Clinical trial NCT02766478
Conditions: Prostate Cancer
Sponsor: Emory University
Start date: 2017-10-16; Completion date: 2021-07-23
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Genistein is a natural supplement that comes from soy. The purpose of this study is to see if genistein has any effect on preventing or reducing heart disease and diabetes risk in men receiving Androgen Deprivation Therapy for prostate cancer. A combination of nutritional measures, blood markers and imaging tools will assess body composition, lipid levels and insulin resistance. Information from this pilot study will increase understanding of interventions which may prevent or reduce health risks during prostate cancer treatment. This project involves 24 men who will receive androgen deprivation therapy for prostate cancer.

Detailed description:
This is a double-blind, randomized, placebo-controlled trial of daily oral genistein in 24 men initiating Androgen Deprivation Therapy (ADT) for prostate cancer (PCa). Genistein is a natural supplement that comes from soy. The purpose of this study is to see if genistein has any effect on preventing or reducing heart disease and diabetes risk in men receiving ADT for PCa. A combination of nutritional measures, blood markers and imaging tools will assess body composition, lipid levels and insulin resistance. Information from this study will increase understanding of interventions which may prevent or reduce health risks during prostate cancer treatment.

All participants will receive standard counseling for diet and exercise by their oncology care team. Participants will be asked to withhold from any additional dietary supplements (with the exception of 1 standard daily multivitamin) during the study period. Participants will also be asked to complete a food diary for three days (on two weekdays and 1 weekend day).

Subjects will be randomized and stratified by diabetes status to either 60 mg/day oral genistein (30 mg taken twice daily), or matching placebo. The goal for randomizing based on diabetes status is to ensure approximately the same number of subjects who have diabetes and do not have diabetes receive genistein and placebo.

During follow-up, subjects will receive weekly reminders via phone call, text, or email to enhance compliance and monitor for potential adverse events. The 3-month study visit will be scheduled to coincide with the subject's standard of care follow-up visit. Three-month assessments will be the same as baseline assessments.

Investigators seek to assess indexes of insulin dynamics (insulin sensitivity and secretion) determined from an oral glucose tolerance test before and 12 weeks after a daily genistein or placebo supplement. Measures of vascular function before and 12 weeks after a daily genistein or placebo supplement will also be assessed via ultrasound along with other metabolic measures via blood draw.

Arms: arm 1: Participants with and without diabetes will receive 60 mg/day oral genistein (30 mg taken twice daily) for 12 weeks. arm 2: Participants with and without diabetes will receive placebo taken twice daily for 12 weeks.
Interventions: intervention 1: Genistein intervention 2: Placebo
Intervention descriptions: intervention 1: Genistein is a natural supplement that comes from soy. Genistein will be taken orally (30 mg twice daily) for 12 weeks. intervention 2: A placebo pill will be taken orally for 12 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
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Genistein Supplementation to Mitigate Cardiometabolic Dysfunction in Patients 
Undergoing Androgen Deprivation Therapy for Prostate Cancer 
 
IRB00086186 
 
NCT# NCT02766478 
 
Date: 03/26/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. TITLE: Genistein Supplementation to Mitigate Cardiometabolic Dysfunction in 
Patients Undergoing Androgen Deprivation Therapy for Prostate Cancer 
 
Alternate Title: GeniPro (Genistein Supplementation to Mitigate Cardiometabolic Dysfunction in 
Patients Undergoing Androgen Deprivation Therapy for Prostate Cancer) 
 
Principal Investigator: Jessica A. Alvarez, PhD, RD; Co-Investigators: Dr. Omer Kucuk, MD, 
Dr. Guillermo Umpierrez, MD, Dr. Arshed Quyyumi, MD,Dr. Thomas Ziegler, MD, Dr. Mehmet 
Bilen, and Dr. Bradley Carthon 
 
Protocol draft date: 
03/26/2020 
 
2. EXTERNAL COLLABORATORS: There are no external collaborators. 
 
3. PRECIS/ABSTRACT 
Androgen deprivation therapy (ADT) is a widely used treatment for prostate cancer (PCa). 
Despite its benefits in improving survival in men with advanced PCa, ADT itself is associated 
with increased metabolic syndrome, diabetes, and cardiovascular disease (CVD) risk. The rapid 
and sustained decrease in serum testosterone levels induced by ADT results in an increase in 
body fat, dyslipidemia, insulin resistance, and arterial stiffness—all associated with CVD risk 
and many of which are evident within 3 months of ADT initiation. Unfortunately, few studies 
have been conducted to investigate therapies that may prevent or mitigate ADT-induced 
cardiometabolic dysfunction in patients with PCa. We hypothesize that genistein, a naturally- 
occurring soy isoflavone that functions as a selective estrogen receptor modulator, will be 
beneficial in promoting cardiometabolic health in men with PCa undergoing ADT. Dietary intake 
of soy products has long been known to correlate with indexes of metabolic health, and 
experimental and animal studies have shown genistein to improve insulin sensitivity and lipid 
metabolism through several mechanisms of action. Clinical trials, primarily in postmenopausal 
women, suggest that oral genistein administration decreases fasting lipid and insulin 
concentrations. Co-Investigator, Dr. Omer Kucuk, has shown that genistein supplementation 
decreases serum total cholesterol levels in men with PCa. Here, we propose a pilot,  
randomized, double blind, placebo-controlled trial of daily oral genistein (60 mg/d) with 
comprehensive cardiometabolic profile testing in 24 men initiating ADT for PCa. 
4. INTRODUCTION and BACKGROUND: 
Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer in men, with an 
estimated prevalence of >2,700,000 men in the U.S1. Androgen deprivation therapy (ADT), the 
chemical or surgical inhibition of testosterone and other androgens to minimize prostate cancer 
cell growth, is among the most common treatment modalities for PCa2. ADT has established 
benefits in improving survival in patients with advanced PCa2,3. Although evidence does not 
support the use of ADT for low-risk, localized PCa, utilization rates in this sub-set remain high4,5. 
Given the ubiquitous roles of androgens in physiological homeostasis, the implications of 
widespread ADT use are significant. Adverse effects of androgen deprivation include adverse 
body composition and cardiometabolic changes, such as increases in body fat, decreases in 
muscle mass, insulin resistance, and serum lipid alterations6-16, which could have negative long- 
lasting effects on quality of life and morbidity in PCa survivors, especially if coupled with age- 
related metabolic alterations. Changes in cardiometabolic risk factors, such as insulin resistance 
and arterial stiffness have been observed as early as 12 weeks7-10,13,17. Recent meta-analyses 


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investigating ADT morbidity have indicated a 75% increased risk for metabolic syndrome18, 36% 
increased risk for diabetes18, and a 38% increased risk for CVD19. Unfortunately, only a limited 
number of studies have been conducted to investigate therapies that may ameliorate the 
adverse metabolic effects of ADT20. These studies have primarily been exercise-based 
interventions, and, although inducing some beneficial changes in body composition and physical 
fitness, have generally not been effective at changing metabolic parameters20,21. Additional 
therapies that may prevent or mitigate ADT-induced cardiometabolic dysfunction in patients with 
PCa are critically needed. 
Genistein, a naturally-occuring soy isoflavone, may be a viable alternative for improving 
cardiometabolic health in men requiring ADT. Dietary intake of soy products has long been 
known to correlate with reduced chronic disease risk, including PCa22,23. The beneficial effects  
of soy products have been attributed to isoflavones, phytochemicals (or phytoestrogens) that  
are structurally similar to 17β-estradiol and function as selective estrogen receptor modulators24. 
Genistein is the most biologically active isoflavone, whose molecular actions, among others, 
include modulating the expression of genes involved in cell survival, cell cycle, and apoptosis24. 
Several clinical studies, including one by Co-Investigator and Mentor, Dr. Omer Kucuk, have 
described the efficacy and safety of genistein/soy in decreasing or stabilizing serum and tissue 
prostate specific antigen in patients with PCa25-27. The 
beneficial effects of genistein also extend to 
cardiometabolic health. Meta-analyses of controlled, 
clinical trials confirm the insulin sensitizing and plasma 
lipid lowering effects of soy products in non-cancer 
populations28-30. Experimental studies have shown 
genistein to improve cardiometabolic health through 
several mechanisms of action, including promoting 
activation of peroxisome-proliferator activated 
receptors (PPAR) and 5’-adenosine-monophosphate- 
activated protein kinase (AMPK), important for insulin 
action and lipid homeostasis31,32; and regulation of 
HMG-CoA reductase and acyl-CoA:cholesterol 
acyltransferase, important for cholesterol synthesis 
and esterification33. In men with PCa, Dr. Kucuk has 
shown that genistein supplementation significantly 
Fig 1. Decrease in blood total cholesterol 
following genistein supplementation24. N = 47 
men with prostate cancer were randomized to 30 
mg genistein daily or placebo for 3-6 wks prior to 
prostatectomy. *P < 0.05 
decreases serum total cholesterol levels over a period of several weeks (Fig. 1)25. Given the 
metabolic changes that occur following ADT initiation in men with PCa and the beneficial 
metabolic effects of genistein in other populations, we hypothesize that genistein will be 
beneficial in reducing insulin resistance and cardiovascular dysfunction, in men with PCa 
undergoing ADT. 
Genistein is a safe, natural product with long-known therapeutic benefits. Previous clinical trials 
investigating genistein’s metabolic effects have primarily focused on postmenopausal 
women30,34-36. Only one previously published study has investigated the cardiometabolic effects 
of soy isoflavones in men receiving ADT37, although patients had already been on ADT for a 
minimum of 12 months. This proposed study will provide the first data in determining if genistein 
supplementation initiated at the start of ADT therapy is beneficial in mitigating the 
cardiometabolic adverse effects of ADT in men with PCa. Furthermore, the majority of previous 
studies have primarily relied on crude measurements of cardiometabolic outcomes derived from 


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fasting plasma concentrations, such as fasting insulin and glucose and fasting lipids. Here, we 
propose a panel of comprehensive, dynamic tests that will provide more physiological insight 
into the cardiometabolic effects of genistein in PCa. 
5. OBJECTIVES 
Specific Aim 1): Assess indexes of insulin dynamics (insulin sensitivity and secretion) 
determined from an oral glucose tolerance test before and 12 weeks after a daily 
genistein or placebo supplement. The primary outcome will be the Matsuda index of whole- 
body insulin sensitivity. β-cell insulin secretion capacity will be assessed with the Insulinogenic 
Index. Additional indexes of insulin resistance and secretion derived from fasting and post- 
challenge measurements of plasma glucose, insulin, and C-peptide will be assessed. We 
hypothesize that a) insulin sensitivity and secretion will decline following initiation of ADT; and b) 
supplementation with genistein will improve insulin sensitivity and secretion compared to 
placebo. 
Specific Aim 2): Assess, in Aim 1 subjects, measures of vascular function before and 12 
weeks after a daily genistein or placebo supplement. Arterial stiffness will be assessed with 
augmentation index and pulse wave velocity measured by applanation tonometry. Vascular 
endothelial function will be assessed with flow-mediated dilation (FMD) measured by 
ultrasound. Additional CVD-related outcomes will be a fasting comprehensive serum lipid 
profile. We hypothesize that a) arterial stiffness will increase and FMD will decrease following 
initiation of ADT, and b) supplementation with genistein will improve these key measures of 
vascular health compared to placebo. 
This proposed clinical trial of genistein supplementation is a novel approach that may help to  
alleviate major adverse metabolic comorbidities associated with ADT in men with prostate 
cancer and help to ensure a healthy, extended quality of life. 
 
Aim 1 rationale: Testosterone influences insulin sensitivity, independently of its effects on body 
composition, in a variety of insulin target tissues (e.g., muscle, liver, adipose), with molecular 
mechanisms similar to those of genistein, including PPAR activation and AMPK signaling38,39. 
The majority of clinical trials investigating genistein effects on insulin resistance have used the 
homeostatic model assessment of insulin resistance (HOMA-IR) and/or fasting insulin as 
outcomes30,34-36_ENREF_33, which do not take into account the post-challenge tissue response to 
glucose40 and may more reflect hepatic, as opposed to whole-body, insulin resistance41. 
Experimental data have also shown genistein to promote glucose-stimulated insulin secretion by 
pancreatic β-cells42-44, although few, if any, clinical trials have verified such an effect. Use of an 
OGTT in this pilot study will allow for the assessment of the dynamic metabolic changes that 
occur following a glucose challenge and thus, provide a better indication of the effects of 
genistein on whole-body insulin sensitivity, as well as insulin secretion. 
Aim 2 rationale: In addition to alterations in plasma lipids, low testosterone is associated with 
other predictors of cardiovascular risk in non-cancer populations, including flow-mediated 
dilation (FMD) and arterial stiffness, as shown by Co-Investigators Dr. Umpierrez45 and Dr. 
Quyyumi46, respectively, and others47-51. However, the handful of studies that have investigated 
the effects of ADT on these additional vascular outcomes have provided conflicting 
results8,9,13,14. As with androgens, genistein has been shown (primarily in postmenopausal 
women) to influence cardiovascular function independently of changes in plasma lipids, 
including increased FMD34,36,52,53 and reduction in arterial stiffness54,55. Genistein’s lipid- 


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independent effects on vascular function may be mediated by a reduction in vascular injury via 
inhibition of thrombosis and platelet activation and aggregation56 and/or activation of nitric oxide 
signaling pathways52,57. In this study of men undergoing ADT, we will assess the effects of 
genistein with outcomes that represent a variety of potential mechanisms associated with 
cardiovascular risk. 
 
 
6. STUDY DESIGN AND METHODS: 
Overall Study Design: This will be  
a pilot double-blind, randomized, 
placebo-controlled trial of daily oral 
genistein in 24 men initiating ADT for 
PCa, as detailed in Fig. 2. Metabolic 
testing will be performed following an 
overnight fast in the Emory 
University Hospital Clinical Research 
Network (CRN) of the Atlanta Clinical 
and Translational Science      
Institute (ACTSI) before initiation of 
ADT and study drug, and will be 
repeated 12 weeks after baseline 
testing. 
Study initiation and baseline 
assessments: All patients will 
receive standard counseling for diet 
and exercise by their oncology care 
team. Patients will be asked to 
withhold from dietary supplements 
containing genistein or soy. If 
subject are consuming dietary 
supplements with genistein or soy, 
 
 
 
 
 
Fig. 2. Study Schema. Subjects will ingest 60 mg daily oral genistein or 
matching placebo for 12 weeks. Cardiometabolic testing will be performed 
following an overnight fast before initiation of ADT and study drug, and will 
be repeated 12 weeks after baseline testing. The primary endpoint will be 
whole-body insulin sensitivity derived from an oral glucose tolerance test 
(Specific Aim 1). Vascular function will be assessed with applanation 
tonometry and ultrasound (Specific Aim 2). Dietary intake and changes in 
body composition will also be assessed. 
they will undergo a 2 week washout period prior to study initiation. Patient who are taking a 
multivitamin or dietary supplements without soy or genistein may continue with these vitamins 
and supplements during the study period. Baseline study assessments (procedures described 
below) will occur at the Emory CRN on the same day (morning) they initiate ADT therapy and 
study drug. Participants will be required to be fasted for at least 12 hours. Participants will be 
offered a standard meal (not research related) following the study visit procedures. 
Randomization/Intervention: Subjects will be block randomized to either 60 mg/day oral 
genistein (30 mg BonisteinTM taken twice daily in the form of two I-Cool® tablets daily, provided 
by DSM Nutritional Products, Ltd., Basel Switzerland) or matching placebo. 
Follow-up: Subjects will receive weekly reminders via phone call to enhance compliance and 
monitor for potential adverse events. Compliance will be assessed with pill counts returned at 
the end of study and plasma genistein concentrations. The 3-month study visit will be scheduled 
to coincide with the subject’s standard of care follow-up visit. Three-month assessments will be 
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Procedures to be performed (all for research purposes only. See Table 1 for specific data 
collection information): 
1. Medical examination: Medical history and medications will be reviewed by a member of the 
research team, and a physical exam will be completed by a licensed physician. 
2. Urine collection: Urine will be collected for measurement of urinary oxidative stress 
markers (e.g., F2-isoprostanes). The clean catch method will be used to collect urine. 
3. Anthropometric measurements: Height and weight will be measured without shoes. 
Height will be measured with a manual stadiometer. Weight will be measured with a digital 
scale. Body mass index (BMI) will be calculated from height and weight. 
4. Flow mediated dilation (FMD): We will determine endothelium-dependent FMD of the 
brachial arteries using two-dimensional ultrasound images46. Briefly, the brachial artery of 
the non-dominant arm will be imaged using a high-resolution 10-MHz ultrasound transducer. 
Supra-systolic pressures will be used to produce 5 min of ischemia in the forearm. Upon 
reflow, imaging will be performed to measure FMD. Arterial diameter will be measured using 
validated software (Medical Imaging Applications, Coralville, Iowa). The end point will be % 
change in diameter in response to reactive hyperemia. FMD is calculated as (post-ischemia 
diameter-baseline diameter)/baseline diameter x 100. 
Arterial stiffness: Arterial stiffness will be assessed as pulse wave velocity (PWV) and 
radial pulse wave analysis measured noninvasively using the SphygmoCor® Pulse Wave 
Velocity system (PWV Medical, NSW, Australia)46. In brief, peripheral pressure waveforms 
will be recorded from the radial artery at the wrist, using applanation tonometry with a high- 
fidelity micromanometer. After 20 sequential waveforms have been acquired, a validated 
generalized transfer function will be used to generate the corresponding central aortic 
pressure waveform. Augmentation index (AIx) and pulse pressure amplification are derived 
and AIx normalized for heart rate of 75 bpm (AIx75). Carotid-femoral artery PWV will be 
determined using transcutaneous Doppler flow velocity recordings simultaneously over the 
common carotid artery and the femoral artery. 
5. Oral glucose tolerance testing (OGTT): The OGTT will consist of a 75g glucose challenge 
with repeat blood sampling minutes by trained nurses in the CRN. This test will occur after 
the above vascular function tests. To perform the test, a flexible intravenous catheter will be 
placed in the antecubital space of the left arm. At time “zero", a 75 g dose of oral glucose 
will be provided. Subjects will be required to consume the glucose within 5 minutes of 
administration. Blood will be drawn at baseline, prior to the initiation of glucose consumption. 
Subsequent blood samples will be drawn at 10, 20, 30, 60, 90, and 120 min following 
initiation of glucose ingestion. 
a. Indexes of insulin sensitivity/insulin resistance: The primary outcome will be the 
whole-body insulin sensitivity index (ISI) assessed by the method of Matsuda and 
DeFronzo58. This index has been validated against the gold-standard euglycemic 
clamp technique, and represents a composite of both hepatic and peripheral tissue 
sensitivity to insulin. It is calculated as: 10,000 ÷ square root of [(fasting glucose x 
fasting insulin) x (mean OGTT glucose concentration x mean OGTT insulin 
concentration)]. HOMA-IR will be determined as a secondary measure of insulin 
resistance and calculated as: [fasting insulin (µU/ml) × fasting glucose (mmol/l)] ÷ 
22.5 40. 


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b.  Indexes of insulin secretion: β-cell insulin secretion capacity will be assessed with 
the Insulinogenic Index and calculated as: ΔInsulin(t30-t0)/ ΔGlucose(t30-t0) 59. Additional 
indexes of insulin secretion will include fasting insulin and HOMA-β% calculated as: 
[20 x fasting insulin (µU/ml)] ÷ [fasting glucose (mmol/l) – 3.5] 40, and fasting and 
post-glucose challenge C-peptide/glucose ratios60. 
 
6. Blood sampling: Up to approximately 43 ml of fasted blood will be collected from a 
peripheral vein. Blood will be drawn for determination of circulating glucose, insulin, c- 
peptide, lipids, metabolomics, redox biomarkers, genistein, and collection of mononuclear 
cells. Epigenetic markers and/or telomere length may also be measured in the buffy coat or 
plasma. At 10, 20, 30, 60, and 90 minutes following oral glucose ingestion, approximately 7 
ml blood will be drawn for determination of circulating glucose, insulin, and C-peptide. Two 
hours after glucose ingestion, approximately 16 ml blood will be drawn for determination of 
glucose, insulin, C-peptide, redox biomarkers, and metabolomics. A total of 85 ml blood will 
be drawn in one study visit. 
7. Handgrip strength: A small, handheld dynamometer will be used to measure grip strength. 
Participants will be asked to squeeze the instrument as hard as they can for 3 seconds, 
which will measure the pounds of force applied. 
8. Body composition analysis: DEXA will be used to estimate total and regional body 
composition, which will include body fat, lean body mass, and bone mineral content/density. 
Participants will be asked to lie still on a scanning table with their arms at their sides for 
approximately 15-20 minutes. Body composition may also be assessed using bioelectrical 
impendence analysis (BIA); for this procedure participants will lie still on a table for <5 
minutes with electrodes placed on hands and feet. Waist and hip circumference will also be 
measured with a measuring tape to assess fat distribution. 
9. Three-day food records: Participants will be asked to complete a food diary for three days 
(2 weekdays and 1 weekend day) where they will record everything they eat and drink, 
including supplements. They will be given food records prior to their study visit and asked to 
return completed food records on the day of their visit. Alternatively, participants may 
choose to email or mail study investigators the completed food record. 
10. Questionnaires: Participants will be asked to complete a questionnaire assessing their 
physical activity over the past 7 days. Participants will be asked to complete two 
questionnaires assessing quality of life issues, the EPIC – Expanded Prostate Cancer Index 
Composite, and the RAND 36-Item Short Form Survey Instrument (SF-36). 
 
Potential Risks/Discomforts: 
The risk of participating in this study is minimal. 
 
a. Genistein: There are few reported side effects of this dietary supplement. Some studies 
have reported gastrointestinal (GI) effects. A previous study in men with PCa 
supplementing 450 mg (7.5 x the dose proposed by the current study) reported loose 
stools as a side effect (de Vere White RW 2010 Nutr Cancer). Another study in 
postmenopausal women supplementing a similar dose as ours (54 mg/day) reported GI 
symptoms such as epigastric pain, abdominal pain, dyspepsia, and constipation (Marini 
H 2007 Ann Intern Med), although other similar studies in postmenopausal women 


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reported no difference in side effects from those taking placebo (Atteritano 2014 J Clin 
Endocrinol Metab, Squadrito 2013 J Clin Endocrinol Metab, Irace 2013 Eur J Clin 
Invest). 
b. Venipuncture: There is some minor discomfort and risk of mild bruising during 
venipuncture. Standard sterile techniques will be used during phlebotomy; thus, infection 
is unlikely. Disposable pre-sterilized needles and syringes will be used for all blood 
drawing in this study; needles and syringes will not be reused. 
c. DEXA: DEXA involves exposure to small amounts of radiation. The radiation dose is 
equal to or less than the amount of background radiation received in a round-trip flight 
from New York to Los Angeles or the natural environmental radiation the average person 
receives in the United States annually. The risk from radiation exposure of this 
magnitude is considered to be negligible when compared to everyday risks. 
d. BIA: The BIA machine passes a weak electrical current through electrodes attached to 
hands and feet. Participants will not feel anything. There are no known risks associated 
with the procedure, although participants who have pacemakers or other implantable 
electronic devices will be excluded from this procedure (but may participate in other 
procedures) 
e. Flow-mediated dilation: This test requires use of a blood pressure cuff which may 
cause some mild discomfort during cuff inflation. There will be a period of time after the 
test when a trained technician will monitor for any unusual reactions to the testing. There 
are no risks or discomforts caused by applanation tonometry. 
f. Other: The fixed timing of procedures may be inconvenient to some subjects. Additional 
risks will be associated with confidentiality issues surrounding the collection/recording of 
data, but steps will be taken to minimize these risks, as described in the DSMP. 
 
Potential Benefits: 
a. Direct: Participants will be compensated a total stipend of $100 for their time and 
inconvenience. Subjects will also receive a comprehensive history and physical 
examination by a physician and gain detailed information about their habitual dietary 
nutrient intake and body composition by a registered dietitian, as well as results of their 
OGTT test and blood lipid panel. Some of these tests are not a part of routine care for 
patients, thus subjects may obtain further information regarding their nutritional health. 
Participants will be encouraged to share the results with their healthcare providers. 
There may be no specific health benefit to patients’ participation in the study. 
b. Indirect: The long-term goal of this study is to identify intervention strategies to minimize 
adverse cardiometabolic health consequences associated with ADT therapy. If our 
hypothesis is correct, genistein would be an inexpensive, easily obtainable 
phytochemical that could be supplemented in this population. 
c. The anticipated benefits of the proposed research study outweigh the potential risks to 
participating subjects. The risks incurred are minimal relative to the potential benefit of 
finding an effective therapy to reduce the adverse effects of ADT therapy. 
 
Data Collection: Table 1 summarizes the data to be collected. Specimens to be collected at 
baseline and follow-up will include blood and urine. Participants will be asked questions 


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regarding their contact information, social history (such as education, marital status, 
employment status), and medical history (such as smoking, sun exposure, alcohol consumption, 
supplement use) from participants to be recorded in case report forms. Relevant information 
from the patients’ medical record will be collected by investigators or study coordinators and 
include data needed to complete or verify the self-reported information; demographics, routine 
clinical laboratory markers (such as albumin, calcium, creatinine, 25(OH)D, vitamins, and 
minerals), cancer diagnosis and medical history glucose tolerance, medication and supplement 
intake. 
 
 
Table 1. Data to be collected and source 
Data Item 
Source 
Visit 
-Vitals (e.g, blood pressure, pulse, 
temperature) 
Medical Exam 
All 
-Demographic Information 
Self-report; Electronic 
Baseline 
Medical Record 
-Medical history (e.g., cancer dx, , 
Self-report; Electronic 
All 
microbiology, standard clinical 
Medical Record 
laboratories) 
-Social history (e.g., education, marital 
Self-report; Electronic 
Baseline 
status, employment status) 
Medical Record 
-Dietary supplement and medication 
Self-report; Electronic 
All 
intake 
Medical Record 
-Glucose tolerance 
Oral glucose tolerance 
All 
test 
-Plasma glucose, plasma insulin, 
Oral glucose tolerance 
All 
plasma c-peptide 
test 
-Plasma metabolomics 
Blood draw 
All 
-Plasma aminothiols (GSH, GSSG, Cys, 
Blood draw 
All 
CySS) 
-Mononuclear cells 
Blood draw 
All 
-Epigenetic markers and telomere 
Blood draw 
All 
length 
-Plasma lipids 
Blood draw 
All 
-Plasma genistein levels 
Blood draw 
All 
-Urinary markers of oxidative stress 
Spot urine collection 
All 
-Handgrip strength 
Hand-held 
All 
dynamometer 
-Whole body and regional body 
Dual energy X-ray 
All 
composition 
absorptiometry 
-Body composition and total body water 
Bioelectrical impedance 
All 
analysis (BIA) 
-Waist and hip circumference 
Measuring tape 
All 
-FMD, Flow Mediated Dilation 
Ultrasound 
All 
-Arterial Stiffness, PMV and 
Applanation tonometry 
All 
Augmentation Index 
-Height, weight, BMI 
Manual stadiometer and 
All 
digital scale 
-Dietary intake 
Three-day food record 
All 


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-7-day physical activity (PA) 
International PA 
Questionnaire 
All 
 
-Qualilty of life (with Prostate Cancer) 
EPIC 
All 
-Quality of life (overall health) 
RAND (SF-36) 
All 
 
 
 
 
Randomization and Blinding: Subjects will be block randomized and stratified to either 60 
mg/day oral genistein (30 mg BonisteinTM taken twice daily in the form of two I-Cool® tablets 
daily, provided by DSM Nutritional Products, Ltd., Basel Switzerland) or matching placebo. The 
Investigational Drug Pharmacy will provide the randomization scheme. 
 
 
7. ARCHIVED SPECIMENS: Specimens that remain after completion of the study will be stored 
for future studies beyond the scope of the current study only if subjects provide written informed 
consent to grant long term storage of samples. Any stored samples will be de-identified with a 
specific code whose identity can only be accessed by authorized study personnel appointed by 
the PI. 
 
8. COMMUNITY PARTICIPATION: Aside from participation in the study, this proposed study 
will not involve the community in the design or conduct of the study as the hypothesis is still in 
its infancy and would require larger confirmatory studies. Results of the research will be shared 
via publication in the scientific literature. Should our hypothesis prove correct, we will see 
additional funding for larger, confirmatory studies. If larger studies agree with the hypothesis, 
future studies will consider community-based research to impart the knowledge within the PCa 
community. 
 
 
9. PARTICIPANT SELECTION: 
 
Sample size: A total of 24 male adults with prostate cancer who will undergo ADT therapy will 
be recruited. As this is a pilot study, we have not accounted for expected refusals or 
withdrawals. 
Inclusion criteria: 1) Medical indication for ADT via luteinizing hormone-releasing hormone 
(LHRH) analog ± oral anti-androgen, 2) diagnosis of prostate cancer, 4) ECOG performance 
status ≤ 2, 5) life expectancy > 6 months, and 6) ability to provide informed consent 
Exclusion criteria: 1) Transmural myocardial infarction, unstable angina, or congestive heart 
failure requiring hospitalization within the last 6 months, 2) acute coronary event within the past 
month, 3) chronic liver disease, 4) current use of cytotoxic or immunosuppressive drugs, 5) 
chronic glucocorticoid or acute glucocorticoid or other synthetic steroid intake within the last 
month, 6) chronic diarrhea or malabsorptive diseases (e.g., Crohn’s disease), 7) stage 5 chronic 
kidney disease or need for hemodialysis, 8) supplemental oxygen dependency, 9) brain 
metastasis, 10) severe cognitive dysfunction impairing ability to provide informed consent or 
consume study drug, 11) dysphagia or requirement for artificial feeding, 12) surgery or 
hospitalization within the last month, 13) chemotherapy or radiation therapy within the last 60 


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days, 14) type 1 or type 2 diabetes, 15) HIV/AIDS, 16) hx of organ transplant, and 17) ECOG 
performance status > 2 
Subject recruitment plan: Potential subjects will be recruited among patients seen by Dr. 
Omer Kucuk and his Genitourinary Oncology group at the Emory, St. Joseph’s, and Grady 
campuses. 
Screening for eligibility: Patients will be pre-screened for eligibility using the Emory University 
Hospital (EUH) electronic medical record, and eligible subjects will be approached during their 
clinic visit. Potential study subjects will be identified among patients seen by Dr. Omer Kucuk 
and his Genitourinary Oncology group at the Emory, St. Joseph’s, and Grady campuses. Dr. 
Kucuk and his multidisciplinary oncology group initiate ADT therapy in approximately 8 patients 
per month. A study investigator or a study coordinator will conduct screening for eligibility 
among patients for whom ADT therapy is indicated. 
 
Study withdrawal: Participants may withdraw from the study at any time. Automatic withdrawal 
occurs when a participant moves away, refuses to take study drug, or refuses assessments for 
Specific Aim 1. 
 
10. INFORMED CONSENT PROCESS: 
A written and signed informed consent will be obtained in person in a private area. After 
identification of a person as eligible for the study, approved study personnel will explain the 
study in detail in the consent form as well as verbally. Potential participants will be informed of 
the purpose of the study, the study protocol, and the routine and potential risks associated with 
the study procedures. All risks, costs, and benefits will be discussed. Participants will be 
assured of their right to withdraw at any time without prejudice to their care. They will be 
assured of confidentiality in maintaining records and reporting of results. Any additional 
information regarding questions or concerns from potential or confirmed study participants will 
be provided. 
 
We will request a partial HIPAA waiver to be able to access the medical record for screening. 
 
The consent process will take place during a patient’s clinic visit. Potential study participants will 
have the option of taking the blank, unsigned consent forms home to consider prior to signing 
the consent forms, in which case patients who decide to participate will complete a verbal 
consent by telephone and will complete the full, written consent process during their study visit 
(prior to any procedures). Participants will have ample time to call the study team with 
questions/concerns and make an informed decision about their participation in the study. 
 
An approved study designee will provide verbal and written consent. The study is discussed 
thoroughly with each potential participant, and he/she will be encouraged to ask questions 
regarding the study and his/her participation. If the potential participant decides to enroll, he/she 
will sign the written informed consent, as will the study team member conducting informed 
consent. A copy of the signed consent form will be provided to enrolled study participants. 


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Subjects must be able to read, write and understand the consent documents. Study personnel 
will subjectively assess the capacity to give informed consent through the use of questions to 
ensure understanding and comprehension of the study. Only adults ages 18 yrs and older will 
participate in this study. 
 
If indicated (e.g., if a patient decides to take forms home to think about it), a verbal consent by 
telephone will be obtained to account for any study activities that occur prior to the first study 
visit. These include a 3-day food record, a wash-out period (if applicable), and fasting before the 
first visit. These procedures will be thoroughly explained by phone, and the study personnel 
conducting the consent by telephone will sign the verbal consent form. 
 
 
11. INCIDENTAL FINDINGS: Subjects will be receiving a DEXA and FMD scan for research 
purposes only.  The research does not require health professionals to read the scans. The 
researchers are not qualified to interpret the images for healthcare purposes, and the scans will 
not be used for clinical or diagnostic purposes.  If the researchers have a question about 
something on the scan, the subject will be told and the subject will have an option to have the 
scan sent to a qualified health professional for review and any further medical treatment. The 
DEXA procedure generates a report that includes bone mineral density (as well as body fat and 
lean body mass); however, it does not include medical interpretation. This report will be given to 
participants, and they will be encouraged to share this information with their healthcare 
providers in making a diagnosis about the state of his/her bones, body fat, and muscle mass. 
 
Subjects will also undergo oral glucose tolerance testing, as well as blood lipid and blood 
pressure testing. This information will be made available to the subjects and their physicians if 
desired. In addition, with the subject’s permission, we will notify the subject’s primary physician 
of findings that may have medical importance, such as abnormalities in blood pressure and 
blood tests. We will not provide medical care for the potential abnormalities but we will refer the 
subjects to their own physicians. In absence of a primary physician, we will assist the subjects 
to find appropriate referrals. 
 
12. COMPENSATION: Participants will be paid a total of $100 for completion of the 2 study 
visits ($50 per visit), in the form of cash. Participants will be paid upon the completion of each 
visit. Participants will only be paid for visits in which they participated. There will be no 
compensation or reimbursement for travel, parking or other expenses. 
 
13. STATISTICAL ANALYSIS: 
 
Descriptive statistics will be performed on all variables. The normality of distributions will be 
examined on continuous variables, and log-transformations performed as needed. All statistical 
analyses will be 2-sided with an alpha of 0.05. We will use mixed-model repeated measures 
ANOVA to determine if there are any effects of time, treatment, or group-by-treatment 
interactions on insulin sensitivity, insulin secretion, vascular function measures, or body 
composition. Biostatistician, Kirk Easley, MS, will be consulted, as needed and using de- 
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The primary endpoint for this study will be whole-body ISI. Sample size calculations were based 
on the only available study investigating changes in whole-body ISI in PCa patients receiving 
ADT17. Assuming a decline in whole-body ISI on average of 2.12 units over 3 months in the 
control group, on average no change in whole-body ISI in the genistein group, and an estimated 
pooled standard deviation in each group of approximately 1.77 units, a sample size of 12 PCa 
patients per treatment group (24 subjects total) will ensure 80% statistical power to detect a 
treatment difference of 2.12 units if the true difference between treatments is 2.12 units (two- 
sided two-sample equal-variance t-test and 5% significance level). Assuming a pooled standard 
deviation of 2.26% for FMD8 and 9.11 m/s for PWV13 in men with PCa undergoing ADT, we will 
have 80% power to detect a statistically significant difference of 2.7% and 10.9 m/s between 
treatment groups for FMD and PWV, respectively. 
 
It is possible that we have overestimated the true difference in outcomes between treatment 
groups in sample size calculations. However, this pilot clinical trial will provide important 
estimates of variability (within-subject and between-subject standard deviation) for the primary 
outcome. The estimates of variability, essential components for sample size calculations, will be 
valuable to power future longitudinal clinical studies. Due to the small sample sizes, results from 
this study will focus on the magnitude of the differences for each outcome, consistency of 
findings and clinical significance. Additionally, a sample size of 12 subjects per group has been 
proposed as being adequate for pilot clinical trials and providing useful data on precision about 
the mean difference and standard deviation for an outcome61. 
 
14. DATA AND SAFETY MONITORING PLAN: 
The study will be conducted under the Winship Data and Safety Monitoring Plan (DSMP). For all 
study procedures, trained clinical research study personnel will be with a participant at all times 
to monitor patient safety. Adverse events are expected to be uncommon and to not pose more 
than minimal risk to the study participants. With the exception of blood draws, participants may 
chose not to perform any of the procedures described in the consent form or to cancel 
operations during a procedure without affecting their standing in the study or their medical care 
team. 
Data and Safety Monitoring Committee: The Data and Safety Monitoring Committee (DSMC) 
of the Winship Cancer Institute will provide oversight for the conduct of this study. The DSMC 
functions independently within Winship Cancer Institute to conduct internal monitoring functions 
to ensure that research being conducted by Winship Cancer Institute Investigators produces 
high-quality scientific data in a manner consistent with good clinical practice (GCP) and 
appropriate regulations that govern clinical research. 
Depending on the risk level of the 
protocol, the DSMC review may occur every 6 months or annually.  For studies deemed High 
Risk, initial study monitoring will occur within 6 months from the date of the first subject accrued, 
with 2 of the first 5 subjects being reviewed. For studies deemed Moderate Risk, initial study 
monitoring will occur within 1 year from the date of the first subject accrued, with 2 of the first 5 
subjects being reviewed. Subsequent monitoring will occur in routine intervals per the Winship  
Data and Safety Monitoring Plan (DSMP). 
 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute 
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, 


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accuracy and availability of source documents, AEs/SAEs, and essential regulatory documents. 
Following the monitoring review, monitors will provide a preliminary report of monitoring findings 
to the PI and other pertinent individuals involved in the conduct of the study. The PI is required 
to address and respond to all the deficiencies noted in the preliminary report. Prior to the 
completion of the final summary report, monitors will discuss the preliminary report responses 
with the PI and other team members (when appropriate). A final monitoring summary report will 
then be prepared by the monitor. Final DSMC review will include the final monitoring summary 
report with corresponding PI response, submitted CAPA (when applicable), PI Summary 
statement, and available aggregate toxicity and safety data. 
 
The DSMC will render a recommendation and rating based on the overall trial conduct. The PI 
is responsible for ensuring that instances of egregious data insufficiencies are reported to the 
IRB. Continuing Review submissions will include the DSMC recommendation letter. Should 
any revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the 
PI will be responsible for notifying the DSMC of such changes. The Committee reserves the 
right to conduct additional audits if necessary. 
 
Frequency of data analysis: Blood samples will be analyzed on a quarterly basis for clinically 
relevant items such as blood glucose and lipids. Other blood or urine analytes will be measured 
in a single batch at the end of the study. The body composition analysis provide immediate 
results. Vascular function studies and food records will be analyzed on a quarterly basis. All 
items will be analyzed in a blinded fashion. Due to the blinded nature of the study, statistical 
analyses will not be performed until all participants have completed the study. 
Adverse events reporting: 
The Emory University IRB Reportable Events Guidelines for adverse events (AEs) and serious 
adverse events (SAE's) will be followed and timely reporting to the IRB will occur yearly and as 
needed. Any SAEs will be reported to the IND sponsor promptly and to the IRB within 10 days 
of the event if it is (a) an unanticipated problem involving risk to participants or others, (b) a 
death that is possibly, probably, or definitely related to the research, (c) an anticipated event 
occurring with a greater frequency, duration, or severity than what is described in the protocol 
related documents, or (d) any other information that suggests the research places participants 
or others at greater risk of harm than was previously known. A reportable events log will be 
maintained by the PI and reported annually to the IRB (or more frequently if required.) 
 
The clinical course of study participants will be monitored for adverse events on a weekly basis 
through the use of participant reminder calls and assessment of medical records. All AE’s, 
including those related to study procedures and/or those related to the study drug, will be 
recorded throughout the study period and significant clinical events are recorded as narrative 
data in the case report forms. Weekly phone calls will occur for the 12 weeks participants are in 
the study, weekly electronic medical record review will occur throughout the study and until 30 
days after the last dose of study drug is taken. For the purposes of study reporting, all deaths, 
unexpected serious adverse events (SAEs) and any AEs potentially related to study  
participation or study drug (genistein) and occurring following consent and until 30 days after the 
last dose of study drug, are reported using an AE form in the subject’s binder and sent to the 
Emory IRB and the DSMB (per the final DSMB charter). Ongoing SAEs and AEs will be 


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followed until resolved. New onset events beginning more than 30 days after the last dose of 
study drug will not be collected unless the co-investigator, Dr. Omer Kucuk, MD deems that the 
event is study-related (e.g. late onset drug toxicity). Adverse event data are compiled and 
reported to the DSMB. 
All adverse events will be assessed by the investigator as to their severity and attribution 
(unrelated to protocol, or possibly, probably, or definitely related to protocol). Any AE that is 
reported to either the PI or the study team by a study subject or by medical staff caring for the 
subject and which meets the criteria will be documented as such. 
Adverse events will also be further labeled as “expected” AEs (which are predefined and listed 
as potential risks in the informed consent), “unanticipated” AEs, and serious adverse events. 
Serious adverse events (SAE) are predefined as: any experience that suggests a significant 
hazard, such as events which: a) are fatal, b) are life threatening, c) result in permanent 
disability, d) require inpatient hospitalization, or e) involve cancer, a congenital anomaly, or drug 
overdose. 
 
Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious, 
unexpected suspected adverse reactions within 15 calendar days of learning of its occurrence. 
If the event is fatal or is deemed to be life threatening, the report will be made within 7 calendar 
days. The IND sponsor will also make an assessment of whether the event constitutes an 
unanticipated problem posing risks to subjects or others (UP). This assessment will be provided 
to the Emory University IRB, which, in turn will make a final determination. If the Emory IRB 
determines an event is a UP it will notify the appropriate regulatory agencies and institutional 
officials. 
 
Study team oversight: The study PI, Dr. Alvarez, will review all data collection forms on a 
quarterly basis for completeness and accuracy of the data as well as protocol compliance. The 
Emory-provided “Investigator Self-Monitoring Tool” will be completed approximately every 6 
months and signed by a member of the study team and the PI. The PI and research coordinator 
will meet on a weekly basis (and as needed) to discuss study updates, issues, and progress. 
 
Training on study procedures: An in-service will be conducted with all active members of the 
research team that are directly involved in day-to-day study procedures prior to the study start 
date and when significant protocol changes occur. A copy of the most recent protocol will be 
maintained in the study regulatory binder with signatures of all active study team members. 
Documentation of training will be maintained with dates and signatures. 
 
Additional Protections Against Risk: 
All study procedures: A licensed physician will complete a medical history and physical 
examination before study procedures. Experienced personnel will perform all procedures. Since 
the proposed tests are not inherently hazardous, hazard is likely to occur only as the result of 
impaired participant confidence or sudden unwillingness to complete a test. To avoid this 
possibility, study personnel will thoroughly explain all tests to potential participants prior to them 
signing the consent form. Potential participants will have the opportunity to see all test 
equipment and facilities before giving consent or undergoing testing. If any adverse event was 
to arise during the course of testing, a study physician will be on call for support. A qualified 
physician will have primary responsibility for outpatient care. If a participant suffers from 
claustrophobia or other distress during a procedure, the procedure will be discontinued. The 


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participant will then be managed in the Emory ACTSI outpatient CRN, which, if applicable or 
warranted, have immediate access to EKG monitoring, cardiac resuscitation equipment and is 
located in close proximity to the Emory University Hospital, respectively. Every effort will be 
taken to prevent injury or distress that may result from this study. 
 
Subject identification and screening: Our strict inclusion and exclusion criteria for entry will 
minimize potential risks. 
 
Blood sampling: Experienced nurses will perform blood draws and heparin lock insertion 
procedures using aseptic techniques. Disposable pre-sterilized needles and syringes will be 
used for all blood drawing in this study; needles and syringes will not be reused. Participants will 
be asked to stay hydrated with water the day before the study visit. Discomforts associated with 
venipuncture are rapidly reversible. 
 
Flow-mediated dilation: There will be a period of time after the test when a trained technician 
will monitor for any unusual reactions to the testing. 
 
Genistein supplements: Subjects will receive weekly phone calls, text, or encrypted email to 
monitor for potential adverse events. We will screen specifically for GI symptoms, as well as any 
signs of allergic reaction (rash, shortness of breath). If a participant reports any symptoms 
potentially related to the study drug, the PI will consult with study physicians (Drs. Ziegler and/or 
Kucuk) who will follow-up with the participant by phone to determine the clinical severity of the 
symptoms. Based on the severity of symptoms, the study physicians will decide whether to 
continue the study drug as prescribed, lower the dose to 30 mg/day, or discontinue completely. 
Regardless of decision on study drug, subjects will continue to be followed and follow-up 
procedures performed as per study protocol. 
 
Confidentiality: Only Emory institutional review board (IRB)-approved study personnel will 
have access to individually identifiable information about human subjects. Confidentiality will be 
assured by the use of subject codes rather than personal identifiers. All subject records will be 
kept in locked file cabinets or password-protected electronic files and will be accessible only to 
the PI and the investigative team. After the study is completed, all data will be kept according to 
NIH regulations in a locked file. 
 
Stopping rules: The Winship DSMB will make a recommendation to the investigator and 
sponsor whether or not the study should be stopped based on adverse events. Individual 
participants will be able to withdraw at any point in the study and for any reason. 
 
15. CONFIDENTIALITY 
All participant interactions will be conducted in private settings (either behind closed doors or in 
individual curtained cubicles.) Only institutional review board (IRB)-approved study personnel 
will have access to individually identifiable information about human subjects. This may include 
the study PI (Jessica Alvarez), co-investigators, research coordinators and other approved 
study personnel. All information and materials will be obtained for research purposes only and 
the data will be kept in strict confidence for use in this proposed research only. Confidentiality 
will be assured by the use of subject codes rather than personal identifiers. All subject records 
will be kept in locked file cabinets in the PI’s research office and will be accessible only to the PI 
and the investigative team. The master list connecting the subject codes to identifying 
information will be secured in a web-based case report form (RedCap) that is supported for 
faculty by the ACTSI. All data maintained in the computerized database will be accessible only 


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with a login and protected password. After the study is completed, all data will be kept in a 
locked file. 
 
 
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