCD 
• 
CMP (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, 
alkaline phosphatase, AST, ALT, calcium) 
• 
PSA, testosterone 
• 
Research blood, urine, and stool samples as outlined (see Appendix A) 
• 
24hr food intake recall questionnaire 
• 
Quality of life questionnaires (FACT-P and AUA; see Appendices B, C) 
• 
Measurement of tissue AGE level by skin autofluorescence using the AGE Reader 
device. 
 
On day 29 of the study, a phone call will be made to the patient to assess any possible adverse 
events (AEs).  
 
The following clinical assessments are made on day 85/End of study 
• 
Interim medical history and focused physical exam to review: 
o Changes to the patient’s medical history, 
o Changes to ADT 

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o Changes to familial history of diabetes 
o Change to medication list 
o Overall health and any side effects they may be experiencing.   
• 
Height, weight  
• 
CBCD 
• 
CMP (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, 
alkaline phosphatase, AST, ALT, calcium) 
• 
PSA 
• 
Research blood and urine samples as outlined (see Appendix A) 
• 
24hr food intake recall questionnaire 
• 
Measurement of tissue AGE level by skin autofluorescence using the AGE Reader 
device. 
• 
Day 85:  Quality of life questionnaires (FACT-P and AUA; see Appendices B, C) 
5.3  Subject Recruitment 
This study will take place at the MUSC and one other cancer center (to be determined).   
• Subjects will be identified by the designated IRB approved study team or will be referred 
by colleagues who care for the patient populations under study.  
• Designated IRB approved study research team personnel may screen records to identify 
potential subjects.  Records and/or areas that may be reviewed include pathology/surgical 
reports, and pharmacy records.  
• Potential subjects will only be approached for the study after they have been informed of 
the study by someone involved with their clinical care. 
• Potential subjects who have previously agreed to be contacted for research may be 
approached by the study team. 
5.4 Informed Consent Process 
• Subjects who are interested in participating will be interviewed in clinic.  A designated 
IRB approved member of the study will explain the nature of the study, the benefits and 
risks.  Informed consent will be obtained by designated IRB approved research members 
in clinic. Consent will be documented by obtaining the subject’s signature on the 
approved consent form, and documenting the consent process through a progress note in 
the participant’s clinical or research record. 
 
• Consent may be obtained the same day the patient is presented with the trial. 
5.5 Disease Assessment 
Disease response will be obtained by the assessment of PSA at enrollment and at the time the 
patient comes off study.  PSA will not be repeated at these times if it has been done within 2 
weeks for clinical care.  Imaging studies will be done only if clinically indicated and/or at the 
discretion of the subject’s primary oncologist. 

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5.6 Toxicity Assessment 
See Section 7. 
5.7 Schedule of Assessments 
See Appendix A.   
5.8 Correlative Studies 
Samples will be processed and stored locally in Dr. Lilly’s lab in HO334.  The trial will be 
carried out at MUSC and one other cancer center (to be determined).  Correlative studies will be 
done and will be exchanged between participating institutions.  Samples may be stored for future 
use.   
 
6 
STUDY DRUG INFORMATION - CHITOSAN 
 
6.1 Agent Description.   
Chitosan is a natural polycationic linear polysaccharide derived from partial deacetylation of 
chitin.  It is the structural element in the shell of insects, certain shellfish, and the cell walls of 
fungi.  After cellulose, it is the most abundant natural polysaccharide.  Chistosan is made up of 
B-(1-4)-lined D-glucosamine and N-acetyl-D-glucosamine randomly distributed within the 
polymer.     
 
This study will use LipoSan Ultra® brand of chitosan, to reduce blood and tissue levels of 
advanced glycation endproducts, as an adjunct to prostate cancer treatment.  LipoSan Ultra® is a 
proprietary combination of chitosan and succinic acid.   Its composition and manufacture is 
covered by US Patent No. 6,130,321; it is manufactured in the US by Swanson Health.  LipoSan 
Ultra® has also been awarded a certificate of compliance with the Tún Standards for Certified 
Natural Products. 
 
6.1.1 Supply  
Chitosan will be provided in 500mg capsules.  Chitosan will be stored at the investigational 
pharmacy located at each participating center.  Chitosan will be distributed by the investigational 
pharmacy at each participating center. Due to COVID-19 restrictions Chitosan can also be 
mailed to the subject directly.  It will be purchased from an external supplier and repackaged by 
the investigational pharmacy at each participating center.  The packaging will include the label 
information required per 21 CFR part 312.  
 
6.1.2 Storage.  
The capsules should be stored at a controlled room temperature, with excursions to 15-30°C (59-
86°F) permitted. All capsules should be kept in a secured storage area.  
 
6.1.3 Administration. 
See section 4.2 for chitosan administration instructions.   

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6.1.4 Known Potential Toxicities.   
Patients with allergies to any shellfish should not take Chitosan as it can cause anaphylactic 
shock.  Known toxicities of chitosan include included flatulence, increased stool bulkiness, 
bloating, mild nausea, and heartburn.   Chitosan may interfere with how your body absorbs some 
medications, including certain beta blockers (propranolol), blood thinners (warfarin), diuretics 
(thiazides), cholesterol medications (zetia), diabetes medications (rosiglitazone), and antibiotics 
(ciprofloxacin).  It is important that you take the study drugs as instructed by the study doctor to 
avoid any possible drug interactions.   
 
7 RISKS AND BENEFITS 
7.1 Potential Risks 
See Section 6.1.4 for the potential risks of Chitosan. 
• The physical risk to participants is minimal.  Venipuncture may produce momentary 
discomfort from needle stick, bruising or infection.  Fainting could occur.  The 
volume of blood removed is insignificant. 
• The risk of distress from inappropriate release of PHI is low, due to the plan for de-
identification of clinical data, as well as the likelihood that the clinical collaborators 
will already be involved in the subjects’ health care. 
7.2 Protection Against Risk 
• The proposed procedures are inherently of low physical risk.  We believe the 
psychological risks are also extremely low, since the investigators will already be 
treating the patients.  
• We do not anticipate the occurrence of adverse events requiring treatment, or 
necessitating a data and safety monitoring board.  
• Samples and results will be coded through the assignment of a unique study number 
to subject.  Study labs will not have access to the ID log that contains the subject 
identifier.  It will be stored separately from the research data. 
 
7.3 Potential benefits of the proposed research to the subjects and others  
There is no direct benefit to the participating subjects.  Society may benefit if the new assays 
provide greater certainty about the diagnosis and behavior cancer and its response to therapy.  
In view of the extremely low risk of this study, the risk:benefit ratio seems favorable. 
7.4 Withdrawal of subjects 
Subjects can withdrawal from the study at any time without if affecting their regular care.  
The subject can be removed from study at any time if it is determined it is not in the subject’s 
best interest to remain on the trial, the subject is non-compliant, or if the study is closed.   
 

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If the subject withdraws or is withdrawn from the study, the study team will stop collecting 
new information and specimen from the subject, but information and specimens already 
collected may still be used in the data analysis.   
 
8 ADVERSE EVENTS 
 
8.1 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.) 
 
Adverse events will be named and graded using CTCAE v 5.0 and will be recorded prospectively 
during the study and entered into the REDCap database.  Adverse events will be reported from 
the first day of study intervention until the last day of study intervention. 
 
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.  
 
8.2 
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 

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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 102898 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. 
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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. 
8.3 Unanticipated Adverse Device Effects 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety, 
any life-threatening problem or death caused by, or associated with a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
application; or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects. 
 
UADEs will be reported to the FDA by the PI within 10 working days of being notified of the 
event.    
 
9 DATA SAFETY MONITORING 
 
9.1 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. 

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9.2 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.  
9.3 Food and Drug Administration Review 
An IND for chitosan will be submitted to the FDA in accordance with 21 CFR 312.   
 
Review of the AGE Reader by the Food and Drug Administration is not indicated as this study 
does not meet the significant risk device criteria under 21 CFR 812.3(m).  This study will follow 
the abbreviated reporting requirements found under 21CFR 812.2(b), which includes that the 
device will be labeled in accordance with 21CFR 812.5 (Caution – investigational device.  
Limited by Federal lab to investigational use).  The label or other labeling shall describe all 
relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings 
and precautions.   
 
10 STATISTICAL METHODS AND POWER ANALYSIS 
10.1 
Escalation Design    
The investigators will use a 3+3 design for assignment to cohorts.  The cohorts are shown in 
Table 3.  An initial 3 subjects will be enrolled at dose level 1.  Dose-limiting toxicities (DLT) 
will be defined only in the first 28 days of therapy.  If there are no DLTs after the final patient 
has been treated for 28 days, then the next 
cohort will be enrolled in dose level 2, and so 
forth.  If a DLT occurs, then 3 more subjects 
will be enrolled into that cohort.  If two DLTs 
occur in the first 3 patients in a dose level, 
then dose will be de-escalated and 3 additional 
patients will be enrolled in the lower dose 
Table 3.  Clinical Trial Cohorts 
Dose Level 
Chitosan 
number 
-1 
500mg QD 
3 (+3) 
1 
500mg BID 
3 (+3) 
2 
1000mg BID 
3 (+3) 
3 
1500mg BID 
3 (+3) 
4 
2000mg BID 
3 (+3) +30 
 

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level unless 6 have already been treated at that dose level.  The MTD will be defined as the dose 
at which no more than 1 out of 6 subjects experiences a DLT.   
 
Definition of DLT:   
• Grade 3 or higher hypophosphatemia  
• Grade 3 or higher of any of the following toxicities, that the investigator deems related to 
chitosan, that do not improve or resolve within 7 days of onset:  flatulence, increased 
stool bulkiness, bloating, nausea, heartburn 
10.2 
Expansion Cohort Design and Statistical Analysis.   
Once the MTD is established, 27 additional subjects will be recruited at that dose level to better 
define toxicity and changes in AGEs.  The maximum number of patients that can be accrued is 54.  
The primary measure of change in AGE is defined as a binary indicator of a 30% or greater 
decrease in plasma total AGE level between baseline and day 85 specimens. The proportion of 
patients with a 30% or greater decrease with be calculated with its exact 95% confidence interval.  
An exact binomial test will be based on a null hypothesized true proportion of 0.25 (i.e., 25% of 
patients have a ≥30% reduction in AGE levels) which is too low to be of further interest.  With an 
alternative of 0.50 and 33 patients, assuming a 1-sided alpha of 0.05, the power is 0.88.  Graphical 
displays will be made to demonstrate patterns in AGE between baseline and day 85. The following 
analyses will be performed, and then data will be stratified by race, and analyses repeated to 
evaluate differences by race. Summary statistics (mean change between timepoints, standard 
deviations, medians) will be reported. Scatterplots and paired t-tests will be used to compare the 
mean change between baseline and day 85 with a 2-sided alpha of 0.05 for changes in AGE levels 
and changes in other variables of interest (e.g. race, BMI).  Linear regression will be used to 
evaluate associations between continuous variables and changes in AGE levels with changes in 
AGE levels as the outcome.  Transformations will be taken as appropriate and residual plots will 
be examined to evaluate assumptions of linear regression model.  The investigators will add 
baseline levels of clinical parameters in the linear regression model to account for starting levels. 
Regression coefficients will be evaluated in terms of clinical effect size and statistical significance. 
Model results will be reported with 95% confidence intervals. 

NCT # NCT03712371 
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Version Date: 09/09/2020 
 
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(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. 
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prostate cancer are differentially expressed in African American and European American men. 
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of new-onset diabetes mellitus and worsening glycaemic variables for established diabetes in 
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during combined androgen blockade for prostate cancer. Urology 2008 Feb;71(2):318-322.  
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the metabolic syndrome is associated with shorter time to castration-resistant prostate cancer. 
Ann Oncol 2011 Apr;22(4):801-807.  
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associated with risk of progression for low-risk prostate cancers managed expectantly. Eur Urol 
2014 Nov;66(5):841-848.  
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survival after radical prostatectomy. J Urol 2014 Oct;192(4):1100-1104.  
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obesity prevention measures may improve prostate cancer outcomes using data from a 
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obesity on outcomes after definitive dose-escalated intensity-modulated radiotherapy for 
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(40) Keto CJ, Aronson WJ, Terris MK, Presti JC, Kane CJ, Amling CL, et al. Obesity is 
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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.  
(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.  

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(44) 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.  
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methylglyoxal and N (epsilon)-(carboxyethyl)lysine, the major factors contributing to the 
pathogenesis of nephropathy. Springerplus 2015 Jul 3;4:312-015-1106-4. eCollection 2015.  
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Nephrotoxicity via a Carbonyl Stress-Dependent Pathway. Biomed Res Int 2015;2015:675714.  
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chitosan on oxidative stress and related factors in hemodialysis patients. Carbohydr Polym 2014 
Nov 4;112:152-157.  
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(50) Kean T, Thanou M. Biodegradation, biodistribution and toxicity of chitosan. Adv Drug 
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genomic history of a diverse protein family. BMC Evol Biol 2007 Jun 26;7:96-2148-7-96.  
(52) National Institutes of Health. NTP Technical Report on the Toxicity of Chitosan. 2017.  
(53) Thanou M, Verhoef JC, Junginger HE. Oral drug absorption enhancement by chitosan and 
its derivatives. Adv Drug Deliv Rev 2001 Nov 5;52(2):117-126.  
(54) Illum L. Chitosan and its use as a pharmaceutical excipient. Pharm Res 1998 
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(55) Kumar MN, Muzzarelli RA, Muzzarelli C, Sashiwa H, Domb AJ. Chitosan chemistry and 
pharmaceutical perspectives. Chem Rev 2004 Dec;104(12):6017-6084.  
(56) Ravi Kumar M,N.V.  
(57) Xu G, Huang X, Qiu L, Wu J, Hu Y. Mechanism study of chitosan on lipid metabolism in 
hyperlipidemic rats. Asia Pac J Clin Nutr 2007;16 Suppl 1:313-317.  
(58) Gades MD, Stern JS. Chitosan supplementation and fecal fat excretion in men. Obes Res 
2003 May;11(5):683-688.  
(59) Tapola NS, Lyyra ML, Kolehmainen RM, Sarkkinen ES, Schauss AG. Safety aspects and 
cholesterol-lowering efficacy of chitosan tablets. J Am Coll Nutr 2008 Feb;27(1):22-30.  
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(61) Azad AK, Sermsintham N, Chandrkrachang S, Stevens WF. Chitosan membrane as a 
wound-healing dressing: characterization and clinical application. J Biomed Mater Res B Appl 
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patients with chronic renal failure. J Pharm Pharmacol 1997 Jul;49(7):721-723.  

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(63) Baek KS, Won EK, Choung SY. Effects of chitosan on serum cytokine levels in elderly 
subjects. Arch Pharm Res 2007 Dec;30(12):1550-1557.  
(64) Lehtimaki T, Metso S, Ylitalo R, Rontu R, Nikkila M, Wuolijoki E, et al. Microcrystalline 
chitosan is ineffective to decrease plasma lipids in both apolipoprotein E epsilon 4 carriers and 
non-carriers: a long-term placebo-controlled trial in hypercholesterolaemic volunteers. Basic 
Clin Pharmacol Toxicol 2005 Aug;97(2):98-103.  
(65) Bokura H, Kobayashi S. Chitosan decreases total cholesterol in women: a randomized, 
double-blind, placebo-controlled trial. Eur J Clin Nutr 2003 May;57(5):721-725.  
(66) Guerciolini R, Radu-Radulescu L, Boldrin M, Dallas J, Moore R. Comparative evaluation of 
fecal fat excretion induced by orlistat and chitosan. Obes Res 2001 Jun;9(6):364-367.  
(67) Ho SC, Tai ES, Eng PH, Tan CE, Fok AC. In the absence of dietary surveillance, chitosan 
does not reduce plasma lipids or obesity in hypercholesterolaemic obese Asian subjects. 
Singapore Med J 2001 Jan;42(1):6-10.  
(68) Pittler MH, Abbot NC, Harkness EF, Ernst E. Randomized, double-blind trial of chitosan 
for body weight reduction. Eur J Clin Nutr 1999 May;53(5):379-381.  
(69) Anraku M, Fujii T, Furutani N, Kadowaki D, Maruyama T, Otagiri M, et al. Antioxidant 
effects of a dietary supplement: reduction of indices of oxidative stress in normal subjects by 
water-soluble chitosan. Food Chem Toxicol 2009 Jan;47(1):104-109.  
(70) Cornelli U, Belcaro G, Recchia M, D'Orazio N. Long-Term Treatment of Overweight and 
Obesity with Polyglucosamine (PG L112): Randomized Study Compared with Placebo in 
Subjects after Caloric Restriction. Curr Dev Nutr 2017 Sep 22;1(10):e000919.  
(71) Trivedi VR, Satia MC, Deschamps A, Maquet V, Shah RB, Zinzuwadia PH, et al. Single-
blind, placebo controlled randomised clinical study of chitosan for body weight reduction. Nutr J 
2016 Jan 8;15:3-016-0122-8.  
(72) Hernandez-Gonzalez SO, Gonzalez-Ortiz M, Martinez-Abundis E, Robles-Cervantes JA. 
Chitosan improves insulin sensitivity as determined by the euglycemic-hyperinsulinemic clamp 
technique in obese subjects. Nutr Res 2010 Jun;30(6):392-395.  
 
 

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APPENDIX A.  SCHEDULE OF PROCEDURES AND ASSESSMENTS 
  
 
 
Study Activity 
Screenc 
Day 1c 
Day 14g 
 
Day 29 
Day 57g 
Day 85/    
End of 
studya, d 
Specimen 
Demographics 
X 
 
 
 
 
 
 
Full Physical Exam,  
X 
 
 
 
 
 
 
Focused Physical Exam,  
 
X 
 
 
 
X 
 
Medical History to include: 
• 
Duration of ADT 
• 
Extent of cancer 
• 
Personal history of diabetes 
mellitus 
• 
Current medications 
X 
X 
 
 
 
 
 
Interim Medical History 
 
X 
 
 
 
X 
 
Anthropometric Measurements (height, 
weight) 
X 
X 
 
 
 
X 
 
CBCD 
X 
X 
 
 
 
X 
 
CMP (fasting)g 
X 
X 
 
 
 
X 
 
Phosphorus 
X 
X 
 
 
 
X 
 
PSA 
X 
X 
 
 
 
X 
 
Assessment of toxicity 
 
X 
Xg 
Xg 
Xg 
X 
 
testosterone 
X 
X 
 
 
 
X 
 
Chitosan 
 
 
      X-------------------------------------X 
Drug diary reviewe 
 
 
 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
 
Insulin Resistance (HOMA-IR) 
Xf 
 
 
 
X 
Plasmab 
CRP, AGE species and precursors 
Xf 
 
 
 
X 
Serumb 
RedOx status (ORP, reduced glutathione) 
Xf 
 
 
 
X 
Plasmab 
RAGE, TLR expression, signaling 
Xf 
 
 
 
X 
Whole bloodb 
Microbiome profiling  
Xf 
 
 
 
X 
Stool 
AGE species 
Xf 
 
 
 
X 
Urinei 
Tissue AGE level by autofluorescence 
X 
 
 
 
X 
 
Food Recall Dietary AGE contenth 
Xf 
 
 
 
X 
 
QOL (FACT-P and AUA) 
Xf 
 
 
 
X 
 
a) 
All days are +/- 5 days 
b) 
2x7mL EDTA blood (=plasma), 2x7mL clot tube (=serum), 1x7mL sodium heparin tube (=whole blood). 
c) 
Screening assessments to be done within 28 days of registration.  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.   
d) 
If the subject goes off study less than 2 weeks after start of dosing, "end of study" labs and questionnaires will not be 
done. 
e) 
The drug diary will be given to each subject for completion during the study.   
f) 
Research procedures (excluding informed consent) may be done at any point after informed consent and prior to first 
dose of drug (on day 1).  Research blood, urine and stool samples will be taken to the participating research lab(s) for 
processing.   

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g) 
On day 14,day 29, and day 57 (+/- 5 days), compliance and adverse events will be assessed via phone using the phone 
contact guide in appendix D.  
h) 
Food recall using the NCI quick food scan and the NIH’s “Eating at America’s Table Study” Quick food scan. 
i) 
10mL of urine collected in a sterile cup such as those used for clinical urine specimens 
 
APPENDIX B:  FACT-P QUALITY OF LIFE QUESTIONNAIRE 
See Next Page

Study ID: 
Initials: 
Date:  
 
 
English (Universal) 
 
19 November 2007 
Copyright 1987, 1997 
 
Page 1 of 3 
 
 
FACT-P (Version 4) 
 
Below is a list of statements that other people with your illness have said are important.  Please circle or 
mark one number per line to indicate your response as it applies to the past 7 days.   
 
 
PHYSICAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
Much 
GP1 I have a lack of energy………………………………… 
0 
1 
2 
3 
4 
GP2 I have nausea…………………………………………... 
0 
1 
2 
3 
4 
GP3 Because of my physical condition, I have trouble 
meeting the needs of my family……………………….. 
0 
1 
2 
3 
4 
GP4 I have pain……………………………………………... 
0 
1 
2 
3 
4 
GP5 I am bothered by side effects of treatment…………….. 
0 
1 
2 
3 
4 
GP6 I feel ill………………………………………………… 
0 
1 
2 
3 
4 
GP7 I am forced to spend time in bed………………………. 
0 
1 
2 
3 
4 
 
 
 
SOCIAL/FAMILY WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
Much 
GS1 
I feel close to my friends……………………………… 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my friends………………. 
0 
1 
2 
3 
4 
GS3 
I get support from my friends…………………………. 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness……………………. 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness………………………………………………….. 
0 
1 
2 
3 
4 
GS6 
I feel close to my partners (or the person who is my 
main support…………………………………………… 
0 
1 
2 
3 
4 
Q1 
Regardless of your current level of sexual activity, 
please answer the following question.  If you prefer not 
to answer it, please mark this box          and go to the 
next section.   
 
 
 
 
 
GS7 
I am satisfied with my sex life…………………………. 
0 
1 
2 
3 
4 
 

Study ID: 
Initials: 
Date:  
 
 
English (Universal) 
 
19 November 2007 
Copyright 1987, 1997 
 
Page 2 of 3 
 
 
 
FACT-P (Version 4) 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.   
 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
Much 
GE1 I feel sad………………...……………………………... 
0 
1 
2 
3 
4 
GE2 I am satisfied with how I am coping with my illness….. 
0 
1 
2 
3 
4 
GE3 I am losing hope in the fight against my illness……….. 
0 
1 
2 
3 
4 
GE4 I feel nervous…………………………………………... 
0 
1 
2 
3 
4 
GE5 I worry about dying……………………………………. 
0 
1 
2 
3 
4 
GE6 I worry that my condition will get worse……………… 
0 
1 
2 
3 
4 
 
 
FUNTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
Much 
GF1 
I am able to work (include work from home) …….…... 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling…………. 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life………………………………….. 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness……………………………... 
0 
1 
2 
3 
4 
GF5 
I am sleeping well……………………………………… 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun………….. 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of life right now………… 
0 
1 
2 
3 
4 
 
 
 
 
 

  
Study ID: 
Initials: 
Date:  
 
 
English (Universal) 
 
19 November 2007 
Copyright 1987, 1997 
 
Page 3 of 3 
 
 
FACT-P (Version 4) 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.   
 
 
ADDITIONAL CONCERNS 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
Much 
C2 
I am losing weight……………………………………... 
0 
1 
2 
3 
4 
C6 
I have a good appetite………………………………….. 
0 
1 
2 
3 
4 
P1 
I have aches and pains that bother me…………………. 
0 
1 
2 
3 
4 
P2 
I have certain parts of my body where I experience pain 
0 
1 
2 
3 
4 
P3 
My pain keeps me from doing things I want to do…….. 
0 
1 
2 
3 
4 
P4 
I am satisfied with my present comfort level………….. 
0 
1 
2 
3 
4 
P5 
I am able to feel like a man……………………………. 
0 
1 
2 
3 
4 
P6 
I have trouble moving my bowels……………………... 
0 
1 
2 
3 
4 
P7 
I have difficulty urinating……………………………… 
0 
1 
2 
3 
4 
BL2 
I urinate more frequently than usual…………………… 
0 
1 
2 
3 
4 
P8 
My problems with urinating limit my activities……….. 
0 
1 
2 
3 
4 
BL5 
I am able to have and maintain an erection……………. 
0 
1 
2 
3 
4