A Phase 2 Double-blind, Placebo-controlled Study of the Effects of Muscadine Grape Extract in Men With Prostate Cancer on Androgen Deprivation Therapy
Phase: PHASE2
Conditions: Recurrent Prostate Cancer
Sponsor: Wake Forest University Health Sciences

Phase 2 Double-blind, Placebo-controlled Study of the Effects of Muscadine Grape Extract in 
Men with Prostate Cancer on Androgen Deprivation Therapy 
Comprehensive Cancer Center of Wake Forest University; CCCWFU #85417 
 
4/2/2025 
 
Principal Investigator: 
 
Heidi D. Klepin, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
Co-Investigator(s):  
 
Rhonda L. Bitting, MD 
Section on Medical Oncology 
Duke University School of Medicine 
 
 
Ronald Davis III, MD, MBA 
Department of Urology 
Wake Forest School of Medicine 
 
 
Bart Frizzell, MD 
Department of Radiation Oncology 
Wake Forest School of Medicine 
 
 
Patricia Gallagher, PhD 
Hypertension & Vascular Research Center 
Wake Forest School of Medicine 
 
 
Michael Goodman, M.D. 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
Ashok Hemal, MD 
Department of Urology 
Wake Forest School of Medicine 
 
 
Michael McCormack, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 

Phase 2 Double-blind, Placebo-controlled Study of the Effects of Muscadine Grape Extract in 
Men with Prostate Cancer on Androgen Deprivation Therapy 
Comprehensive Cancer Center of Wake Forest University; CCCWFU #85417 
 
4/2/2025 
 
E. Ann Tallant, PhD 
Hypertension & Vascular Research Center 
Wake Forest School of Medicine 
 
 
 
 
 
 
 
 
Jing Li, MD, PhD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
Biostatisticians: 
Janet A. Tooze, PhD 
Wake Forest Baptist Comprehensive Cancer Center  
 
 
 
Scott Isom, MS 
Wake Forest Baptist Comprehensive Cancer Center 
 
 
 
Study Coordinators:  
 
Brittany M. Davis, MDiv, MBA 
Hypertension & Vascular Research Center 
Wake Forest School of Medicine 
 
 
 
Marisela Velasquez de Kamm, MD, MS 
Hypertension & Vascular Research Center 
Wake Forest School of Medicine 
 
 
Regulatory Contacts: 
 
Emily Teal 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
Research Nurse (RN): 
 
WFBH Forest Clinical Research Unit 
 
 
 
 
 
 
Madison Skotcher, MSN, RN, BSHA 
 
 
 
 
 
Comprehensive Cancer Center of Wake Forest University  
 
 
 
 
 
 
 
 
 
 
 
 
Data Manager: 
Deanna Hissim 

Phase 2 Double-blind, Placebo-controlled Study of the Effects of Muscadine Grape Extract in 
Men with Prostate Cancer on Androgen Deprivation Therapy 
Comprehensive Cancer Center of Wake Forest University; CCCWFU #85417 
 
4/2/2025 
 
 
Participating Institutions:     
Coordinating Center 
Wake Forest University in Winston-Salem, NC 
 
Other Sites 
W.G. (Bill) Hefner VA Medical Center 
1601 Brenner Avenue 
Salisbury, NC 28144 
Site PI: Michael Goodman, MD 
 
 
Version Date: 
 
 
4/2/2025 

 
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Table of Contents 
SCHEMA ....................................................................................................................................... 7  
1.0 
Introduction and Background ...........................................................................................  8 
1.1 Preclinical Studies with Muscadine Grape Products ........................................................... 8 
1.2 Preclinical Toxicity Studies with MGE ............................................................................... 12 
1.3 Clinical Studies with Muscadine Grape Products .............................................................. 14 
1.4 Rationale for MGE Dosing ................................................................................................. 12 
1.5 Rationale for MGE Dosing in Biochemically Recurrent Prostate Cancer .......................... 14 
2.0 
Objectives ....................................................................................................................... 16 
2.1 
Primary Objective ........................................................................................................ 16 
2.2 
Secondary Objectives ................................................................................................. 17 
2.3 
Exploratory Objectives ................................................................................................ 17 
3.0 
Patient Selection ............................................................................................................. 18 
3.1 
Inclusion Criteria.......................................................................................................... 18 
3.2 
Exclusion Criteria ........................................................................................................ 19 
3.3 
Inclusion of Women and Minorities ............................................................................. 19 
4.0 
Screening, Registration, and Randomization Procedures............................................... 20 
4.1 
Screening .................................................................................................................... 20 
4.2 
Registration (Lead Site) ............................................................................................... 20 
4.3 
Randomization (Lead Site) .......................................................................................... 20 
4.4 
Registration and Randomization (Participating Sites) ................................................. 21 
4.5 
Blinding........................................................................................................................ 21 
4.6 
Multicenter Guidelines ................................................................................................. 21 
5.0 
Study Outcomes and Study Measures ............................................................................ 22 
5.1 
Primary Outcome ........................................................................................................ 22 
5.2 
Secondary Outcomes .................................................................................................. 23 
5.3 
Exploratory Outcomes ................................................................................................. 25 
6.0 
Treatment Plan ................................................................................................................ 26 
6.1 
Study-Related Activities .............................................................................................. 26 
6.2 
Treatment Administration ............................................................................................ 27 
6.3 
General Concomitant Medication and Supportive Care Guidelines ............................ 28 
6.4 
Study assessments ..................................................................................................... 28 

 
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6.5 
Duration of Study Intervention ..................................................................................... 29 
6.6 
Duration of Follow Up .................................................................................................. 30 
6.7 
Criteria for Removal from Study Intervention .............................................................. 30 
7.0 
Dosing Delays/Dose Modifications .................................................................................. 30 
7.1 
Missed doses .............................................................................................................. 30 
7.2 
Dose modification ........................................................................................................ 31 
8.0 
Adverse Events List and Reporting Requirements ......................................................... 31 
8.1 
Adverse Event List ...................................................................................................... 31 
8.2 
Adverse Event Characteristics .................................................................................... 31 
8.3 
STRC SAE Reporting Requirements .......................................................................... 32 
8.4  
WFUHS IRB AE Reporting Requirements .................................................................. 32 
9.0 
Pharmaceutical Information ............................................................................................ 33 
9.1 
Pharmaceutical Accountability .................................................................................... 33 
9.2 
Muscadine Grape Extract (MGE) ................................................................................ 33 
9.3 
Placebo ....................................................................................................................... 34 
10.0 
Correlative/Special Studies ............................................................................................. 34 
10.1 
Biomarkers of antiogenesis, inflammation and oxidative stress .................................. 35 
10.2 
Pheolic Assays ............................................................................................................ 35 
10.3 
Plasma, PBMC, and whole blood specimen banking .................................................. 35 
10.4 
Manganese superoxide dismutase genotype .............................................................. 35 
11.0 
Data Management ........................................................................................................... 37 
12.0 
Statistical Considerations ................................................................................................ 37 
12.1 
Analysis of Primary Objective (fatigue) ....................................................................... 37 
12.2 
Analysis of Secondary Objectives ............................................................................... 37 
12.3 
Analysis of Exploratory Objectives .............................................................................. 37 
12.4 
Power and Sample Size .............................................................................................. 40 
12.5 
Estimated Accrual Rate ............................................................................................... 40 
12.6 
Estimated Study Length .............................................................................................. 40 
12.7 
Interim Analysis Plan ................................................................................................... 40 
References .................................................................................................................................. 40 
APPENDIX A: Registration Form, see eIRB “Other Documents”  
APPENDIX B: Race and Ethnicity Verification, see eIRB “Other Documents”  
APPENDIX C: Eligibility Screener, see eIRB “Other Documents”  

 
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APPENDIX D: Serious Adverse Event (SAE) Notification SOP, see eIRB “Other Documents” 
APPENDIX E:  Baseline Data Collection Form, see eIRB “Other Documents”  
APPENDIX F:  Month 3/9 Data Collection Form, see eIRB “Other Documents”  
APPENDIX G: Month 6/12 Data Collection Form, see eIRB “Other Documents” 
APPENDIX H: PROMIS v1.0 Fatigue 7a, see eIRB “Other Documents”  
APPENDIX I: PROMIS v1.2 Global Health, see eIRB “Other Documents”  
APPENDIX J: Hot Flash Related Daily Interference Scale, see eIRB “Other Documents”  
APPENDIX K: PROMIS v1.0 Sleep Disturbance 8a, see eIRB “Other Documents”  
APPENDIX L: PROMIS v2.0 Cognitive Abilities 4a, see eIRB “Other Documents”  
APPENDIX M: PROMIS v2.0 Physical Function 10a, see eIRB “Other Documents”  
APPENDIX N: Short Physical Performance Battery (SPPB), see eIRB “Other Documents”  
APPENDIX O: 6 Minute Walk Test Protocol, see eIRB “Other Documents”  
APPENDIX P: Telephone Follow-Up Form, see eIRB “Other Documents”  
APPENDIX Q: AE Ascertainment Form (CTCAE v5), see eIRB “Other Documents”  
APPENDIX R: Adverse Event (AE) Log,  see eIRB “Other Documents” 
APPENDIX S: Serious Adverse Event Reporting Form, see eIRB “Other Documents” 
APPENDIX T:  Disease Progression, see eIRB “Other Documents”  
APPENDIX U: Participant Status Change Form, see eIRB “Other Documents” 
APPENDIX V:  End-of-study Follow-up Form, see eIRB “Other Documents”  
APPENDIX W: Pre-Toxicity Form, see eIRB “Other Documents” 
 
APPENDIX X: DXA Questionnaire, see eIRB “Other Documents” 
 
APPENDIX Y: Adherence Telephone Script, see eIRB “Other Documents” 
 
 

 
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SCHEMA 
 
 
 
Follow-up every 3 months; 
Primary endpoint assessed at 6 
months 
Eligibility, consent and pre-study data collection 
1:1 randomization 
MGE (n= 53) for 12 
months 
Placebo (n= 53) for 12 
months 
End of treatment at 12 months or 
at disease progression resulting in 
change in therapy 
Off Study @ 12 months 

 
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1.0 
Introduction and Background 
 
It is estimated that one-third of the more than 7 million deaths from cancer worldwide are 
attributable to potentially modifiable risk factors, with 374,000 deaths preventable through diet 
modification alone (not including those attributable to obesity or physical inactivity).1 Diet 
supplementation for the prevention or treatment of cancer is attractive, as implementation is 
relatively easy, even in populations with reduced incomes and resources.  Grape extracts or 
active components isolated from grapes have received attention as chemopreventive or 
therapeutic agents based upon their anti-proliferative, anti-inflammatory, and anti-oxidant 
properties.2  
 
The muscadine grape (Vitis rotundifolia), found in the warm, humid climate of southeast United 
States, has a distinct phytochemical composition as compared to other grape varieties.  The 
muscadine grape contains a high concentration of anthocyanin 3,5-diglucosides, ellagic acid, 
ellagic acid precursors, gallic acid, flavan-3-ols and flavonols.3  Several preclinical studies with 
muscadine grape products have revealed anti-tumor activity, including inhibition of tumor cell 
growth and induction of apoptosis.4-7 Evidence from preclinical trials also suggests that muscadine 
grape products may decrease systemic inflammation.8-11  Higher levels of inflammation may not 
only increase cancer recurrence risk,12 but also impair quality of life.  Higher levels of systemic 
inflammation are associated with increased fatigue13, reduced levels of physical activity, 
adiposity14,15 and lower levels of physical function16-18.  By reducing levels of circulating 
inflammatory markers such as CRP and IL-6, muscadine grape products may improve cancer 
outcomes by decreasing symptom burden, particularly fatigue. 
 
Despite reports indicating potential anti-tumor activity,4-6 there are limited clinical studies on the 
efficacy of muscadine grape products in the prevention or treatment of cancer or cancer-related 
side effects, representing an opportunity for novel investigation.  This study builds upon promising 
preclinical and clinical evidence to determine if the addition of a proprietary muscadine grape 
extract (MGE) to androgen deprivation therapy improves symptoms in men with prostate cancer.    
 
1.1 Preclinical Studies with Muscadine Grape Products 
 
Literature overview:   The anti-tumor properties of muscadine grapes have been demonstrated 
in preclinical models.4-7 In a mouse model, Porter et al examined the effects of muscadine grape 
extract on lung tumor formation in the fetus following transplacental exposure to a carcinogen and 
showed that muscadine exposure through drinking water reduced both tumor proliferation and 
angiogenesis, leading to a decrease in tumor burden and multiplicity.19 Exposure to muscadine 
grape extract through drinking water similarly reduced breast tumor burden and multiplicity in c-
neu mice.20  In a study by God et al, four varieties of muscadine grape were tested and showed 
significant inhibition of 2-aminoanthracene mutagenesis, high antioxidant activity, and the ability 
to inhibit activities of metalloproteinases, implying that muscadine products could inhibit 
carcinogenesis.6 In colon carcinoma cells, muscadine exposure induced cell death.4,5  In prostate 
cancer cell lines, treatment with muscadine grapes induced both cell cycle arrest and apoptosis, 
by downregulating the phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway.7 The PI3K/Akt 
pathway is a key oncogenic signaling pathway that has been linked to tumorigenesis and 

 
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resistance to anticancer therapies in a wide variety of tumor types.21  A study by Burton et al 
examined the effects of muscadine grape product on bone turnover in prostate and breast cancer 
cell models overexpressing Snail transcription factor.22  They show that Snail regulation can be 
antagonized by muscadine exposure, leading to decreased cell invasion, migration and bone 
turnover, and thus suggesting that muscadine grapes could be a promising bioactive treatment 
for bone metastatic cancer. 
Overview of data from the investigative team:  Preliminary studies from the investigative team 
(Gallagher/Tallant laboratory) demonstrate that extracts of muscadine grape seeds and skins 
reduced the proliferation of both human breast and prostate cancer cell lines. The reduction in 
breast cancer cell growth was associated with a decrease in activated mitogen activated protein 
(MAP) kinase, a critical enzyme involved in cell proliferation.  In addition, muscadine grape liquid 
extract reduced the tumor burden in a transgenic model of spontaneous breast cancer with a 
concomitant attenuation in proliferation, tumor blood vessel formation, and tumor-associated 
fibrosis. These data are described below and 
provide additional rationale to assess the 
efficacy of MGE on cancer outcomes in 
clinical studies. 
Inhibition of Prostate Cancer Cell Proliferation by 
Muscadine Grape Components  
Actively growing human LnCaP or PC3 prostate 
cancer cells were treated for 7 days with 
increasing concentrations of muscadine grape 
extracts, to determine whether the extracts 
reduced prostate cancer cell proliferation.  As 
shown in Figure 1, extracts from both grape 
seeds and skin reduced the proliferation of LnCaP 
or PC3 human prostate cancer cells.  The 
responses were dependent upon the dose of 
extract used, and similar responses were 
obtained with grape seed extract compared to 
grape skin extract.   
 
Inhibition of Breast Cancer Cell Proliferation by 
Muscadine Grape Components  
Actively growing human breast cancer cells — 
ZR-75-1 ER+ breast cancer cells, MDA-MB-231 
or SKBR3 triple negative breast cancer cells -- 
were treated for 7 days with increasing 
concentrations of extracts from either muscadine 
grape seeds or skins, to determine whether the 
extracts reduced breast cancer cell proliferation. 
Similar to the effects seen in prostate cancer cell 
lines, muscadine grape extract reduced the proliferation of human breast cancer cells. The 
Con     
.5
5
50
    
.5
5
50
0
50
100
150
**
**
**
**
   Nature's Pearl
Grape Seed Extract
         (µg/mL)
   Nature's Pearl
Grape Skin Extract
         (µg/mL)
LnCaP
Cell Growth
PC3
Con
  
.5
5
50
  
.5
5
50
0
50
100
150
**
**
**
   Nature's Pearl
Grape Seed Extract
         (µg/mL)
   Nature's Pearl
Grape Skin Extract
         (µg/mL)
Cell Growth
Figure 1. LnCaP or PC3 human prostate cancer 
cells 
were 
incubated 
with 
increasing 
concentrations of either muscadine grape seed 
or grape skin extracts and cell proliferation was 
quantified by counting the number of cells per 
well. The data are presented as the percent of 
the Control (Con), which was not treated with 
either extract. n = 12, ** denotes p < 0.01. 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
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responses were dependent upon the dose of extract used, and similar responses were obtained 
with grape seed extract compared to grape skin extract. 
 
Because treatment with muscadine grape seeds versus skins showed no significant 
difference in effect on cancer cell lines, additional preclinical studies were performed with 
muscadine grape extract (MGE), which contains both seeds and skins. 
 
In vitro and in vivo studies with MGE 
 
To study the effects of muscadine grape extract in humans, the muscadine grape liquid extract is 
dried, converted to powder form, and encapsulated.  This proprietary product is the muscadine 
grape extract (MGE) used in the preclinical studies described below.  However, because rodents 
do not swallow capsules, the MGE powder is reconstituted and added to the drinking water.    
 
MGE reduced the migration of triple negative and HER2 over-expressing breast cancer cells 
(Collard, Gallagher, and Tallant, presented at 2017 Experimental Biology Annual Meeting).  
Treatment of murine and human triple negative breast cancer cells with MGE altered the 
expression of 2196 and 2840 genes, respectively, with 298 genes common between the two cell 
lines with respect to time of incubation.  These genes are involved in numerous cellular processes 
including proliferation, angiogenesis, energy metabolism, protein processing, cellular structure, 
DNA replication, DNA repair, and autophagy.  
 
Treatment of triple negative breast cancer cells with MGE was associated with a significant 
reduction in the hyaluronan-mediated motility receptor (RHAMM), a regulator of both proliferation 
and migration, as well as phospho-RB which modulates the expression of RHAMM and cyclin D1, 
a critical component of the cell cycle.  MGE inhibited protein kinase B (AKT) signaling in human 
triple negative breast cancer cells and mitogen activated protein kinase (MAPK) signaling in 
murine triple negative breast cancer cells, suggesting differential regulation of molecular 
pathways that control the cyclin D1/phospho-RB/ HMMR pathway in triple negative breast cancer 
(Collard, Tallant and Gallagher, submitted for presentation at the 2018 American Society of 
Nutrition annual meeting).   
 
The MGE-induced reduction in HER2 over-expressing breast cancer was associated with a 
decrease in phosphorylation and activation of protein kinase B (AKT) which regulates proliferation 
and migration as well as phosphoinositide-dependent kinase-1 (PDK1), a primary activator of 
AKT. AKT activation inhibits Forkhead box protein (FOXO1) transcription factor, decreasing 
expression of negative cell-cycle regulators, including cyclin-dependent kinase inhibitor 1B (p27), 
resulting in increased proliferation.  Treatment with MGE significantly increased FOX01 and p27, 
suggesting a mechanism for the inhibition of cell cycle progression by MGE. Further, S-phase 
kinase-associated protein 2 (SKP2) which targets p27 and FOX01 for degradation, was reduced 
in HER2 over-expressing breast cancer following incubation with MGE, demonstrating multiple 
molecular mechanisms for the reduction in proliferation in HER2 over-expressing breast cancer 
(Mackert, Gallagher and Tallant, submitted for presentation at the 2018 American Society of 
Nutrition Annual Meeting).   
 

 
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As described above, the growth of 2 different prostate cancer cell lines was also significantly 
reduced by MGE. RNA seq analysis of human prostate cancer cells treated with MGE identified 
2768 genes that were altered by the extract, including genes involved in cell proliferation, cell 
division, mitosis, energy metabolism, protein processing, cellular structure, DNA replication, DNA 
repair, and autophagy. In addition, 614 genes were common between the prostate cancer cells 
and the breast cancer cells, suggesting that the extract may regulate common signaling pathways 
in a variety of cancer cell types. Ongoing studies are interrogating the major pathways that are 
regulated by MGE in prostate cancer cells. 
 
To determine if MGE reduces the 
growth of human tumors in vivo, 
nude mice were given MGE in their 
drinking 
water. 
Human 
breast 
cancer cells were injected into the 
mammary fat pad and human 
prostate cancer cells into the flank. 
Tumor size was measured. Both 
breast 
and 
prostate 
tumors 
measured significantly smaller in 
mice receiving MGE compared to 
mice drinking water without MGE, 
as shown in Figure 2.    
 
Specifically for the prostate cancer 
tumors, athymic mice (male, 15-20 g, 5-6 weeks of age) were injected subcutaneously on the 
lower flank with 1.6 x 106 LNCaP cells.  When the tumors reached 100 mm3, the mice were 
randomized to drinking water with MGE or untreated water. After 5 weeks, the mice were 
sacrificed and the tumors were weighed. The volume of prostate tumors growing in the flank of 
nude mice drinking water with MGE was markedly reduced compared to the size of the tumors 
from control mice (n=6, p<0.001). Further, the weight of prostate tumors from mice drinking MGE 
was also significantly decreased, [0.96 ± 0.14 g (control) as compared to 0.41 ± 0.11 g (MGE)]; a 
reduction of 57% (p < 0.05).  Five micron tumor sections were incubated with an antibody to CD34 
and tumor vessels were identified by positive immunoreactivity and morphology. In the prostate 
tumors, there were fewer blood vessels visualized and decreased expression of vascular 
endothelial growth factor and placental growth factor, suggesting that MGE inhibits angiogenesis 
(Gallagher and Tallant, presented at AACR 2017 annual meeting). These results demonstrate 
that MGE reduces prostate tumor growth in a mouse model, by inhibiting angiogenesis, 
suggesting that MGE may be an effective treatment for prostate cancer. 
 
There is also preclinical evidence that muscadine products decrease systemic inflammation.8-11  
Higher levels of inflammation may not only increase cancer recurrence risk,12 but also increase 
fatigue,13 adiposity14,15 and decrease physical function.16-18 By lowering levels of circulating 
inflammatory markers, treatment with muscadine products may impact these processes.  The 
effect of MGE on exercise was assessed in female hemizygous (mRen2)27 transgenic rats, a 
well-characterized model of hypertension.  The rats were chronically administered MGE (20 mg 
of total phenolics/kg body weight/day) in the drinking water starting at 14 weeks of age.  Control 
**p <0.01 
***p <0.001 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
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rats received water only. At 70 weeks of age, exercise tolerance was assessed by treadmill.  As 
shown in Figure 3, long-term consumption of MGE did not reduce or exacerbate hypertension, 
but did increase the exercise capacity, workload performance, and time to exhaustion in female 
hypertensive rats. This effect was associated with a decrease in 8-OH-deoxyguanosine, a 
circulating marker of oxidative stress (Duncan AV et al, presented at 2017 Experimental Biology 
annual meeting). Additional preclinical studies evaluating fatigue and exercise capacity are 
ongoing. In cardiac cells, MGE increased maximal respiration, spare respiratory capacity and ATP 
production, suggesting that an increase in energetic capacity and bioenergetics may participate 
in the enhanced exercise capacity in hypertensive rats. 
 
 
 
1.2 Preclinical Toxicity Studies with MGE 
 
The primary goal of the rodent toxicity tests with MGE was to identify the range of doses that 
caused no life-threatening or adverse effects, thereby providing critical information for conduct of 
clinical trials to assess toxicity in humans with cancer and establishing an estimated clinical 
margin of safety.   
  
Male C57 black mice (8 weeks of age) were randomized into groups to receive drinking water 
alone (control) or drinking water with MGE at four escalating doses of MGE, as determined by 
measurement of total phenolics. Daily observations of the mice included evaluations for weight 
loss, diarrhea, dehydration, edema, abdominal enlargement or ascites, progressive dermatitis, 
rough hair coat or unkempt appearance due to lack of grooming, hunched posture indicative of 
pain, lethargy or persistent decumbency due to loss of appetite, coughing, labored breathing, 
nasal discharge, jaundice, cyanosis, pallor/anemia, neurological signs indicated by inappropriate 
head carriage or shaking of the head, bleeding from any orifice, or any condition interfering with 
daily activities. Prior to sacrifice, the mice were placed in metabolic cages for 24 hours, and food 
intake and fecal and urine output were measured to quantify markers of renal damage. During 
the 4th week of treatment, blood pressure was determined by tail cuff plethysmography in 

 
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conscious mice and cardiac function was assessed in mice anesthetized with isofluorane, using 
a non-invasive, small animal VEVO ultrasound imaging system to measure or calculate ejection 
fraction, fractional shortening, stroke volume, heart rate and cardiac output.  The mice were 
sacrificed after one month of treatment; tissues (heart, kidney, lung, liver, spleen and brain) were 
weighed, fixed in 4% formalin, embedded in paraffin, sectioned at 5 microns and stained with 
Hematoxylin & Eosin (H & E) for analysis by a veterinary pathologist to assess any gross structural 
abnormalities. 
 
Four concentrations of the MGE were tested for the toxicity studies in mice, based upon the 
studies in the Gallagher/Tallant laboratory reported above.  MGE at 0.25, 0.5, 1 and 2 mg total 
phenolics/mouse/day was administered to the mice in their drinking water. Total phenolic content 
was determined using the Folin-Ciocalteau reagent with gallic acid as the standard.  Because an 
average mouse of this age weighs approximately 25 g or 0.025 kg, this corresponds to a dose 
range of 10, 20, 40 and 80 mg total phenolics/kg/day.   
 
Results: 
During the 4 week administration of the MGE at the four doses, there were no observations of 
diarrhea, dehydration, edema, abdominal enlargement, loss of hair coat, reduced grooming, or 
decreased level of activity, appetite, drinking or breathing. There were no indications of pallor, 
jaundice or cyanosis or any neurological signs of discomfort. There was no bleeding or discharge. 
These results suggest that the mice were free from any pathology that affected their normal daily 
activities or health.  The weight of the mice at the end of the 4-week treatment period was similar 
with the three lowest concentrations of the MGE compared to the control group.  Mice treated with 
the highest concentration of MGE had a small but significant decrease in total body weight (from 
28.6 ± 1.2 grams to 25.0 ± 1.3 grams, which represents less than 15% of their total body weight). 
However, there was no effect on food intake, fecal output or urine volume compared to the 
untreated mice, measured during the last week of treatment, suggesting little effect of the MGE 
on eating and drinking behaviors. 
 
At the time of sacrifice, organs were removed and weighed and the organ weights of mice treated 
with each dose of MGE were compared to the untreated control group. A portion of each organ 
was fixed in formalin, sectioned and stained with H & E, for assessment by a veterinary 
pathologist.  In addition, the heart and kidney were assessed by echocardiography and 
radioimmunoassay of urinary proteins, respectively, as a further measure of heart and renal 
function. There was no difference in the weight or structure of the hearts of mice treated with 
increasing doses of MGE. Cardiac parameters including ejection fraction, fractional shortening, 
cardiac output, stroke volume and heart rate were all similar in mice treated with MGE compared 
to untreated Control mice. There was no difference in the weight or structure of the lungs of mice 
treated with MGE compared to the untreated control mice. The weight of the livers of mice treated 
with the two lowest MGE (0.25 and 0.5 mg phenolics/mouse/day) and the highest MGE (2 mg 
phenolics/mouse/day) concentrations were no different than the weight of the livers of the 
untreated mice.  However, the weight of the livers of mice in the 1 mg phenolics/mouse/day) was 
slightly increased compared to the control. Spleen weight of mice treated with MGE was not 
significantly different than untreated control mice and the spleens of mice were generally within 
normal limits with one mouse in the highest MGE treatment group having some extra medullary 
hematopoiesis. The weight of the brains of mice treated with MGE was not significantly different 
than untreated mice. The brains were subdivided into four regions—cortex, cerebellum, 
hypothalamus and brainstem. All brain regions examined were within normal limits.  
 
Conclusions from toxicity studies: 
Little toxicity was observed at any of the doses tested.      

 
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1.3 Clinical Studies with Muscadine Grape Products 
 
Muscadine grape skin extract has been evaluated in clinical trials to a limited extent in the setting 
of cardiovascular disease23 and diabetes.24 In a randomized, double-blind, placebo-controlled 
crossover trial, 50 adults with coronary disease or ≥1 cardiac risk factor received muscadine grape 
seed supplementation (1300 mg daily) and placebo for 4 weeks each, with a 4-week washout, 
and no adverse events were reported.23 Similarly, a randomized study of non-diabetic and type 2 
diabetic participants using 150 mL of muscadine grape juice, muscadine grape wine, and 
dealcoholized muscadine grape wine over a 28-day period had no adverse events reported.24 
 
A muscadine grape product has also been examined in a phase 1/2 trial of men with biochemically 
recurrent prostate cancer.25 The phase 1 portion of the study evaluated increasing doses of 
pulverized muscadine grape skin in a product called MPX (Muscadine Naturals Inc, Clemmons 
NC) in cohorts of two patients, with six patients at the highest dose of 4,000 mg (n=14). Dose 
selection was based on unpublished preclinical work in animal studies. Four patients experienced 
grade 1 adverse gastrointestinal symptoms possibly related to the study agent, including 
flatulence, soft stools, and burping. No other related adverse events were reported.  Six of the 14 
patients came off study for disease progression after exposure for a median of 15 months.  Median 
within-patient PSA doubling time increased by 5.3 months (non-significant, P=0.17).  Based on 
the favorable safety profile and a possible lengthening of PSA doubling time, the phase 2 portion 
of this study was expanded to 125 patients randomized to placebo, 500 mg/d, or 4000 mg/d MPX 
arms. Compared to placebo, there was no lengthening of the PSA doubling time in prostate cancer 
patients taking MPX. No additional safety signals were seen. The investigators did identify a 
subgroup of patients with manganese superoxide dismutase (MnSOD) genotype AA (21% 
patients) who appeared to benefit, and a larger study in this patient population is planned (Paller 
et al, presented at 2017 ASCO Genitourinary symposium).  MnSOD is an important mitochondrial 
antioxidant enzyme, and patients with MnSOD AA genotype have been shown to be more 
sensitive to antioxidant treatment.26 Treatment with pomegranate extract in a similar patient 
population was also suggested to benefit patients with the MnSOD AA genotype.27   
 
We conducted a phase 1 study of MGE in patients with advanced solid tumors (clinicaltrials.gov 
identifier NCT02583269). Adult patients with metastatic or unresectable malignancy progressing 
on standard therapies were assigned to MGE (~160 mg total phenolics/capsule, Piedmont R&D) 
in a standard 3 + 3 design. Five dose levels were tested (320 to 1600 mg total phenolics/day).   
Safety and maximum tolerated dose (MTD) were assessed after 4 weeks.  Patients were 
evaluated for response at 8 weeks and continued on MGE if clinically stable. 23 pts (lung n=7; 
gastrointestinal n=7; genitourinary n=6; other n=3) were treated. Two patients were inevaluable at 
4 weeks (1 withdrew, 1 noncompliant).  The evaluable cohort (median age 72 years [range 43-
86], 48% female, 95% white) was heavily pre-treated. After 4 weeks on MGE, possibly-
attributable grade 2-3 adverse events were decreased lymphocytes (4.7%), fatigue (4.7%), and 
constipation (9.5%), including one dose limiting toxicity for grade 3 constipation requiring 
hospitalization, most likely attributable to progressive peritoneal disease although contribution 
from MGE could not be excluded. Dose level 2 was expanded accordingly.  Otherwise, MGE was 
very well tolerated with no other grade 3 or higher adverse events.  MTD was not reached. 93% of 
pts took ≥ 80% of pills prescribed.  Median time on therapy was 8.1 weeks (95% CI 7.7, 20.3) with 
a 7.1 month median OS (95% CI 4.3, 12.2). Quality of life and fatigue levels were stable from 
baseline to 4 and 8 weeks (p values >0.2).  Higher MGE dose was correlated with improvement 
in self-reported physical function at 8 weeks (r= 0.56, p=0.04). We concluded that MGE is safe 
and well-tolerated in heavily pretreated and elderly cancer patients, and that the relationship 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 15 of 48 
between MGE and improved physical function warrants further study (Bitting RL et al, abstract 
submitted for ASCO 2018 annual meeting). 
 
In summary, muscadine grape products have shown anti-cancer and anti-inflammatory activity in 
preclinical models and have demonstrated a favorable safety profile in preclinical and clinical 
studies.  The proposed study with MGE represents an opportunity to translate promising data with 
a natural product into a clinical trial in men with prostate cancer. 
 
1.4 Rationale for MGE Dosing 
 
There are many muscadine grape products commercially available.  The concentration of 
phenolics in 9 commercially available muscadine products was tested and compared to MGE.  
The concentration of phenolics in MGE was more than three times higher than in any other 
product, at approximately 162 mg phenolics per capsule, compared to approximately 50 mg 
phenolics/capsule or less.  Mass spectrometry was used to further characterize the phenolic 
components of MGE.  MGE had a significantly higher amount of catechin, epicatechin, 
procyanidin, gallic acid, and ellagic acid compared to the other supplements tested.   Resveratrol 
and quercetin were below the assay detection limit (Duncan et al, presented at 2017 Experimental 
Biology annual meeting).  Ongoing experiments are planned to determine the biologically relevant 
components of MGE. 
 
The initial studies looking for an anticancer effect of MGE in both breast and prostate cancer 
mouse models examined 4 different dose levels: 0.25, 0.5, 1 and 2 mg of phenolics per mouse 
per day. A statistically-significant effect on tumor growth was seen at all 4 dose levels compared 
to placebo, and while there was a trend toward better efficacy at higher doses, there was no 
significant difference between the dose levels.  An average mouse weighs 0.025 kg, therefore 
this corresponds to a dose range of 10, 20, 40, and 80 mg of phenolics/kg/day.   
 
A dose 20 mg of phenolics/kg/day was chosen for additional preclinical studies in mice and rats.  
As described above, these studies show a significant improvement in exercise capacity and 
workload, along with decreased markers of oxidative stress.  This dose is roughly equivalent to 8 
capsules of MGE daily. The phase 1 dose-escalation study with MGE in advanced cancer patients 
described above evaluated patients at and above this dose level. Based on the preclinical data 
and the phase 1 study, 8 capsules of MGE per day was chosen for phase 2 prostate and breast 
cancer studies, in which both effects on cancer and effects on fatigue will be assessed. 
 
1.5 Rationale for MGE in Biochemically Recurrent Prostate Cancer 
 
Prostate cancer is the most prevalent non-skin cancer in American men, with >225,000 cases 
diagnosed annually. Prostate cancer may manifest as localized disease, recurrent disease with 
rising PSA only, and metastatic disease. Delaying or preventing progression along this spectrum 
is critical because metastatic prostate cancer is incurable and is the second leading cause of 
cancer death in men in the United States. 
 
Approximately 1 in 3 men will develop recurrent prostate cancer after definitive local therapy with 
either surgery or radiation. Biochemical recurrence, which is defined as a rising PSA level after 
prostatectomy or external beam radiation therapy, heralds the development of local recurrence 
and/or metastatic disease.  However, the clinical course is highly variable.  Patients with features 
suggesting a high risk for local recurrent disease may benefit from curative-intent salvage 
radiation therapy to the prostate bed. However, even following salvage radiation therapy for PSA-

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 16 of 48 
only disease, many men will again develop biochemical recurrence and eventually metastatic 
prostate cancer.28  
 
Men with biochemically recurrent prostate cancer have a median time from recurrence to prostate 
cancer death of 16 years.29  Risk factors for PSA progression despite local therapy include fast 
PSA kinetics, lower doses of radiation, high Gleason sum, advanced tumor stage, and positive 
surgical margins.28,30  Of those, PSA doubling time (PSADT) is the strongest prognostic factor, 
and PSADT <3 months is strongly associated with prostate cancer mortality, while a PSADT >15 
months predicts for a non-prostate cancer cause of death.31  Therefore, PSADT is often used to 
risk-stratify patients with biochemical recurrence after local therapy. Patients with a PSADT <3 
months are likely to develop metastatic disease within 1 year. In contrast, men with a PSADT >15 
months will likely not develop metastatic disease for 15 years. Men with PSADT 3-9 months or 9-
15 months have a metastasis-free survival of 4 years and 13 years, respectively.32  
 
In patients who relapse after primary therapy for local prostate cancer, the next step in treatment 
is androgen deprivation therapy (ADT), though the timing of when to begin ADT is controversial, 
as it is not curative.  ADT refers to surgical castration (orchiectomy) or medical castration using a 
gonadotropin-releasing hormone (GnRH) agonist or antagonist. Many men with biochemically 
recurrent prostate cancer are observed off treatment until they develop a rapid PSADT or 
metastatic disease, at which time ADT is initiated. ADT-associated side effects include fatigue, 
impotence, decrease in bone density, loss of muscle mass, weight gain, cognitive changes, and 
symptomatic hot flashes. Fatigue is very commonly reported by patients on ADT but has not been 
rigorously studied. In a small prospective study evaluating ADT-related fatigue, two thirds of 
patients report a subjective increase in fatigue within 3 months of starting ADT.33  In patients on 
a minimum of 6 months of ADT, clinically relevant fatigue (defined as fatigue that limits 
functioning) is reported by 43% of men.34 Men on ADT who participate in an exercise program 
have improvement in fatigue.35 Exercise has also been shown to improve strength and physical 
function in men on ADT36 and is commonly recommended as an adjunct to ADT. Other strategies 
to mitigate ADT-related side effects have been inconsistent and largely unsuccessful.37 Because 
patients initiating ADT are expected to live for many years, it is important to address these ADT-
related side effects so that both quantity and quality of life are maintained at the highest possible 
levels. 
 
As described above, anti-tumor properties of muscadine grapes have been demonstrated in 
preclinical models. These studies as well as the preliminary results of the investigative team 
provide the rationale for the treatment of men with prostate cancer with MGE. Also described 
above, there is evidence that muscadine products decrease systemic inflammation, and therefore 
may improve fatigue and physical functioning. The primary goal will be to determine whether 
treatment with MGE can improve measures of fatigue in men with prostate cancer 
receiving ADT. The impact of MGE on PSA progression, quality of life, and physical function will 
also be examined in this study.  
   
2.0 
Objectives 
 
This phase 2 study is a randomized, double-blind, placebo-controlled study evaluating 
the effect of MGE on fatigue in men with prostate cancer receiving androgen deprivation 
therapy. 
 
2.1 
Primary Objective 
 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 17 of 48 
To compare levels of fatigue in the MGE group compared to the placebo group at 
6 months.   
 
Hypothesis:  Subjects receiving MGE will report decreased fatigue (PROMIS-
fatigue) at 6 months compared to those receiving placebo. 
 
2.2 
Secondary Objectives 
 
2.2.1 To compare levels of fatigue in the MGE group compared to the placebo 
group at 3, 9, and 12 months. 
 
Hypothesis:  Subjects receiving MGE will report decreased fatigue 
(PROMIS-fatigue) at 3, 9, and 12 months compared to those receiving 
placebo. 
 
2.2.2 To compare quality of life in men in the MGE group compared to the 
placebo group. 
 
Hypothesis:  Subjects receiving MGE will report better health-related 
quality of life at 3, 6, and 12 months compared to the placebo group.    
 
2.2.3 To compare physical function, physical fitness, and body composition in 
men in the MGE group compared to the placebo group. 
 
Hypothesis:  Subjects receiving MGE will demonstrate better physical 
performance (Short Physical Performance Battery), physical fitness (6 min 
walk), decreased adiposity (dual energy x-ray absorptiometry – DXA), 
increased bone density (DXA) at 12 months compared to those in the 
placebo group. DXA will be performed only on participants enrolled at the 
main campus of the lead site (Wake Forest). 
 
2.2.4 To compare time to PSA progression (from study entry) in men in the MGE 
group compared to the placebo group. 
 
Hypothesis:  Subjects receiving MGE will have a longer time to PSA 
progression compared to placebo.   
 
2.2.5 To compare progression-free survival (from study entry) in men in the 
MGE group compared to the placebo group. 
 
Hypothesis:  Subjects receiving MGE will have better progression free 
survival.   
 
2.3 
Exploratory Objectives 
 
2.3.1 To examine if differences in levels of fatigue at 6 months by intervention 
group vary in those participants who report meaningful fatigue at baseline 
compared to those who did not have meaningful fatigue at baseline. 
 
2.3.2 To examine if differences in levels of fatigue at 6 months by intervention 
group vary by completing at least 80% of the dose for the full course of 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 18 of 48 
treatment (i.e., completing 12 months of treatment taking ≥80% of pills 
averaged over the 12 month period) compared to those who did not 
complete at least 80% of the dose for the full course of treatment. 
 
2.3.3 To compare levels of circulating biomarkers of angiogenesis, inflammation, 
and oxidative stress at baseline, 6, and 12 months between the MGE and 
placebo groups.   
 
2.3.4 To compare phenolic levels and circulating phenolic metabolites at 
baseline, 6, and 12 months between the MGE and placebo groups.   
 
2.3.5 To correlate PSA changes with changes in circulating biomarkers of 
angiogenesis, inflammation, oxidative stress, phenolic levels, and phenolic 
metabolites. 
 
2.3.6 To assess for the manganese superoxide dismutase genotype AA at 
baseline and to correlate genotype with fatigue and PSA levels at 6 
months.  
 
2.3.7 To bank blood for the future study of prostate cancer-related biomarkers 
such as mitochondrial function, circulating exosomes, and tumor-derived 
microRNA at baseline, 6, and 12 months.  
 
2.3.8 To examine if differences in levels of fatigue at 6 months by intervention 
group vary by ADT alone compared to those taking ADT plus at least one 
additional androgen-pathway directed therapy. 
3.0 
Patient Selection 
3.1 
Inclusion Criteria 
 
3.1.1 Men age ≥18 years who are fluent in English. 
 
3.1.2 Histologically confirmed prostate adenocarcinoma. 
 
3.1.3 Prior surgical castration or active ongoing use of androgen deprivation 
therapy (ADT) with expectation by the treating physician that patient would 
remain on ADT for the upcoming 12 months.  ADT in the setting of 
definitive radiation therapy permitted. Concurrent treatment with androgen 
pathway inhibitors (examples include enzalutamide, abiraterone, 
darolutamide, apalutamide) permitted. 
 
3.1.4 Normal organ and marrow function (labs within 30 days prior to study 
entry) as defined below: 
 
White blood cell count  
>3,500/mcL (or 3.5 (x103)) 
 
Platelet count 
>75,000/mcL (or 75 (x103)) 
 
Hemoglobin 
>9 g/dL 
 
Total bilirubin 
<2.5 X institutional upper limit of normal 
 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
 
Creatinine 
<2.5 X institutional upper limit of normal  

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 19 of 48 
 
3.1.5 Able to ambulate (use of assist device is acceptable). 
 
3.1.6 Able to cooperate with study-related activities. 
 
3.1.7 The effects of MGE on the developing human fetus are unknown.  Men 
must agree to use adequate contraception (barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  
 
3.1.8 Ability to understand and the willingness to sign an IRB-approved informed 
consent document (either directly or via a legally authorized 
representative). 
3.2 
Exclusion Criteria  
 
3.2.1 Symptomatic metastatic disease requiring medical treatment (i.e. painful 
metastases to bone). 
 
3.2.2 Prostate cancer-related surgery or radiation within 60 days prior to study 
entry. 
 
3.2.3 Documented rise in PSA (defined as rise of > 0.5 ng/mL) while on current 
prostate cancer therapy, determined by PSA values, at least one of which 
must be during the 6 months prior to study entry. PSA values must be at 
least 7 days apart. 
 
3.2.4 Planned cessation of ADT or planned use of cytotoxic chemotherapy (i.e. 
docetaxel) within 12 months after study entry.  
 
3.2.5 Ongoing use of any other investigational cancer-directed agents.  
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to MGE. 
 
3.2.7 Inability to swallow oral medications.  
 
3.2.8 Malabsorption due to bowel resection or gastrointestinal disease leading to 
uncontrolled diarrhea, or persistent nausea or vomiting requiring daily 
antiemetic therapy for symptom management within the past week. 
  
3.2.9 Uncontrolled intercurrent illness, including but not limited to: active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.3 
Inclusion of Women and Minorities 
 
Men of all races and ethnicity who meet the above-described eligibility criteria are 
eligible for this trial. Women do not get prostate cancer and are therefore 
excluded from participation. 
 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 20 of 48 
4.0 
Screening, Registration, and Randomization Procedures  
 
4.1 
Screening 
 
Study coordinators will pre-screen appropriate patients to assess eligibility via 
IRB-approved HIPAA waiver. Patients who are eligible will be contacted by 
phone. Study coordinators will explain the study to potential participants to 
determine their interest and willingness. If a patient is likely eligible, but there is 
not adequate information available to confirm eligibility, the patient will be 
contacted for further assessment.  If the patient has documentation of the 
necessary laboratory studies within the specified window that does not appear in 
the medical record, the study coordinator will obtain and review these 
documents. If the patient needs additional studies in order to assess eligibility, 
the study coordinator will arrange to obtain the necessary studies. Signed 
consent for eligibility screening will be obtained prior to performing the additional 
studies. If the patient meets eligibility criteria, the study coordinator will arrange 
for the baseline study visit, which will include informed consent, registration, 
randomization, and day 1 study activities. 
 
4.2 
Registration (Lead site) 
 
Patients must be registered prior to the initiation of treatment. The following 
steps will be followed to register a patient: 
 
1) Obtain informed consent 
2) Complete the Eligibility Checklist in OnCore (Wiser) 
3) Register the patient in Wiser – this will alert the cancer center registrar, who 
will then review the signed informed consent and confirm the eligibility.   
 
After registration is complete, Wiser will assign the participant a study number 
and assign him to a study arm (randomize). 
 
 
         
   
 
 
Patients will not be registered without all required supporting documents. 
 
Note: For any screening activities performed at an outside institution, the source 
documentation must be provided.   
 
4.3  
Randomization   
 
After written informed consent has been obtained and the patient registered and 
randomized in Wiser, the study site will obtain a unique patient identifier, which 
will stay the same throughout the entire study. Patients who give consent but are 
not registered and/or randomized for any reason will be documented as a Screen 
Failure.  
 
 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 21 of 48 
Patients will be randomized with equal probability to one of the two treatment 
arms using Wiser. Balance in treatment assignment will be achieved using 
blocks. Randomization will be carried out via computer generated random 
assignment within Wiser stratified by study site. All patients must commence 
treatment within 14 calendar days from date of randomization. 
 
4.4  
Registration and randomization (Participating sites) 
 
Central registration for this study will take place at Wake Forest Baptist Medical 
Center (WFBMC). To complete registration and enroll participants from other 
institutions, the study coordinator will contact the designated research 
coordinator at WFBMC. 
 
The following documents must be submitted prior to participant enrollment: 
• 
the completed eligibility checklist 
• 
the signed informed consent  
• 
supporting source documentation for eligibility questions 
• 
registration & ethnicity forms  
 
Participating sites will not share the following data of individuals, screened or 
enrolled, with the lead site: names, medical record numbers, dates of birth, social 
security numbers, addresses, phone numbers, email addresses.  
 
If the participant meets all criteria and all source documentation is received, the 
research coordinator will send the completed registration documents back to the 
site. The participant will be enrolled at WFBMC and assigned a unique study ID. 
This unique study ID will be relayed back to staff at participating centers via email 
and will serve as the confirmation of enrollment. 
 
4.5 
Blinding 
 
This is a double-blinded study. Only the investigational pharmacists and the 
statisticians will unblinded. The blind will be maintained until the study is 
complete. 
 
4.6 
Multicenter Guidelines 
 
Principal Investigator: the PI is responsible for performing the following tasks: 
• 
Coordinating, developing, submitting, and obtaining approval for the protocol 
as well as its subsequent amendments. 
• 
Assuring that all participating institutions are using the correct version of the 
protocol. 
• 
Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
• 
Participating sites will enroll a minimum of 40 patients to the trial.  
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
• 
Reviewing data from all sites. 
 
Lead Site: Wake Forest Baptist Medical Center is responsible for performing the 
following tasks: 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 22 of 48 
• 
Ensuring that IRB approval has been obtained at each participating site prior 
to the first patient registration at that site, and maintaining copies of IRB 
approvals from each site. 
• 
Managing central patient registration. 
• 
Collecting and compiling data from each site. 
• 
Establishing procedures for documentation, reporting, and submitting of AEs 
and SAEs to the PI and all applicable parties. 
• 
Facilitating audits by securing selected source documents and research 
records from participating sites for audit, or by auditing at participating sites. 
• 
The lead site is the central location and coordinating center for the collection 
and maintenance of documentation of adverse events and is responsible for 
submitting adverse event reports to the PI promptly. The lead site will 
maintain documentation of all adverse event reports for each participating 
site. Adverse event reports submitted to the lead site must be signed and 
dated by the participating site’s PI. The lead site will provide appropriate 
forms to be used by all participating sites for reporting adverse events. See 
section 8.3 and Appendix D for details on this process.  
 
Participating Sites:  Participating sites are responsible for performing the 
following tasks: 
• 
Following the protocol as written, and the guidelines of Good Clinical Practice 
(GCP). 
• 
Submitting data, identifiers redacted, to the lead site for oversight and 
monitoring. 
• 
Registering all patients with the lead site by submitting patient registration 
form and signed informed consent promptly. 
• 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the 
protocol. 
• 
Maintaining regulatory binders on site and providing copies of all required 
documents to the lead site. 
• 
Collecting and submitting data according to the schedule specified by the 
protocol. 
• 
Participating sites are responsible for reporting adverse events to their IRB 
according to its specific requirements and to the lead site  
 
5.0 
Study Outcomes and Study Measures 
 
5.1 
Primary Outcome 
 
5.1.1 Fatigue at 6 months is the primary outcome for this trial. The PROMIS 
Fatigue 7a Short-Form assesses the experience (3 items) and impact (4 
items) of fatigue during the past week.  In the PROMIS initiative, fatigue 
is divided into the experience of fatigue (frequency, duration, and 
intensity) and the impact of fatigue (upon physical, mental, and social 
activities). Item responses are rated on a five-point scale ranging from 
“never” to “always” and are summed for a total score and transformed to 
a T-score metric, which has a mean of 50 and a standard deviation of 
10. Higher scores indicate more fatigue. The PROMIS Fatigue Short-
Form 7a has shown robust reliability and validity across multiple 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 23 of 48 
samples.38-42 Complete reliability and validity information on the 
PROMIS Fatigue can be found on the Assessment Center website 
(www.assessmentcenter.net).  Recommendations for classifying fatigue 
based on the T scores are as follows: <50 normal; 50-59 mild; 60-69 
moderate; ≥70 severe.43    
 
All patients will be evaluable for the primary outcome from the time of 
randomization.  
 
5.2 
Secondary Outcomes 
 
5.2.1 Quality of life  
 
General Quality of Life will be measured using the Patient Reported 
Outcomes Measurement Information System© (PROMIS©) Global Health 
Short Form (SF), a 10-item instrument representing multiple domains.44  
Items assess self-reported measures of general aspects of physical, 
mental and social health in adults. Raw scores are summed within each 
sub-domain and converted to T-scores using a conversion table. T-score 
distributions are standardized such that a 50 represents the average for 
the US general population, and the standard deviation around that mean 
is 10 points. Higher scores indicate better general health than the general 
population. 
 
Quality of life will also be assessed by the Hot Flash Related Daily 
Interference Scale (HFRDIS). HFRDIS is a 10-item scale that assesses 
the degree to which hot flashes interfere with a variety of daily activities 
and quality of life. Interference is rated on an 11-point scale (0=not 
interfere; 10=completely interfere). The validity of the HFRDIS has been 
demonstrated in breast cancer survivors and healthy women.45   HFRDIS 
has also been used in prostate cancer patients receiving ADT.46   
 
Sleep disturbance will be measured using the PROMIS Sleep 
Disturbance (SD) SF 8a.47,48  The PROMIS-SD items assess self-reported 
perceptions of sleep quality, sleep depth, and restoration associated with 
sleep. This includes perceived difficulties and concerns with getting to 
sleep or staying asleep, as well as perceptions of the adequacy of, and 
satisfaction with, sleep. The PROMIS-SD SF is not disease-specific and 
assesses sleep disturbance over the past seven days. It has been tested 
and exhibited validity evidence (e.g., expected associations, 
discrimination among known groups) in a wide range of populations 
including, but not limited to, parents in neonatal ICU,49 individuals with 
neurological conditions,50 patients with pelvic pain,51  and head and neck 
cancer patients.52 Each question has five response options ranging in 
value from one to five. The lowest possible raw score is 8; the highest 
possible raw score is 40. Raw scores are converted to a standardized T-
score; final scores are represented by the T-score with a mean of 50 and 
a standard deviation of 10. Higher scores indicate more sleep 
disturbance. 
  

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 24 of 48 
Cognitive abilities will be measured using the PROMIS Cognitive Abilities 
SF 4a, which assesses patient-perceived functional abilities related to 
mental acuity, concentration, and memory. The PROMIS Cognitive 
Abilities SF is not disease-specific and assess abilities over the past 
seven days. It has been successfully validated in adult medical 
outpatients,53 and elderly individuals.54  It has also been proven 
comparable to the FACT-Cog often used with cancer patients.55. Raw 
scores are converted to a standardized T-score; final scores are 
represented by the T-score with a mean of 50 and a standard deviation of 
10. Higher scored indicate more cognitive ability. 
 
5.2.2 Physical function, physical fitness, and body composition  
 
Self-reported physical function will be measured using the PROMIS 
Physical Function 10a SF, which is designed to assess self-reported 
capability rather than actual performance of physical activities.42,56 
Capabilities include the function of upper extremities, lower extremities, 
and central regions, as well as instrumental activities of daily living. The 
form consists of 10 items, is universal rather than disease-specific, and 
assesses current function rather than function over a specified time 
period. Studies show PROMIS physical function short forms are valid and 
reliable in multiple patient populations including but not limited to prostate 
cancer, other cancers, and rheumatoid arthritis.57-59  Raw scores are 
summed within each sub-domain, and converted to T-scores using a 
conversion table. T-score distributions are standardized such that a 50 
represents the average for the US general population, and the standard 
deviation around that mean is 10 points. Higher scores indicate better 
physical function general health than the general population. 
 
Physical performance will be objectively assessed using the Short 
Physical Performance Battery (SPPB). This validated measure comprises 
a short walk, repeated chair stands, and balance test. Each performance 
measure is scored ranging from 0-4 (0 = unable to complete; 4 = highest 
performance level), with total sum score range from 0-12. Lower score on 
the SPPB have been associated with increased risk of disability, 
hospitalization and worse survival among older adults with and without 
cancer.60-62  
 
Submaximal (6-minute walk) exercise capacity will be measured to 
assess physical fitness.  The 6-minute walk63 is a measurement that is 
easy to administer in a clinical setting, feasible, and accurately assesses 
submaximal exercise capacity.  The 6-minute walk is an independent 
predictor of mortality and is correlated with peak V02 testing.64   
 
Body composition: ADT has been associated with changes in body 
composition, specifically a decrease in lean body mass and an increase 
in adiposity.65  Whole body lean mass, fat mass, and bone mass will be 
measured in participants, enrolled at the main campus of lead site only 
(Wake Forest), by duel energy X-ray absorptiometry (DXA).66  BMI will be 
calculated from height and weight.   
 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 25 of 48 
 
5.2.3 PSA progression and progression-free survival 
 
PSA will be measured at screening, 6, and 12 months while patient is on 
MGE/placebo, but all PSA measurements obtained per standard-of-care 
over 12 months (from initiation of MGE/placebo) will be captured.   
 
PSA progression is defined as two serial increases in PSA from time of 
randomization (at least two weeks apart) and a PSA ≥0.2 ng/mL in 
prostatectomy patients and ≥2.0 ng/mL in radiation patients (based on 
local lab measurements). The first date of increasing PSA at or above 
these thresholds is considered the PSA progression date. Patients will be 
followed for up to 12 months from study initiation for PSA progression.  
Participants will be censored at time of loss to follow-up, or at the end of 
study, or at disease progression (defined as radiographic progression, 
need for new anticancer therapy, or death).  
 
Progression-free survival is defined as the time from randomization to 
disease progression or death.  Participants are censored if lost to follow-
up or, at the end of 12 months, if no event has occurred. Radiographic 
evidence of disease progression, initiation of new systemic therapy by the 
treating physician, or death is considered disease progression regardless 
of PSA. Radiographic assessment of the prostate cancer will be per the 
discretion of the treating physician. 
 
5.3 Exploratory Outcomes 
 
5.3.1 Biomarkers of angiogenesis, inflammation, and oxidative stress include but 
are not limited to 8-OH deoxyguanosine.  
 
5.3.2 Phenolic levels and metabolites in the blood and in the urine will be 
assessed using mass spectrometry. 
 
5.3.3 Manganese superoxide dismutase genotype AA will be assessed using 
germline DNA derived from white blood cells at baseline. 
 
 
 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
Page 26 of 48 
6.0 
Treatment Plan      
 
6.1 
Study-Related Activities  
 
Measures / Forms 
Pre- 
Studya Baseline 
Week 
2 
Week 
6 
Week 
12b 
(3 mo) 
Week 
16 
Week 
20 
Week 
24b 
(6 mo) 
Week 
36b 
(9 mo) 
Week 
48b,c 
(12 mos) 
Off-
study 
(12 mos) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical and oncologic history   
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Vital signs 
 
X 
 
 
 
 
 
X 
 
X 
 
ECOG performance status 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event assessment 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Drug dispensingd 
 
X 
 
 
X 
 
 
X 
X 
 
 
Pill count 
 
 
 
 
X 
 
 
X 
X 
X 
 
ADT administration statuse 
X 
 
 
 
X 
 
 
X 
X 
X 
 
Telephone follow-upf  
 
 
X 
X 
 
X 
X 
 
 
 
 
Survival statusc,g 
 
 
 
 
 
 
 
 
 
 
X 
Standard-of-care Evaluations 
INR level, for patients on 
warfarinm 
 
 
 
X 
 
 
 
 
 
 
 
Research Evaluations 
Body composition (height, 
weight, DXA – DXA in Wake 
main campus participants only)n 
 
X 
 
 
 
 
 
 
 
X 
 
Physical function & fitness 
(SPPB, 6-min walk) 
 
X 
 
 
 
 
 
X 
 
X 
 
CBCi 
X 
 
 
 
 
 
 
X 
 
X 
 
Serum chemistriesi 
X 
 
 
 
 
 
 
X 
 
X 
 
Serum PSAj 
X 
 
 
 
 
 
 
X 
 
X 
 
Serum testosteronek 
 
X 
 
 
 
 
 
X 
 
X 
 
(Partially fasting) labs for 
phenolic levels (blood and urine)k 
 
X 
 
 
 
 
 
X 
 
X 
 
(Partially fasting) labs for 
correlative studiesl  (blood and 
urine) 
 
X 
 
 
 
 
 
X 
 
X 
 
DNAl (correlative) 
 
X 
 
 
 
 
 
 
 
 
 
PROMIS Fatigue survey 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Other patient-reported outcomes: 
PROMIS Global QOL, HFRDIS, 
PROMIS-SD, PROMIS Cog, 
PROMIS physical function 
 
X 
 
 
X 
 
 
X 
 
X 
 
a Labs to assess eligibility must be completed within 30 days prior to the first dose of MGE/placebo.  
b Follow-up study visits will occur every 12 weeks and will have a ±14 day allowance window which 
includes not just the visit itself, but any of the activities at that visit. For example, if labs cannot be 
collected at the actual study visit, the ±14-day window permits a second attempt at lab collection; all 
activities, however, must be completed in the ±14-day window from the expected visit date. At the lead 
site, these visits will occur in the Clinical Research Unit and may not be coupled with MD visits. At the 
discretion of the study team, due to COVID-19, follow-up visits may occur in whole or in part by phone, 
followed by the pills being shipped to participants who remain on treatment. 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
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c PSA and disease status will be assessed for up to 12 months per review of treating physician notes or 
phone call as needed. 
d Study drug (MGE or placebo) will be dispensed as a 90-day supply at each visit. 
e Confirmation of continuous ADT dosing while on MGE/placebo. Androgen deprivation therapy (ADT) will 
be given per the treating physician. Any GnRH agonist or antagonist is permitted and dosing needs to 
be continuous for 1 year while on study (given within 42 days of due date). Surgical castration is also 
allowed.  
f Adherence will be assessed at each study visit. In addition, participants will be contacted by phone to 
assess adherence as follows, ±3 days: Wk2, Wk6, Wk16, Wk20.  At the Wk6 call, we will also assess 
potential adverse events. Monthly adherence after the 6M time point will continue only for participants 
who return >125 pills at the 6M visit. 
g Survival status will be assessed by chart review or phone every 6 months for up to 12 months from 
study enrollment. 
h <deleted> 
i Safety laboratory assessments must be done within 30 days of first dose of MGE/placebo and then on 
the study visits indicated.  These labs include: 
 Complete blood count (CBC): WBC count, platelet count, hemoglobin, and hematocrit. 
 Serum chemistries: creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total 
bilirubin, and alkaline phosphatase. 
j PSA levels will be obtained at screening, 6, and 12 months on study. In addition, all standard-of-care 
PSA measurements will be recorded for 12 months after MGE/placebo initiation. 
k  Testosterone levels will be obtained at baseline, 6, and 12 months on study. 
l Phenolic levels and other research labs will be obtained at baseline, 6 months, and 12 months (±14 
days). Patients are asked to avoid coffee, tea, fruit juice, fruit, chocolate or wine after midnight prior to 
blood draw. Blood for manganese superoxide dismutase genotype will be collected at baseline only.   
m Participants on warfarin should have their INR checked within 4 weeks (+/- 14 days) of starting MGE to 
ensure there is no clinically significant interaction. This can be performed locally. Further blood work to 
monitor INR levels are at the discretion of the treating physician per usual care. We will verify that an 
INR check was performed (if needed) during the call at 6 weeks. 
n Only subjects participating at WFUHS main campus will participate in the DXA scan. 
 
6.2 
Treatment Administration 
 
Treatment will be administered on an outpatient basis. No investigational or commercial 
agents or therapies, other than those described below, may be administered with the 
intent to treat the patient's malignancy.  
 
Patients will be randomized 1:1 basis to either MGE or placebo. The study is double-
blind and the patients will take 4 capsules by mouth twice daily.   
 
6.2.1 Investigational agent 
 
This phase 2 study uses a specific formulation of muscadine grape extract 
(MGE) produced by Piedmont Research & Development Corporation from a 
powdered extract obtained from NPC Corporation, formerly known as Nature’s 
Pearl (Advance, NC). The same product was used for a phase 1 study in 
advanced cancer patients (FDA IND 128937; clinicaltrials.gov NCT02583269).  
Each capsule will contain 500mg of MGE, which corresponds to approximately 
165 mg total phenolics per capsule. 
 
 
A matching placebo will be supplied by Clinical Encapsulation Services (CES) 
(Schenectady, NY), an FDA-registered facility, registration number 
16691092818. The capsules will contain 500 mg of microcrystalline cellulose 

 
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tinted to match MGE via Colorcon or Chromatech, and will be encapsulated 
with a vegetable capsule of hypromellose obtained from ACG (South Plainfield, 
NJ) or Capsugel (Charlotte, NC) of the same size as the MGE capsules.  Both 
the MGE and matching placebo will be bottled and labeled by CES. 
 
6.2.2 Other Agent 
 
Androgen deprivation therapy (ADT) is to be started prior to initiation of 
MGE/placebo.  Any form of medical or surgical castration is permitted. If medical 
castration is used, the dosing should be continuous without interruption for the 12 
months of treatment with MGE/placebo. For the purpose of this study, continuous 
dosing is defined as ADT given within 6 weeks (42 days) of ADT due date. 
Intermittent dosing ADT after 12 months on study is acceptable, per the 
discretion of the treating physician. Androgen pathway inhibitors such as 
enzalutamide, abiraterone, darolutamide, and apalutamide, are not considered 
ADT. Therefore, ceasing use of inhibitors is not a reason to come off-study as 
long as ADT continues. 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients should receive full supportive care, including antibiotics, antiemetics, 
transfusions of blood and blood products, etc., as clinically indicated. Anti-inflammatory 
or narcotic analgesics may be offered as needed. Medications considered necessary for 
the patient's well-being may be given at the discretion of the treating physician, i.e., 
chronic treatments for concomitant medical conditions, as well as agents required for 
life-threatening medical problems.  
 
Participants on warfarin should have their INR checked within 4 weeks of starting MGE 
to ensure there is no clinically significant interaction. This can be performed locally. 
Further blood work to monitor INR levels are at the discretion of the treating physician 
per usual care. 
 
6.4 
Study assessments   
 
All study-related activities at the lead site will occur at the Wake Forest Baptist 
Medical Center Clinical Research Unit and will not be coupled with standard-of-
care clinic visits. At the discretion of the study team, in response to COVID-19, 
follow-up visits may occur in whole or in part by phone, followed by the pills being 
shipped to participants who remain on treatment. Participants will receive a $10 
gift card at the completion of each study assessment (for up to $50 total). This 
gift card serves to cover all or part of their travel expenses in attending study 
appointments. 
6.4.1 Vitals signs, performance status  
 
Vital sign assessment consists of pulse, blood pressure, respiration rate, 
temperature.  
 
Performance status will be assessed at baseline using the ECOG performance 
status scale.  
 

 
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6.4.2 Laboratory assessments (safety) 
 
The following laboratory studies will be obtained at specified intervals to assess 
subject safety while on study: 
 
• 
Complete blood count (CBC): Total white blood cell count (WBC), 
hemoglobin, hematocrit, and platelet count. 
• 
Blood chemistry: Creatinine, total bilirubin, alkaline phosphatase, AST 
(SGOT), ALT (SGPT). 
• 
Participants on warfarin should have their INR checked within 4 weeks of 
starting MGE to ensure there is no clinically significant interaction. This 
can be performed locally. Further blood work to monitor INR levels are at 
the discretion of the treating physician per usual care. 
 
Critical laboratory values will be reported to the PI and to the treating physician. 
 
6.4.3 Laboratory assessments (other) 
 
The following laboratory studies will be obtained at specified intervals while on 
study: 
 
• 
Prostate specific antigen (PSA). All PSA measurements obtained, both 
per study requirements and per standard-of-care, will be recorded during 
the 12 months on study.   
• 
Testosterone level 
• 
Correlative research labs (refer to section 10.0) 
 
6.4.4 Imaging 
 
Imaging may be performed as clinically indicated per the discretion of the treating 
physician, as per standard-of-care.     
 
6.4.5 Body composition and physical function assessment 
 
Height and weight will be obtained at specified intervals. Whole body lean mass, 
fat mass, and bone mass will be measured by duel energy X-ray absorptiometry 
(DXA).  DXA will be performed only on participants who enroll at the main 
campus of lead site (Wake Forest). 
 
Physical performance will be objectively assessed using the Short Physical 
Performance Battery (SPPB). This validated measure comprises a short walk, 
repeated chair stands, and balance test. Submaximal (6-minute walk) exercise 
capacity will be measured to assess physical fitness.   
 
6.4.6   Patient reported outcomes 
 
 
 
The PROMIS fatigue survey will be administered at baseline, 3, 6, 9, and 12 
months.  Other patient-reported outcomes will be administered at baseline, 3 
months, 6 months, and 12 months as outlined in the study calendar (see section 
6.1).   

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
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6.5 
Duration of Study Intervention 
 
Treatment with MGE/placebo will continue for 12 months or until one of the following 
criteria applies: 
 
• 
Prostate cancer disease progression requiring a new cancer therapy  
• 
Intercurrent illness that prevents further administration of treatment; 
• 
Unacceptable adverse event(s) attributable to MGE/placebo; 
• 
Patient decides to stop ADT or opts for intermittent ADT therapy prior to 12 
months of continuous ADT (see section 6.2.2). No longer taking androgen 
pathway inhibitors is permissible;  
• 
Patient misses more than 28 consecutive days of treatment for any reason; 
• 
Changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the treating physician; 
• 
Patient decides to withdraw from the study; or 
• 
Patient is noncompliant, determined at the discretion of the principal 
investigator in conjunction with the treating physician. 
 
6.6 
Duration of Follow Up 
 
Patients will be followed for toxicity/adverse events for 72 hours after the last dose of the 
study drug and while on study per Table 6.1. 
 
Patients will be instructed to inform the study staff of any medical concerns that arise 
during the first 3 days after stopping the study drug for any reason.  The study team will 
assess for toxicity/adverse events and determine attribution. Of note, a 24-hour washout 
period was adequate in the Phase 1 protocol with the same drug (CCCWFU #01815). 
 
Patients removed from the study intervention for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event.  All participants who 
discontinue taking the study drug (see section 7.1) will be asked to continue study visits 
per protocol for the duration of the year. If they are unable or unwilling to come to the 
CRU as planned, study staff will attempt to collect fatigue and other QOL data in lieu of 
study visits as long as consent is not withdrawn. All participants will be followed for the 
study outcomes until the end of the study. 
 
Patients will be followed for up to 12 months from study initiation for disease progression 
or death.  
 
6.7 
Criteria for Removal from Study Intervention 
 
All participants will be expected to complete the 6 month study visit, unless they 
withdraw consent or are medically unable, even if they have stopped MGE/placebo.  All 
participants will be asked to also complete the 12 month study visit, but if they are 
unable or unwilling, they will be contacted by phone and asked to complete the survey-
based data. 
 
Participant will be removed from study intervention when any of the criteria listed in 
section 6.5 applies.   

 
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6.8 
Procedures for removal from study treatment 
 
If a participant discontinues his MGE/placebo or is removed from the study intervention 
for any reason, he will be seen at the next scheduled follow-up. He will be asked to 
return all pills and to complete the study-related activities. 
 
 
 
7.0 
Dosing Delays/Dose Modifications 
 
7.1 
Missed doses 
 
If a dose of MGE/placebo is missed, the participant will be instructed to take his next 
dose as scheduled. Missed doses should not be added to the next dose.  
 
If treatment must be held for any reason, it must be restarted within 28 days, or the 
participant will be removed from the study intervention. Unused pills will be collected at 
the next study visit. No more pills will be dispensed if 28 consecutive days are missed. 
 
At each study visit, participants will be sent home with blank calendar pages for the 
upcoming 3 months, where they can mark am/pm doses as they are taken. Participants 
will be contacted by phone at Weeks 2, 6, 16, 20 (± 3 days) to assess adherence 
between study visits (see Appendix Y). After the 6-month study visit, adherence calls will 
cease unless the participant returns ≥125 pills at the 6M study visits. In that event, calls 
will continue until the 9-month visit. After the 9-month study visit, adherence calls will 
cease unless the participant returns ≥125 at the 9-month visit. Adherence data from 
phone calls will be kept in the study file. 
 
7.2 
Dose modification  
 
There will be no dose-modifications on study. Either the patient or the treating physician 
can choose to discontinue MGE/placebo at any time. If necessary, MGE can be held for 
up to 28 days. 
 
Participants or physicians who notify the study team of potential study drug-related 
toxicities will be contacted by the study PI for further information. Participant will 
permanently discontinue the study drug for any attributable grade 4 toxicity. Otherwise, 
appropriate supportive care recommendations will be made, and the study team will 
follow up with the participant to make sure toxicity has resolved to grade 0-1. If the 
participant continues to experience grade 2 or 3 toxicity, he will hold the study drug for 
up to 27 days, and the study team will again follow up with the participant to ensure 
toxicity has resolved to grade 0-1. If the toxicity persists beyond 27 days and is possibly 
attributable to the study drug, the study drug will be permanently discontinued. If the 
toxicity resolves to grade 0-1, the participant will restart the study drug. If the same 
grade 2 or higher possibly-attributable toxicity returns despite appropriate supportive 
care measures (e.g. diarrhea despite use of anti-diarrheal medication), the participant 
will permanently discontinue the study drug.  
 
8.0 
Adverse Events List and Reporting Requirements 
 
8.1 
Adverse Event List 
 

 
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8.1.1 MGE/placebo 
 
Expected: Based on previous studies, minimal AEs are expected, which may 
include flatulence, diarrhea, nausea, dyspepsia, constipation, and abdominal 
cramping. 
 
8.1.2 Androgen deprivation therapy 
 
Surgical or medical castration can cause side effects due to changes in the levels 
of testosterone. All patients will be receiving ADT, and this is not the intervention 
being studied. 
 
Expected side effects of ADT include but are not limited to: fatigue, reduced or 
absent libido, impotence, hot flashes, breast tenderness or growth of breast 
tissue, decreased bone density, anemia, decreased mental acuity, loss of muscle 
mass, weight gain. Patients receiving medical castration may also experience 
injection site tenderness or swelling. These side effects will not be considered 
study-related adverse events. 
 
8.2 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 8.1.1 
above) for expedited reporting purposes only.   
 
Attribution of the AE: 
Definite: 
The AE is clearly related to MGE/placebo.    
Probable: The AE is likely related to MGE/placebo.    
Possible: The AE may be related to MGE/placebo.    
Unlikely: 
The AE is doubtfully related to MGE/placebo.  
Unrelated: The AE is clearly NOT related to MGE/placebo.    
 
8.3 
STRC SAE Reporting Requirements 
 
The Safety and Toxicity Reporting Committee (STRC) is responsible for reviewing SAEs 
for WFBCCC institutional studies as outlined in Appendix D. STRC requires that all 
unexpected 4 and all grade 5 SAEs on these trials be reported to them for review. All 
WFBCCC Clinical Research Management (CRM) staff members assisting a PI in 
investigating, documenting and reporting an SAE qualifying for STRC reporting are 
responsible for informing a clinical member of the STRC as well as the entire committee 
via the email notification procedure of the occurrence of an SAE. 
 
See section 6.6 and Appendix D for details. 
 

 
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Data Safety and Monitoring 
The protocol is being conducted at additional sites external to WFBH. In conjunction with 
the STRC at WFBH, the principal investigator (PI) is responsible for overall monitoring of 
the data and safety of study participants at all sites. The PI will assure that the study is 
conducted, recorded, and reported in accordance with the protocol and applicable 
regulations. Data for safety and SAEs will be monitored on an ongoing basis through 
regular study team meetings, including data from all sites involved. 
 
For external sites, SAEs, whether or not considered drug-related, should be reported by 
the study team to the lead site within 24 hours of discovery. The process is as follows: 
• 
Research nurse or study team member becomes aware of the SAE. 
• 
Within 24 hours of the SAE discovery: 
o Site follows its own SAE reporting protocol, notifies the site PI, and 
documents the event in entirely within 24 hours if its discovery. 
o Participant’s treating physician reviews data and attributes SAE as 
necessary, acknowledging SAE using their template. 
o Research nurse or study team member notifies WFBMC study staff as 
soon as possible 
of SAE.  All necessary information is provided at that time for 
WFBMC staff to complete required STRC reporting documentation as 
soon as possible (within 24 hours) of becoming aware of the SAE. 
• 
WFBMC study staff notifies WFBMC PI immediately. 
• 
WFBMC study staff notifies STRC immediately, per STRC protocol (Appendix D). 
• 
WFBMC study staff completes data entry of the event into the SAE Reporting 
Form in Wiser immediately. 
• 
VA provides source documentation and completed Serious Adverse Event 
Reporting Form (Appendix S). 
8.4  
WFUHS IRB AE Reporting Requirements 
 
Any unanticipated problems involving risks to subjects or others and adverse events 
shall be promptly reported to the IRB, according to institutional policy. Reporting to the 
IRB is required regardless of the funding source, study sponsor, or whether the event 
involves an investigational or marketed drug, biologic or device. Reportable events are 
not limited to physical injury, but include psychological, economic and social harm. 
Reportable events may arise as a result of drugs, biological agents, devices, procedures 
or other interventions, or as a result of questionnaires, surveys, observations or other 
interactions with research subjects. 
 
All members of the research team are responsible for the appropriate reporting to the 
IRB and other applicable parties of unanticipated problems involving risk to subjects or 
others. The Principal Investigator, however, is ultimately responsible for ensuring the 
prompt reporting of unanticipated problems involving risk to subjects or others to the 
IRB. The Principal Investigator is also responsible for ensuring that all reported 
unanticipated risks to subjects and others which they receive are reviewed to determine 
whether the report represents a change in the risks and/or benefits to study participants, 
and whether any changes in the informed consent, protocol or other study-related 
documents are required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a site 
where the study has been approved by the WFUHS IRB (internal events) must be 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
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reported to the WFUHS IRB within 7 calendar days of the investigator or other members 
of the study team becoming aware of the event. 
 
Any unanticipated problems involving risks to subjects or others occurring at another site 
conducting the same study that has been approved by the WFUHS IRB (external 
events) must be reported to the WFUHS IRB within 7 calendar days of the investigator 
or other members of the study team becoming aware of the event. 
 
Any event, incident, experience, or outcome that alters the risk versus potential benefit 
of the research and as a result warrants a substantive change in the research protocol or 
informed consent process/document in order to insure the safety, rights or welfare of 
research subjects. 
 
AEs will only be collected from the AE Ascertainment Form administered to participants 
per protocol.  No AEs will be collected via screening review of the medical record. 
Specifically, routine review of oncology notes will not be required, but if an AE is noted in 
review of notes such as an ED note or an inpatient note, then it will be captured and the 
details of that AE will be obtained by reviewing all appropriate notes in the medical 
record. We will follow all the standard reporting procedures for SAEs including 
unexpected hospitalizations and/or other issues that arise between study visits as 
discussed in section 8.3 and Appendix D. 
 
9.0 
Confidentiality and Privacy 
 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that 
could directly identify subjects, and maintaining all study information in a secure manner. 
To help ensure subject privacy and confidentiality, only a unique study identifier will 
appear on the data collection form. Any collected patient identifying information 
corresponding to the unique study identifier will be maintained on a linkage file, store 
separately from the data. The linkage file will be kept secure, with access limited to 
designated study personnel. Following data collection subject identifying information will 
be destroyed (state the anticipated time the data will be destroyed, e.g. three years after 
closure of the study, and the method of destruction), consistent with data validation and 
study design, producing an anonymous analytical data set. Data access will be limited to 
study staff. Data and records will be kept locked and secured, with any computer data 
password protected. No reference to any individual participant will appear in reports, 
presentations, or publications that may arise from the study. 
 
10.0 
Pharmaceutical Information 
 
Muscadine grape extract is a nutraceutical compound.  
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 8. 
10.1 
Pharmaceutical Accountability 
 
Patients will be instructed to return their pill bottles and remaining pills at each 
study visit.  Drug accountability logs will be maintained by the Wake Forest 
Investigational Drug Services for the investigative agent (MGE/placebo) used 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
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under this protocol. These logs shall record quantities of study drug received and 
quantities dispensed to patients, including lot number, date dispensed, patient 
identifier number, protocol number, dose, quantity returned, balance remaining, 
and the initials of the person dispensing the medication. At non-Wake Forest 
sites, the site pharmacist will be responsible for collecting the quantity of pills 
returned at each study visit.   
10.2 
Muscadine Grape Extract (MGE)  
 
 
Product description: This phase 2 study uses a specific formulation of 
muscadine grape extract (MGE) produced by Piedmont Research & 
Development Corporation from a powdered extract obtained from NPC 
Corporation, formerly known as Nature’s Pearl (Advance, NC).   The same 
product was used for a phase 1 study in advanced cancer patients (FDA IND 
128937; clinicaltrials.gov NCT02583269). 
 
The muscadine grapes are pressed and processed on site per good 
manufacturing practice (FDA Code of Federal Regulations 21). The extract is 
dried and converted to powder at Pharmachem Laboratories, Inc. (Kearny, New 
Jersey). The MGE is encapsulated with a vegetable capsule of hypromellose, 
bottled, and labeled at Clinical Encapsulation Services (CES) (Schenectady, NY). 
Quality control testing for microbial contamination (aerobic count, yeast and 
mold, E.coli/coliform, staph aureus, enterobacteriaceae, and salmonella) and 
phenolic levels occurs numerous times during the production process. Stability 
testing for both microbial contamination and phenolic levels will continue at 
regular intervals until the study is complete.   
 
Storage requirements: Capsules should be stored at room temperature. 
 
Route of administration: MGE is available for oral administration. 
 
10.3 
Placebo 
 
 
Product description: Placebos will be supplied by Clinical Encapsulation 
Services (CES) (Schenectady, NY), an FDA-registered facility, registration 
number 16691092818. The capsules will contain microcellulose tinted to match 
MGE and will be encapsulated with a vegetable capsule of hypromellose of the 
same size as the MGE capsules. Placebo will be bottled and labeled by CES.  
Quality control testing for microbial contamination (aerobic count, yeast and 
mold, E.coli/coliform, staph aureus, enterobacteriaceae, and salmonella) and 
phenolic level (to ensure no cross contamination) occurs during the production 
process. Stability testing for microbial contamination and content uniformity will 
continue at regular intervals until the study is complete.   
 
Storage requirements: Capsules should be stored at room temperature. 
 
Route of administration: Placebo is available for oral administration. 
 
11.0 
Correlative/Special Studies 
 

 
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11.1 
Biomarkers of angiogenesis, inflammation, and oxidative stress (blood & 
urine) 
 
To be collected at baseline, 6, and 12 months.  Approximately 10 mL of blood will 
be collected into an EDTA tube to measure cytokines and growth factors, 
including but not limited to HGF, VEGF, and 8-OH deoxyguanosine. Plasma will 
be collected and samples will be stored at -80°C indefinitely until batched 
analysis. At least 20 mL of urine will also be collected for 8-OH deoxyguanosine 
levels and stored at -80°C indefinitely until batched analysis. 
    
11.2 
Phenolic assays (blood & urine) 
 
To be collected at baseline, 6, and 12 months.  Total and component phenolics 
will be measured from blood and urine.  Blood assays will require approximately 
10 mL of blood. For the polyphenolic analysis67 one tube of blood at each time 
point will be collected in tubes containing EDTA and stored at -80°C for an 
indefinite period of time. The blood sample will be thawed on ice and used to 
measure polyphenols by ultra-high performance liquid chromatography (UPLC) 
coupled to mass spectroscopy detection (UPLC-MS). 
 
A spot urine collection will be collected at baseline, 6 months, and 12 months. 
The urine will be collected into a urine collection cup and mixed with ascorbic 
acid; 20 mL aliquots will be stored at -80°C. The urine will be thawed on ice and 
used to measure polyphenols by UPLC-MS.   
 
11.3 
Plasma, PBMC, and whole blood specimen banking 
 
Blood will be collected at baseline, at the 6 month visit, and at the 12 month visit 
for the future study of cancer-related biomarkers such as mitochondrial function, 
circulating exosomes, and tumor-derived microRNA.  Approximately 10 mL of 
blood will be drawn into a 10 mL EDTA tube.  3 mL of whole blood will be 
removed and stored at −80°C without additional processing.   The remaining 5-7 
mL will be separated into peripheral blood mononuclear cells (PBMC) and 
plasma by gradient centrifugation. All samples are aliquoted and stored at −80°C 
until further use. The lead site will perform the laboratory analysis.  Neither the 
local sites nor the patients will receive information regarding individual subjects’ 
results. 
 
11.4 
Manganese superoxide dismutase genotype  
 
Peripheral blood will be collected into a single 10 mL EDTA tube at baseline for 
analysis of the manganese superoxide dismutase genotype. Deidentified 
samples will be processed in the Tallant-Gallagher lab for DNA extraction.  
 
The DNA will be stored at -80oC, then batched to Dr. James Eshleman at Johns 
Hopkins for analysis.   
James R. Eshleman, MD, PhD 
Molecular Diagnostics Laboratory Johns Hopkins University School of 
Medicine  
Room 344, Cancer Research Building-II 
1550 Orleans Street 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
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Baltimore, MD 21231 
410-955-3511 
 
12.0 
Data Management 
 
Item/Form  
Location 
Informed consent document 
OnCore/
WakeOne 
Protocol registration & race/ethnicity verification 
OnCore 
Study visit data collection forms: Baseline, forms for months 3, 6, 9, 12 
REDCap 
Labs (CBC, serum chemistry, testosterone, PSA and tumor markers) 
REDCap/
WakeOne 
Correlative labs (blood/urine for phenolics and inflammatory markers) 
REDCap 
Adverse Event Ascertainment and Pre-Toxicity Forms 
OnCore 
PROMIS surveys (fatigue, global health, sleep disturbance, cognitive 
abilities, physical function) 
REDCap 
HFRDIS 
REDCap 
Physical function & fitness forms (SPPB, 6-minute walk test) 
REDCap 
DXA scans (main campus of lead site only) 
OnCore 
Telephone survey @ Wk6 only 
REDCap 
 
12.0 
Statistical Considerations 
 
This two-group, randomized study will have one primary comparison of interest: comparison of 
the MGE arm to the placebo arm. We will use an intention-to-treat approach by collecting data 
from participants on outcome measures (if possible) even if they discontinue the study 
intervention.  
 
12.1 
Analysis of Primary Objective (fatigue) 
 
 
The primary objective of this study is to test the hypothesis that men with prostate 
cancer in the MGE group have less fatigue at 6 months than men in the placebo group.  
We will use an ANCOVA approach to compare the levels of fatigue at 6-months, 
adjusted for the baseline value.  The ANCOVA approach is more efficient than an 
ANOVA to compare the intervention groups.68 Although we do not anticipate that the 
groups will differ due to randomization, we will compare participant characteristics 
between groups and include them in the model to adjust for any group differences, if 
necessary, using a general linear model. 
 
12.2 
Analysis of Secondary Objectives 
 
12.2.1 To compare levels of fatigue in men in the MGE group compared to the 
placebo group at 3, 9, and 12 months. 
 
We will model fatigue over time (at 3, 6, 9, and 12 months) using a 
general linear mixed model (GLMM) ANCOVA approach with adjustment 
for the baseline value and necessary covariates to explore trajectories of 
change over time using linear contrasts to estimate group effects over 
time and with covariates, if necessary.  
 

 
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12.2.2 To compare quality of life in men in the MGE group compared to the 
placebo group. 
 
We will use a general linear mixed model (GLMM) ANCOVA approach 
with adjustment for the baseline value and necessary covariates to 
explore trajectories of change over time using linear contrasts to estimate 
group effects over time and with covariates, if necessary to compare the 
levels of health-related quality of life, hot flashes, sleep disturbance, and 
cognition at 6-months, adjusted for the baseline value and any covariates 
reflecting group differences at baseline if applicable.     
 
12.2.3 To compare physical function, physical fitness, body composition in men 
in the MGE group compared to placebo group. 
 
We will test the hypotheses that the MGE group will have better physical 
performance, physical fitness, and decreased adiposity compared to the 
placebo group. As above, we will model the trajectory of change over time 
by group using an ANCOVA GLMM approach.  
 
12.2.4 To compare time to PSA progression in men in the MGE group compared 
to the placebo group. 
 
Participants will be censored at time of loss to follow-up, or at the end of 
study, or at disease progression (defined as radiographic progression, 
need for new anticancer therapy, or death). We will describe the time to 
PSA progression from the time of randomization using the Kaplan-Meier 
method by group. We will use a log-rank test to compare time to PSA 
progression between the two groups. If there are differences between the 
two groups at baseline, we will use Cox regression with adjustment for 
appropriate covariates to compare the two groups. 
 
12.2.5 To compare progression-free survival in the MGE group compared to the 
placebo group. 
 
Participants will be censored at time of loss to follow-up or end of study. 
We will use the Kaplan-Meier method to estimate progression free 
survival in the two groups.  We will use a log-rank test to compare 
progression-free survival between the two groups.  If there are differences 
between the two groups at baseline, we will use Cox regression with 
adjustment for appropriate covariates to compare the two groups. 
    
12.3 
Analysis of Exploratory Objectives 
 
12.3.1 To examine if differences in levels of fatigue at 6 months by intervention 
group vary in those participants who report meaningful fatigue at baseline 
compared to those who did not have meaningful fatigue at baseline. 
 
To explore whether baseline fatigue is related to differences in level of 
fatigue at 6 months by intervention group, we will perform the analysis 
described for the primary objective for subgroups of baseline fatigue, 

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
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defined as described in Section 5.1.1.  Categories may be collapsed 
depending on the distribution of participants across categories. 
 
12.3.2 To examine if differences in levels of fatigue at 6 months by intervention 
group vary by completing at least 80% of the dose for the full course of 
treatment (i.e.,completing 12 months of treatment taking ≥80% of pills 
averaged over the 12 month period) compared to those who did not 
complete at least 80% of the dose for the full course of treatment. 
 
To explore whether intervention adherence is related to differences in 
level of fatigue at 6 months by intervention group, we will perform the 
analysis described for the primary objective for the subgroups of those 
who complete 12 months of treatment taking ≥80% of pills averaged over 
the 12 month period compared to those who do not. 
 
 
12.3.3 To compare levels of circulating biomarkers of angiogenesis, 
inflammation, and oxidative stress at baseline, 6, and 12 months between 
the MGE and placebo groups. 
 
We will model the trajectory of change over time by group using an 
ANCOVA GLMM approach with contrasts to make comparisons at the 
time points of interest. 
 
12.3.4 To compare phenolic levels and circulating phenolic metabolites at 
baseline, 6, and 12 months between the MGE and placebo groups. 
 
We will model the trajectory of change over time by group using an 
ANCOVA GLMM approach with contrasts to make comparisons at the 
time points of interest.  
 
12.3.5 To correlate PSA changes with changes in circulating biomarkers of 
angiogenesis, inflammation, oxidative stress, phenolic levels, and 
phenolic metabolites. 
 
Change in all measures from baseline to 6 months and from baseline to 
12 months will be calculated and correlated using Pearson correlations.  
We will also consider modeling change in PSA as a function of change in 
the other variables using GLMM. 
 
12.3.6 To assess for the manganese superoxide dismutase genotype AA at 
baseline and to correlate genotype with fatigue and PSA levels at 6 
months.  
 
To assess the impact of the manganese superoxide dismutase genotype 
AA, we will enter it into our model for the primary aim as a main effect and 
as its interaction with group (MGE or placebo) and time. 
 
12.3.7 To examine if differences in levels of fatigue at 6 months by 
intervention group vary by ADT alone compared to those taking ADT plus 
at least one additional androgen-pathway directed therapy. 
 

 
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To explore whether changes in fatigue at 6 months differ in patients 
taking ADT alone compared to ADT plus one additional androgen-
pathway directed therapy, we will perform the analysis described for the 
primary objective for subgroups ADT use (ADT alone vs. ADT plus at 
least one other androgen-pathway directed therapy).  We will also 
examine including the ADT use predictor in the model described for the 
primary objective. 
 
 
12.4 
Power and Sample Size 
With 53 men per group, we will have 87% power to detect a difference in the 
means between the two groups of 0.50 SD at 6 months using an ANCOVA with a 
0.05 two-sided significance level, assuming a 15% drop out rate (N=45 per 
group) and correlation of r=0.65 between baseline and 6 months. This difference 
is consistent with the minimally important difference, which is the difference in a 
score that is considered large enough to reflect a clinically meaningful difference. 
For cancer patients on the PROMIS fatigue scale, the interquartile range of the 
minimally important difference was estimated to be 0.39 to 0.65, with a median of 
0.52. This range of effect sizes corresponds to a difference in the T-score of 3.0-
5.0 points, with a median of 4 points; 0.50 SD corresponds to a T-score of 4.0 
points, assuming an SD of 8.0.43  
 
12.5 
Estimated Accrual Rate 
 
We estimate accruing 4 patients/month, with accrual expected to be completed in 
48 months. 
  
12.6 
Estimated Study Length 
 
Patients will be followed for a total of 12 months, thus the study will be completed 
12 months after the last patient is accrued. 
 
 
12.7 
Interim Analysis Plan 
 
 
There will be no interim analysis.  
 
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APPENDICES 
 
The following Appendices have been separated and moved to the Other Documents section 
of the eIRB in order to make access and administration easier. 
 
Appendix A & B = Protocol Registration Form/Race & Ethnicity Verification Form 
Appendix C = Eligibility Checklist (script remains within this protocol document) 
Appendix D = SAE Notification SOP 
Appendix E = Baseline Data Collection Form 
Appendix F = 3 mo/ 9 mo Data Collection Form 
Appendix G = 6 mo/12 mo Data Collection Form 
Appendix H-M = Surveys (PROMIS and HFRDIS) 
Appendix N & O = Physical Function Measures (SPPB & 6MWT) 
Appendix P = Telephone Survey 
Appendix Q = AE Ascertainment Form 
Appendix R = AE Adverse Event Log 
Appendix S = SAE Reporting Form 
Appendix T = Disease Progression Form 
Appendix U = Status Change Form 
Appendix V = End of Study Follow Up Form 
Appendix W = Pre-Toxicity Form 
Appendix X = DXA Questionnaire 
Appendix Y = Adherence Telephone Script 
 
 
 

 
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Appendix C - Subject Eligibility Checklist Script for Eligibility Screen by Phone 
Text in ALL CAPS is for the recruiter only and should not be read aloud. 
 
A. Hi, my name is _________ from Wake Forest Baptist Health.  I got your name from Dr. 
_______ because s/he thought you might be a good candidate for our study about 
prostate cancer.  Do you have a few minutes for me to tell you about the study and ask a 
few questions? 
 
IF YES, PROCEED TO B. 
IF NO: Is there a better time for me to contact you?   IF YES, MAKE NOTES AND 
RECONTACT.  IF NO, MARK AS REFUSAL ON PAGE 2 OF THE SCREENER AND END THE 
CALL. 
 
B. Great, thanks!   This study is for men with prostate cancer who are receiving androgen 
deprivation therapy (ADT). The goal of the study is to possibly help with side effects 
related to ADT.  First we need to make sure everyone we enroll meets the criteria 
specified by the study.  If you qualify and agree to participate, you will be randomized to 
one of two study groups. Both groups take 4 pills twice a day for a year, but in one group 
the pills are muscadine grape extract, and in the other group, it is a placebo, or ‘sugar 
pill.’ We are testing to see if the muscadine grape extract helps prostate cancer patients 
in any way, particularly with fatigue. 
 
The study will ask everyone to attend a study appointment every 3 months for a year, 
totaling 5 appointments.  All 5 study appointments will involve you completing surveys 
and at 3 appointments we will collect blood and urine ask you to do physical function 
tests which involve walking a short distance.  At 2 visits we will do a body scan called a 
“dexa”. If you qualify, we will provide many more details about these procedures before 
you begin the study. Are you still interested; Can I ask you some questions to see if you 
might qualify? 
 
IF YES, PROCEED TO C. 
IF NO: I understand.  Can I answer any questions for you or provide more information that might 
help you reconsider?  IF YES, DO SO.  AFTERWARDS SAY, “Do you think you might be 
interested in the study?”  IF YES say, “Great, now let’s see if you qualify” AND PROCEED TO 
C.  IF STILL NO, MARK AS REFUSAL ON PAGE 2 OF THE SCREENER AND END THE 
CALL. 
  
C. Now I am going to ask you some questions about your health history. Answer them as 
best you can.  PROCEED TO PAGE 1 OF THE ELIGIBILITY SCREENER AND 
COMPELTE THE OUTSTANDING ITEMS.  IF LABS ARE NEEDED AFTER SCREENING, 
PROCEED TO D.  IF LAB VALUES WERE CONFIRMED PRIOR TO THE CALL, GO TO 
E. 
 
D. Unfortunately, I still don’t know if you are eligible because we need to check some 
bloodwork.  Can I schedule you for an appointment here at Wake Forest Baptist Health? If 
you come in and consent to give some blood, we can use those results to figure out 
whether you will qualify for the study. 
 
IF YES, SCHEDULE HIM OR DISCUSS THE PLAN FOR SCHEDULING HIM IN SECTION F. 
IF NO, ask “Can I answer any questions for you or provide more information that might help you 
reconsider?” IF YES DO SO. AFTERWARDS SAY, “Can I schedule you for a blood draw now?”  

 
Protocol version date 4/2/2025 
 
 
 
 
 
 
 
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IF STILL NO, MARK AS A REFUSAL ON PAGE 2 OF THE SCREENER AND END THE CALL.   
 
E. DETERMINE IF ELIGIBILE OR INELIGIBLE. 
 
IF ELIGIBLE:  Thank you for answering all my questions! It looks like you qualify for our 
study!  Let me tell you what will happen at the first study visit and during the year. USE 
CONSENT FORM TO DESCRIBE THE FIRST VISIT AND SUBSEQUENT VISITS.  ASK 
IF HE HAS QUESTIONS; ANSWER THEM.  THEN SCHEDULE THE BASELINE VISIT; 
SEE SECTION F.  MARK ELIGIBLE ON PAGE 2 OF THE ELIGIBILITY SCREENER.  IF 
HE REFUSES AT THIS POINT, ASK Can I answer any questions for you or provide more 
information that might help you reconsider?”  IF YES, DO SO.  AFTERWARDS SAY, “Can 
I schedule your first study appointment?”  IF YES, SCHEDULE THE APPOITNMENT; SEE 
SECTION F.  IF STILL NO, MARK AS A REFUSAL ON PAGE 2 OF THE SCREENER, 
THANK HIM AND END THE CALL. 
 
IF INELIGIBLE:  Thanks for answering all my questions.  Unfortunately you do not qualify 
for our study because our study requires…..DESCRIBE WHY HE CAN’T ENROLL.  
THANK HIM AGAIN AND END CALL.  MARK INELIGIBLE ON PAGE 2 OF ELIGIBILITY 
SCREENER. 
 
IF UNCERTAIN: Thank you for answering all my questions. I will take this information to 
the doctor in charge and she will let me know if you qualify based on your answers. If you 
qualify, I will call you back to schedule an appointment.  Do you have any questions for me 
before I go?  ANSWER QUESTIONS; THANK HIM; CONSULT WITH PI. 
 
F.  SCHEDULING PLAN/NOTES FROM DISCUSSION HERE: