Clinical trial NCT03535675
Conditions: Adenocarcinoma of the Prostate
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2018-10-30; Completion date: 2022-11-03
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research is being done to determine if men with rising PSA after initial therapy for localized prostate cancer who display the Alanine/Alanine SOD2 genotype of MnSOD and supplement their diet with MPX have greater decrease in PSA slope following treatment compared to men that do not supplement with MPX.

Detailed description:
Prostate specific antigen (PSA) is a single-chain glycoprotein produced by the epithelial cells of the prostate. PSA has been used for early detection and monitoring of patients with prostate cancer who receive a variety of treatments. Due to the widespread use of serum PSA to monitor for prostate cancer recurrence following primary treatment, there exists a group of men with a rising PSA as their only evidence of recurrence. These patients may not demonstrate clinical or radiographic evidence of disease progression for an average 8 years from the time of detectable PSA to detectable metastatic disease by standard imaging. Currently there are limited treatment options for these patients that may delay disease progression or improve survival, including salvage radiation for prior surgical patients, hormonal therapy, and active surveillance.

Although some surgical patients are candidates for salvage radiation, not all patients will want salvage radiation. Even the early initiation of hormonal therapy (e.g., luteinizing hormone releasing hormone (LHRH) analogs) has not demonstrated a survival benefit, although Schroder et al suggests an advantage for early hormone therapy in the setting of metastatic regional lymph nodes. Furthermore, early initiation of androgen ablation is associated with significant morbidity and impact on quality of life, including fatigue, hot flashes, loss of libido, decreased muscle mass, and osteoporosis with long term use. This group of relatively well men with biochemical recurrence are currently offered androgen ablation therapy or active surveillance (regular PSA monitoring and annual scans) until there is evidence of metastatic disease, because other options have not been available. These patients are excellent candidates for innovative treatments hypothesized to slow the progression of clinical prostate cancer and delay the development of metastatic disease.

As the previous section documents, preclinical studies of muscadine grape skin offer evidence that it may extend the time between biochemical recurrence and development of metastatic disease. While the Phase II study described above found no significant difference in PSA doubling time between placebo and either dose of MPX, there was a signal of benefit in the subgroup analysis of men with the Alanine/Alanine superoxide dismutase 2 (SOD2) genotype that received high dose MPX. It is therefore proposed to test the benefits of high dose MPX in capsule formulation in a randomized, controlled study of men who have failed primary therapy, either radiation, surgery or cryotherapy, as primary treatment for prostate cancer. Eligible subjects will have a rising PSA and will have 3 PSA values at least 7 days apart with a recovered testosterone to be able to calculate a baseline PSA doubling time. The primary endpoint of this study will be mean PSA slope during the study period.

Arms: arm 1: Each treatment cycle consists of once daily oral dosing of 4000 mg Muscadine Plus, every day throughout each 12 week (84 day) cycle. Patients may continue to receive additional cycles of study drug and will be followed every three months with standard visits with their physician until completion of 48 weeks of study treatment, disease progression, or until they wish to discontinue the drug. arm 2: Each treatment cycle consists of once daily oral dosing of 4000 mg placebos, every day throughout each 12 week (84 day) cycle. Patients may continue to receive additional cycles of placebo and will be followed every three months with standard visits with their physician until completion of 48 weeks of study treatment, disease progression, or until they wish to discontinue the drug.
Interventions: intervention 1: Muscadine Plus intervention 2: Placebos
Intervention descriptions: intervention 1: Ellagic acid inhibits DNA Methyltransferase. DNA Methyltransferases (DNMTs) are a family of enzymes that regulate chromatin methylation and use S-adenosyl methionine (SAM) as the methyl donor. Ellagic acid's metabolite, urolithin-A inhibits the protein complex nuclear factor kappa-light-enhancer of activated B-cells (NFkB), potentially leading to increased rates of apoptosis and decreases in cancer cell proliferation. Extracts from Vitis rotundifolia have shown inhibition of the phosphatidylinositol 3-kinase-Akt pathway. intervention 2: The placebo capsules are rice flour that will be placed in white opaque capsules identical to the ones used for MPX.

Protocol documents:
Prot_SAP_001.pdf: 
Protocol Version 6.0 Date: July 02, 2021 
J1823 Protocol – Phase III MPX in Prostate Cancer  
Page 1 of 58 
  
 
 
The MAP TRIAL: PHASE III STUDY OF MUSCADINE PLUS (MPX) IN MEN WITH 
PROSTATE CANCER: A RANDOMIZED DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY OF THE EFFECTS OF MPX CAPSULES ON RISING PROSTATE-SPECIFIC 
ANTIGEN LEVELS IN ALANINE/ALANINE SOD2 GENOTYPE MEN FOLLOWING 
INITIAL THERAPY FOR PROSTATE CANCER 
  
 
Coordinating Center:          The Sidney Kimmel Comprehensive Cancer Center (SKCCC) at 
Johns Hopkins 
 
IND #: 109605 
IRB #: IRB00166021 
  
 
Principal Investigator and IND Sponsor:        
 
Channing Paller, MD  
The Sidney Kimmel Comprehensive Cancer  
Skip Viragh Building, Floor 9 
201 N. Broadway, 
Baltimore, MD 21287     
Phone: 410-955-8239,   
Fax: 410-614-1860, Email: (cpaller1@jhmi.edu) 
  
Biostatistics:                          Marianna Zahurak (Zahurma@jhmi.edu) 
 
Research Nurse: 
 
Donna Dowling, RN (ddowlin1@jhmi.edu) 
 
 
 
 
 
SKCCC Study Manager: 
Harry Cao (hcao7@jhmi.edu)  
 
  
Protocol Version 6.0 Date:  July 02, 2021 
 
 
NCT#: NCT03535675


Protocol Version 6.0 Date: July 02, 2021 
J1823 Protocol – Phase III MPX in Prostate Cancer  
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SCHEMA 
 
Prostate cancer patients meeting 
Eligibility criteria 
REGISTRATION:  
Approximately 500 BCR patients screened for MnSOD genotype   
 
 
Randomization by PSADT and Gleason Score of 80 Alanine/Alanine patients 
 
 
 
Obtain baseline antioxidant levels 
TREATMENT: randomly assigned 1:1 to receive placebo or MPX PO daily  
1 cycle = 12 weeks (Total treatment four 12-week cycles) 
 
 
EVALUATIONS: Day 0, 12-Week, 24-Week, 36-Week, 48-Week 
 
OFF STUDY:  Patients continue on protocol until: 
 Completed 4 cycles of 12 weeks of treatment 
 Disease progression 
 Unacceptable toxicity 
 Patient decision to discontinue study drugs 
 Alternate treatment 
 
 
OPEN LABEL 48-WEEK EXTENSION: patients who complete all protocol requirements will 
be offered 48 weeks of MPX treatment and monitoring every 12 weeks. 
 
 
 
Drug Names/Abbreviations  
Generic name: Muscadine Plus (MPX) 
Brand name(s): N/A 


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PROTOCOL TABLE OF CONTENTS 
Page 
1. OBJECTIVES ......................................................................................................................................... 5 
1.1 Primary Objectives .................................................................................................................................... 5 
1.2 Secondary Objectives ............................................................................................................................... 5 
1.3 Tertiary Objectives (correlative exploratory markers) .............................................................. 5 
2. BACKGROUND .................................................................................................................................... 5 
2.1 Prostate Cancer .......................................................................................................................................... 5 
2.2 Muscadine Plus (MPX) and Placebo .................................................................................................... 6 
2.3 Rationale for Studying Muscadine Plus (MPX) in Prostate Cancer Patients ..................... 12 
2.4 Correlative Studies ................................................................................................................................. 12 
3. Eligibility Criteria ........................................................................................................................... 14 
3.1  Inclusion Criteria.................................................................................................................................. 14 
3.2  Exclusion Criteria ................................................................................................................................. 16 
3.3  Inclusion of Minorities ....................................................................................................................... 17 
4. SUBJECT REGISTRATION AND DATA REPORTING ............................................................... 17 
4.1  Subject Registration ............................................................................................................................ 17 
4.2  Data Reporting and Regulatory Requirements ......................................................................... 18 
4.3  Data Management ................................................................................................................................ 18 
4.4  Study Monitoring and Quality Assurance .................................................................................... 19 
5. TREATMENT PLAN ......................................................................................................................... 20 
5.1  MPX Administration ............................................................................................................................ 21 
5.2  Blinding .................................................................................................................................................... 21 
5.3  General Concomitant Medication and Supportive Care Guidelines ................................... 22 
5.4  Definition of Treatment Response and Disease Progression ............................................... 22 
5.5  Duration of Therapy ............................................................................................................................ 23 
5.6  Duration of Follow-Up ........................................................................................................................ 24 
6. DOSING DELAYS ............................................................................................................................... 24 
7. ADVERSE EVENTS: List and Reporting Requirements ....................................................... 24 
7.1   Definitions ............................................................................................................................................... 24 
7.2  Assessment of Adverse Events ........................................................................................................ 25 
7.3  Documentation and Reporting ........................................................................................................ 27 
8. PHARMACEUTICAL INFORMATION .......................................................................................... 29 
8.1   Muscadine Plus ...................................................................................................................................... 29 
8.2  Investigational Products Accountability and Destruction (MPX and Placebo) ............. 30 
9. CORRELATIVE/SPECIAL STUDIES ............................................................................................. 31 
9.1  Blood ......................................................................................................................................................... 31 
9.2   Serum ........................................................................................................................................................ 31 
9.3  Urine ......................................................................................................................................................... 31 
9.4  Microbiome analysis ........................................................................................................................... 32 
10. STUDY CALENDAR ........................................................................................................................ 32 
11. EVALUATION AND STATISTICAL METHODS ....................................................................... 34 
11.1 Analysis Plans for Primary Objective……………………………………………………………………….37 


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11.2 Secondary Efficacy Assessment ...................................................................................................... 38 
11.3 Correlative Studies .............................................................................................................................. 38 
11.4 Additional Analyses ............................................................................................................................ 39 
APPENDIX A: ECOG PERFORMANCE STATUS SCALE ................................................................ 41 
APPENDIX B: Study Drug Compliance - Pill Diary .................................................................... 42 
APPENDIX C: FOOD FREQUENCY QUESTIONNAIRE FOR FRUITS AND VEGETABLES .... 47 
APPENDIX D: Dietary Supplement List ........................................................................................ 53 
REFERENCES .......................................................................................................................................... 54 
 


Protocol Version 6.0 Date: July 02, 2021 
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1. OBJECTIVES 
 
1.1 Primary Objectives 
 
1. To determine if men with rising PSA after initial therapy for localized prostate cancer 
who display the AA genotype of MnSOD and supplement their diet with MPX have 
greater decrease in PSA slope following treatment compared to men that do not 
supplement with MPX. 
1.2 Secondary Objectives           
1. To estimate the prostate specific antigen doubling time (PSADT) of the two treatment 
groups 
 
2. To estimate the fraction of patients with a decrease in PSA of ≥50% from the start of 
treatment (PSA objective response rate) at 24 and 48 weeks.  
 
3. To estimate the time to disease progression for both treatment groups by PSA progression 
as well as by radiologic disease progression (i.e. development of metastatic disease) 
 
1.3 Tertiary Objectives (correlative exploratory markers) 
 
1. To correlate baseline and change of levels of antioxidants (selenium, lycopene, and -
tocopheral) with changes in PSA.  
 
2. To correlate measures of oxidative stress (8-OHdG, Malondialdehyde and F2-
Isoprostanes) with PSA changes. 
 
3. To store blood for future evaluation of biomarkers associated with MPX effect if the 
study is positive.  
 
2. BACKGROUND 
 
2.1 Prostate Cancer 
 
The American Cancer Society reports that prostate cancer is the most common cancer in men 
other than skin cancer and that more than 26,000 men will die of prostate cancer in 2017.1 
Improving techniques in radical surgery and radiation therapy, combined with early detection, 
allow many prostate cancer patients to enjoy permanent disease control.  However, of those 
patients who undergo radical prostatectomies for clinically localized prostate cancer, a 
significant fraction (15%) experience biochemical recurrence (PSA >0.2 ng/mL) and one third of 
those with biochemical recurrence develop metastatic disease within 15 years after surgery. 
Median time to metastatic disease was 8 years after the recurrence of PSA elevation, and median 
time to death after metastatic disease was 5 years.2 
 


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2.2 Muscadine Plus (MPX) and Placebo 
 
Muscadine Plus (MP), manufactured and sold by Muscadine Naturals, Inc., is an encapsulated 
blend of 500 mg skin powder of the Noble cultivar of Vitis rotundifolia.  The study agent uses 
the same dried grape skins as MP, although isolated from only one farm and standardized in 
composition, and the same production and encapsulation facilities as the generally available 
commercial product, but using opaque encapsulation instead of transparent encapsulation used in 
Muscadine Plus (MP), so as to distinguish the study agent from the commercial product.  
Because of these differences, our study agent is designated MPX.   
 
The investigational product, MPX is formulated as a brown powder composed of the pulverized 
skin of Vitis rotundifolia of the Noble cultivar.  It is encapsulated in clear capsules for oral 
administration for phase I and white opaque capsules for phase II.  Each size 0 capsule contains 
500 mg of dried grape skin powder.  Size 0 capsules are 7.65 mm in diameter and 21.7 mm long.  
The capsules are bottled in a 150 cc white HDPE (high-density polyethylene) bottle with 38 mm 
white ribbed cap, and a neck band seal for consumer protection. Cotton and desiccant are added. 
Bottles will be labeled at the time of bottling with drug name, date, and lot number.  The placebo 
capsules are rice flour that will be placed in white opaque capsules identical to the ones used for 
MPX.  
 
In this phase III study, patients will be randomized 1:1 to receive placebo or high (4000 mg) dose 
MPX.  Each patient will receive a 3 month supply of opaque capsules in coded bottles. 
 
2.2.1 Safety profile for Muscadine Plus (MPX)  
 
The Vitis rotundifolia grape grows wild in the southeastern United States and is also grown in 
vineyards and used in winemaking.  The Physicians’ Desk Reference for Herbal Medicine lists 
the related Vitis vinifera and details many health benefits, concluding, “No health hazards or side 
effects are known in conjunction with the proper administration of designated therapeutic 
dosages.”  The safety of the compound has been demonstrated through the production and sale of 
muscadine skin powder by Muscadine Naturals and other suppliers.  Several companies have 
sold muscadine grape seed powder and extracts as dietary supplements and muscadine wine 
commercially for many years with no ill side effects reported.  MP has been legally marketed in 
the United States and surrounding territories since 2005.  In the last three years, records from 
Muscadine Naturals, Inc. show that more than 19,000 stock keeping units (SKUs), including 
bottles and packets, have been delivered without any reported significant adverse effects.  The 
product has been consumed by the public without complaint and without reports of toxicity to 
the company or to government agencies.  
 
The skin of Vitis rotundifolia of the Noble cultivar has been characterized in a number of studies 
and shown to contain polyphenols that are potent antioxidants.3, 4 An analysis of the constituent 
polyphenols of MPX, provided by Muscadine Naturals, shows the following polyphenol content: 
 
Polyphenol Content, 9/10/2010, Analytical Laboratories, Anaheim, CA: 
Ellagic acid 
   
2.36 mg/g 
Quercetin 
 
18.4 mcg/g 


Protocol Version 6.0 Date: July 02, 2021 
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Trans resveratrol 
8.77 mcg/g 
 
These polyphenols offer health benefits including slowing prostate specific antigen doubling 
time in post-prostatectomy prostate cancer patients with biochemical re-occurrence,5 reducing 
markers associated with progression of diabetic complications,6, 7 inhibiting platelet function as a 
protective role for the cardiovascular system,8 and reducing inflammatory responses.9  The 
polyphenol content has remained stable over several years. 
 
Ellagitannins are the most prevalent polyphenol in MP.4  The principal metabolite of 
ellagitannins, urolithin-A, is preferentially absorbed by the prostate10 and inhibits the protein 
complex NF-B, potentially leading to increased rates of apoptosis and decreases in cancer cell 
proliferation.11   Ellagic acid was also found to be a potent DNA methyltransferase modulator in 
MCF-7 human breast cancer cells.12 
 
Other polyphenols in MP, including quercetin,13 myricetin,14 kaempferol,15 and resveratrol,16 all 
have demonstrated anti proliferative activity individually, and two of them, quercetin and 
resveratrol, along with ellagic acid, have demonstrated synergistic effects greater than what 
would be expected by adding individual effects.17    
 
2.2.2 Preclinical Studies of Muscadine Grape Skin Extract 
 
In research conducted while at the National Institutes of Health, co-investigator Dr. Tamaro 
Hudson showed that Vitis rotundifolia skin powder of the Ison cultivar significantly inhibited 
tumor cell growth in prostate cancer cell lines but did not inhibit growth in normal prostate 
epithelial cells (PrEC).  Prostate tumor cell lines exhibited high rates of apoptosis in response to 
the extract through targeting of the phosphatidylinositol 3-kinase–Akt and mitogen-activated 
protein kinase survival pathways.  The reduction in Akt activity by Vitis rotundifoliaskin extract 
of the Ison cultivar is mediated through a reduction in Akt transcription, enhanced proteosome 
degradation of Akt, and altered levels of DJ-1, a known regulator of phosphatase tensin homolog 
(PTEN).3 
 
Figure 1. Vitis rotundifolia of the Ison 
cultivar inhibits cell growth in prostate 
cancer cells but not normal cells and 
induces apoptosis. The effect of Vitis 
rotundifolia skin extract on the growth 
rate by MTS assay in: A) PrEC, normal, 
B) WPE1-NB26 metastatic cells, C) 
LNCaP. D) Vitis rotundifolia of the Ison 
cultivar induces apoptosis in WPE1-
NB26, and LNcaP prostate cells.   
 
 
 
                                                                                                                          
 
 
 
 
Cell viability 
Absorbance (A490 nm)
Cell viability 
Absorbance (A490 nm)
A.
24
48
72
0.0
0.1
0.2
0.3
0.4
0.5
0.6
ETOH
0
2 ug/ml
5 ug/ml
10 ug/ml
20 ug/ml
TIME (hr)
PrEC
WPE1-NA26
24
48
72
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
ETOH
0
2 ug/ml
5 ug/ml
10 ug/ml
20 ug/ml
*
*
*
*
*
*
TIME (hr)
LNCaP
WPE1-NB26
0
10
20
30
40
50
60
70
80
90
100
Control
20 ug/ml
60 ug/ml
Prostate cell line
Percentage of Apoptotic Cells
Annexin-V-FITC
C.
24
48
72
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0
ETOH
5 ug/ml
10 ug/ml
20 ug/ml
60 ug/ml
LNCaP
Time (hr)
Cell Viability
Absorbance (A490 nm)
*
*
*
*
*
B.
D.


Protocol Version 6.0 Date: July 02, 2021 
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An additional in vitro study in C4-2 human prostate cells similarly showed that cells treated with 
muscadine grape skin extract (MSKE) confirmed these findings that it induces apoptosis and also 
upregulates the stress response of the endoplasmic reticulum and autophagy.  Two of the stress 
response protein markers, IRE-1 alpha and GRP78 were upregulated in the MSKE treated cells 
compared to the control cells as were the proteins PARP and Caspase 12, involved in apopotosis 
(Figure 2).  It was also shown that MSKE induces autophagy, which was able to be blocked with 
co-treatment with chlorogquine, a known autophagy inhibitor, and that this was also correlated 
with increases in apoptosis with upregulation of pro-apoptotic proteins BAX, cleaved caspase-3, 
cleaved caspase-7 and downregulation of the anti-apoptotic protein BCL2.18 
 
 
Figure 2 – Western blot analysis of endoplasmic reticulum stress as indicated by markers IRE1-alpha and GRP78 
(top) and apoptosis as indicated by PARP, Caspase 12 (bottom).18   
 
Although Dr. Hudson had demonstrated in vitro that Vitis rotundifolia skin extract of the Ison 
cultivar is effective in causing reduction in cell growth through Akt there was no data that 
supported its effects in vivo.  As a result he constructed studies that examined the toxic as well as 
the preventive effects of the extract.  Initial toxicity studies involved relatively healthy athymic 
nude mice.  Three groups of 5 nude mice, 4 to 6 weeks old, were administered Vitis rotundifolia 
skin extract of the Ison cultivar in saline orally at 100, 200, and 400 mg/kg bodyweight 5 days a 
week for seven weeks, respectively.  The remaining control group of mice received saline.  The 
mice were evaluated over the seven weeks for weight loss and moribund appearance.  At the end 
of seven weeks blood and tissue samples were collected.  The results revealed that Vitis 
rotundifolia skin extract of the Ison cultivar did not produce any tumors, and had no significant 
impact on body weight.  In addition, histopathological examination of liver, kidney, heart, and 
lung tissue from treated animals revealed no observable tissue toxicity.  Moreover, the 
hematology profile revealed that leukocytes, erythocytes, and thrombocytes were within 
relatively normal range in treated groups compared to control. (Unpublished data from Dr. 
Hudson’s Laboratory at Howard University.) 
 
A second study performed by Dr. Hudson involved a PC-3 prostate cancer xenograft model of 
five additional groups of athymic nude mice, 4 to 6 weeks old, were administered 50-600 mg/kg 
Vitis rotundifolia skin extract of the Ison cultivar by oral gavage before, during, and after tumor 
cell-injection in 0.1 ml saline, 5 days a week for seven weeks. Five animals were in the 600 
mg/kg group; the other groups had 10 animals.  Four-to-six week old athymic nude male mice 


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were injected in the right flank with 1 million cells.  Body weight and diet consumption was 
recorded weekly throughout the study.  After tumors began to grow, their sizes were measured 
twice a week.  No significant differences in mean body weight or food consumption were found 
between control and treatment groups during the bioassay.  Histopathological examination of 
sections of the liver, lung, and kidney tissues from treated animals indicated that the extract did 
not elicit toxic effects in any of these organs.  Vitis rotundifolia skin extract of the Ison cultivar 
significantly (p < 0.05) inhibited PC-3 prostate tumor growth in all five treatment groups 
compared to the control.  (Unpublished data from Dr. Hudson’s laboratory at Howard 
University.) 
 
2.2.3 Phase I and Phase II Clinical Studies of Muscadine Grape Skin Extract 
 
Early clinical studies have now also been completed.  A phase I trial was done in 14 men with 
biochemical recurrent prostate cancer.  The phase I study was designed as a dose finding study, 
showing that the maximal dose, 4,000mg daily, was well tolerated.  That dose was chosen as the 
maximum since it consists of 8 capsules and taking more than that a day raised concerns for 
adherence to therapy.  Six of the 14 patients received the maximum dose.  The most common 
side effect was flatulence (4 of 14 patients reported).  Soft stools, abdominal distention and 
eructation were also reported and all were grade 1 toxicities.  There were no grade 4 adverse 
events and no study drug related grade 3 adverse events.  In this early phase trial, 64% of patients 
had increases in PSADT with 44% of those who had an increase having an increase of more than 
6 months.19   
 
Given the safety and possible signal of benefit, a phase II trial was completed.20  This was a 
randomized, double-blind trial of 112 men with biochemical recurrent prostate cancer who were 
assigned to receive either placebo, 500mg or 4,000mg of MPX in a 1:2:2 design.  The primary 
endpoint was change in PSADT.  There was no significant difference found between the three 
groups (p=0.81) with a change of 0.9 months seen in the placebo group, 1.5 month change in the 
500mg group and 0.9 month change seen in the high dose group.  There was only one patient in 
the 4,000mg dose group who had a decrease in PSA of >50%.  There were no new safety signals 
noted in this trial.   
 
MPX was shown to be a safe therapy.  However, the overall results have been disappointing but 
there have been a few people with responses to therapy.  This led to the hypothesis that there 
may be a subset of patients, who can be identified early on, who would benefit from therapy.  A 
previous studied showed that in patients with a variant of the manganese superoxide dismutase 
gene (SOD2), baseline exposure to antioxidants significantly influences the risk of developing 
prostate cancer.21  Manganese superoxide dismutase (MnSOD) is encoded by the SOD2 gene and 
is one of the major enzymes responsible for detoxification of reactive oxygen species in 
mitochondria.  A mutation at the -9 position results in a change from valine to alanine and alters 
the structure of the protein.22  This mutation (AA), present in about 25% of prostate cancers, was 
shown in an observational study that men who had the alanine/alanine genotype and high 
antioxidant levels had much lower rates of all prostate cancer and clinical aggressive prostate 
cancer.21 
 


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Another antioxidant and natural product, pomegranate, has also been studied in the setting of 
biochemical recurrent prostate cancer.  With pomegranate, there were similar findings as above 
in the MPX trials of no significant change in PSADT in those taking the supplement compared to 
those on placebo.  However, those patients with AA genotype of SOD2 gene did have a 
significant benefit, with a 12 month increase in PSADT (p=0.03, from 13.6 months at baseline to 
25.6 months at follow up) compared to only a 1.8 month change in the placebo group (10.9 
months at baseline to 12.7 months at baseline).23    
 
Based on these data, in the phase II trial we completed using MPX, there was a preplanned 
exploratory analysis to determine if those with the AA genotype had a different response to 
treatment versus placebo.  In that trial, 91 men had SOD2 SNP genotyping done and found that 4 
men in the control group, 8 in the 500mg dose group and 11 men in the 4,000mg dose group had 
the AA genotype.  When comparing the treatment effect in those with the AA genotype, there 
was a signal of benefit.  Those in the high dose treatment group had a 10.3 month median 
increase in PSADT compared to 1.8 months in the control arm.  Those in the low dose group had 
a 2.8 month median increase in PSADT.  These results were not statistically significant however 
are limited due to sample size and are supportive of the larger trial planned.20    
 
2.2.4 Metabolism and Elimination Activity 
 
Metabolism and elimination of these polyphenols in MPX have not been explored in 
combination.  However, ellagic acid, which is also found in pomegranate juice, has been 
explored in humans.  Specifically Seeram et al24 measured ellagic acid in plasma following 
consumption of pomegranate juice containing 25 mg of ellagic acid and found the peak plasma 
ellagic acid was at 1 hour, 31.9+/- ng/ml (0.106 mmol). Cerdá et al.25 investigated blood and 
urinary metabolites in 6 human subjects on a controlled diet (restricted intake of dietary 
ellagitannins and polyphenols) after ingestion of pomegranate juice containing 4.37 g/L 
punicalagin isomers, 0.61 g/L free ellagic acid, 0.6 g/L ellagic acid glucosides and 0.49 g/L 
anthocyanins.  In a preliminary experiment, no juice polyphenols or metabolites were detected in 
plasma during the first 4 hours or at 24 hours after juice consumption. At 24 hr, 3 main 
ellagitannin metabolites were found in the urine of treated subjects but not controls.  The major 
metabolite was a glucuronide derivative of 3,8-dihydroxy- 6H-dibenzo[b,d]pyran-6-one, 
previously detected in rats after ingestion of pomegranate husk ellagitannins; the other 
metabolites were related conjugates.  There was a large variability among the subjects, with the 
plasma metabolites appearing in some on the first day of juice consumption but remaining 
nondetectable in others through the experiment.  When detected, the concentration range in 
plasma was 0.5-18.6 μM.  Three of the plasma metabolites were also detected in urine, along 
with 3 others; the plasma and urine concentrations were unrelated.  Percent of ingested ellagic 
acid equivalents excreted ranged from 1%-50% across individuals.  The urinary metabolites were 
first detected 24hr after ingestion, with maximum excretion occurring between days 3-4.25  
 
A preclinical study of Ison cultivar of Vitis rotundifolia skin powder at the Laboratory of 
Cellular Regulation and Carcinogenesis at the National Cancer Institute, found that the 
compound significantly inhibited tumor cell growth in prostate cancer cell lines but did not 
inhibit growth in normal prostate epithelial cells.3  The study is being repeated for the Noble 
cultivar being proposed for use in this application.  Preliminary results from the new study show 


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that the Noble cultivar used in MP inhibits prostate tumor cell growth in a similar manner to the 
Ison cultivar grapes (unpublished data from Dr. Hudson’s laboratory, Howard University). 
 
2.2.5 Absorption, Distribution, Metabolism, and Excretion 
 
Scalbert et al reviewed the metabolism of polyphenols including flavonoids and ellagitannins.  
Low molecular weight polyphenols are easily absorbed through the gut barrier, whereas large 
polyphenols are poorly absorbed and require extensive metabolism by the microflora prior to 
absorption in the colon.  Once absorbed, polyphenols are conjugated to glucuronide, sulphate and 
methyl groups in the gut mucosa and inner tissues, thereby facilitating excretion in the bile and 
urine, and limiting their toxicity.  At the gut barrier, polyphenols are conjugated to O-
glucuronides; in the liver, to sulfate esters, and O-methyl esters. Free circulating polyphenol 
aglycones are only found in plasma if glucuronidation pathways are saturated.  De-
glucuronidation and demethylation of some polyphenol conjugates, if it does occur at the cellular 
level, may be restricted to inflammatory states.26  
 
2.2.6 Dosage Rationale 
 
 A range of 1500-3000mg daily is most commonly recommended.  The range in dosing 
completed by Dr. Hudson for the mice experiments included 50 mg/kg up to 600 mg/kg daily 
dosing and demonstrated inhibition of PC3 xenograft model throughout the dosing range, 
independent of dose.  Using the NOAEL/Human Equivalent Dose calculation for a 70 kg male, 
the dose range would be from 285 mg up to 3415 mg daily.  A phase I dose-finding study was 
done in 14 men with biochemical recurrent prostate cancer, which tested both 500 mg and 4000 
mg doses.19  The maximum dose used in this dose-finding study was rounded up to 4000 mg (8 
capsules) to account for patients over 70 kgs.  The maximum dose of 4000 mg was received by 6 
of the 14 men and was well tolerated.  The most common side effect was flatulence (4 of 14 
patients reported).  Soft stools, abdominal distention and eructation were also reported and all 
were grade 1 toxicities.  There were no grade 4 adverse events and no study drug related grade 3 
adverse events.  In a subsequent Phase II study, the overall rate of AEs was similar between the 
MPX and placebo control arms.20  Of 102 patients that received MPX, only 6 experienced AEs 
possibly related to study drug.  AEs thought to be related included grade 1 flatulence, diarrhea, 
and fatigue, and grade 2 dyspepsia and reflux disease.  There were no serious adverse events or 
grade 3 or higher toxicities related to study drug.  Therefore, we will use a dose of 4,000mg 
daily.  The phase II trial by Paller et al, showed a larger change is PSADT in the 4000 mg AA 
SOD2 group.20  
 
2.2.7 Potential for Drug Interactions  
 
Many polyphenols, including quercetin, kaempherol, and gallic acid have been shown to inhibit 
CYP3A activity.27-31 CY3PA is a human gene involved in drug metabolism and synthesis of 
cholesterol.  Ellagic acid inhibits CYP2A2, 3A1, 2C11, 2B1, 2B2 and 2C6 in rat liver 
microsomes.32  However, clinical trials of midazolam33 and simvastatin34 with pomegranate juice 
suggest that these polyphenols, at least when combined in pomegranate juice, do not inhibit the 
activity of CY3PA in healthy human volunteers.  
 


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2.3 Rationale for Studying Muscadine Plus (MPX) in Prostate Cancer Patients 
 
PSA is a single-chain glycoprotein produced by the epithelial cells of the prostate.  PSA has been 
used for early detection and monitoring of patients with prostate cancer who receive a variety of 
treatments.  Due to the widespread use of serum PSA to monitor for prostate cancer recurrence 
following primary treatment, there exists a group of men with a rising PSA as their only 
evidence of recurrence.  These patients may not demonstrate clinical or radiographic evidence of 
disease progression for an average 8 years from the time of detectable PSA to detectable 
metastatic disease by standard imaging.2 Currently there are limited treatment options for these 
patients that may delay disease progression or improve survival, including salvage radiation for 
prior surgical patients, hormonal therapy, and active surveillance.  
 
Although some surgical patients are candidates for salvage radiation, not all patients will want 
salvage radiation.  Even the early initiation of hormonal therapy (e.g., LHRH analogs) has not 
demonstrated a survival benefit, although Schroder et al suggests an advantage for early hormone 
therapy in the setting of metastatic regional lymph nodes.35  Furthermore, early initiation of 
androgen ablation is associated with significant morbidity and impact on quality of life, 
including fatigue, hot flashes, loss of libido, decreased muscle mass, and osteoporosis with long 
term use.  This group of relatively well men with biochemical recurrence are currently offered 
androgen ablation therapy or active surveillance (regular PSA monitoring and annual scans) until 
there is evidence of metastatic disease, because other options have not been available.  These 
patients are excellent candidates for innovative treatments hypothesized to slow the progression 
of clinical prostate cancer and delay the development metastatic disease. 
 
As the previous section documents, preclinical studies of muscadine grape skin offer evidence 
that it may extend the time between biochemical recurrence and development of metastatic 
disease.  While the Phase II study described above found no significant difference in PSA 
doubling time between placebo and either dose of MPX, there was a signal of benefit in the 
subgroup analysis of men with the AA genotype that received high dose MPX.  It is therefore 
proposed to test the benefits of high dose MPX in capsule formulation in a randomized, 
controlled study of men who have failed primary therapy, either radiation, surgery or 
cryotherapy, as primary treatment for prostate cancer.  Eligible subjects will have a rising PSA 
and will have 3 PSA values at least 21 days apart with a recovered testosterone to be able to 
calculate a baseline PSA doubling time.  The primary endpoint of this study will be mean PSA 
slope during the study period. 
 
2.4 Correlative Studies   
 
2.4.1 Anti-oxidant Status 
 
There are strong correlations between SOD2 genotype, baseline exposure to anti-oxidants and 
response to treatment with antioxidants.21  Therefore, we think it is important to measure the 
baseline anti-oxidant status prior to MPX treatment.  The most commonly studied antioxidants in 
prostate cancer include blood levels of selenium, lycopene, and vitamin E isoforms α-
tocopherol.1  Levels of vitamin A, C and zinc have also been shown to be altered in prostate 
cancer patients compared to controls.36, 37  It is unknown at this time what effect MPX will have 


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on these levels so they will be measured at baseline and at 12, 24, 36 and 48 weeks on the trial in 
those with AA genotype who are randomized to MPX or placebo.   
 
2.4.2 Oxidative stress lab correlates 
 
There is evidence that the generation of reactive oxygen species, which result in lipid and protein 
peroxidation, contribute to the progression of prostate cancer.38 A number of clinical trials, 
including the SELECT trial of selenium and vitamin E supplementation, studied whether 
supplementation with anti-oxidants would therefore prevent prostate cancer.39, 40 While these 
trials were negative and did not show a benefit in the overall population, there was a subset of 
patients identified with variations of the SOD2 gene, who did seem to derive clinical benefit 
from anti-oxidant therapy.21, 41  Unfortunately, there is no “gold standard” for in vivo measures of 
oxidation status.  The below studies, will be measured at baseline, 12, 24, 36 and 48 weeks.      
 
F2-Isoprostanes  are prostaglandin like compounds that are produced by the peroxidation of 
arachidonic acid which is catalyzed by free radicals and is independent of cyclooxygenase.42  
Urinary measurement gives an accurate measure of in vivo oxidative stress and is considered to 
be one of the most reliable biomarker of oxidative stress.43  Within men with prostate cancer, 
there have been cross-sectional associations with lower levels of 8-isoprostane with higher 
antioxidant intake.44  The data is mixed on association of isoprostanes and incident prostate 
cancer with some studies showing a positive association with F2-isprostane level and risk of 
incident prostate cancer 45, 46 and others showing no association with urinary F2-isoprostanes and 
incident prostate cancer.47, 48  However, the literature suggests this is the most reliable 
biomarker43 and warrants further study in our prostate cancer patients.     
 
8-OHdG – 8-hydroxy-2’deoxyguanosine is a form of damaged DNA caused by excess free 
radicals and is a marker of DNA oxidation which can be measured in the urine.49 At baseline, 
men with prostate cancer have an intermediate level of 8-OHdG detected in urine which was 
shown to be transiently increased after radiation therapy in a small study of seven men.50   
Urinary levels were shown to be decreased in men who were treated in a trial of antioxidants 
with selenium-enriched yeast.51  Serum levels were shown in one study of 32 men with localized 
prostate cancer to be decreased following dietary intervention with lycopene.52  Prostatic tissue 
levels of 8-OHdG were not significantly decreased in a neo-adjuvant trial of 70 men randomized 
to pomegranate extract or placebo.53  In our population, we hypothesize 8-OHdG will be 
decreased in those being treated with MPX compared to placebo, and will correlate with 
response to treatment.     
 
Malondialdehyde (MDA) – Malondialdehyde is a byproduct of lipid oxidative degradation and 
is the most commonly used correlative study to measure oxidative stress in prostate cancer 
patients.54  There have been mostly consistent results within the published literature with one 
study showing no difference between levels in patients with metastatic castration resistant  
prostate cancer compared to controls55 but most cross sectional studies showed higher levels of 
MDA in those with prostate cancer compared to controls.56-65  One study showed a correlation 
between PSA and levels of MDA but not with vitamin antioxidants.66  Another study also 
showed increased risk of disease progression with higher levels of MDA.67  Due to the frequency 
and consistency of the results, we think it is reasonable to include this in our correlative analysis. 


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However, there are pitfalls to the measurement some variability based on the method used to 
measure MDA and it is highly bound in serum.68  
 
Additional oxidative correlatives that will be stored and analyzed if sufficient funding allows. 
 
Superoxide dismutase activity - Superoxide dismutase is a ubiquitous enzyme that converts 
oxygen free radicals to hydrogen peroxide and oxygen.69  In humans there are 3 forms, SOD1 
found in cytoplasm, SOD2 found in mitochondria and SOD3 found extracellularly.70  SOD1 and 
SOD2 activity, defined as the amount of enzyme needed to exhibit 50% dismutation of the 
superoxide radical, can be generated separately from a serum sample.  Baseline levels of SOD 
activity in the study population (AA genotype) will be compared to men in the screened 
population to determine if genotype influences phenotype of activity levels.  It has been 
previously shown polymorphisms in MnSOD (SOD2) gene are not associated with increased risk 
of prostate cancer.21, 71  However, there are strong correlations between genotype, baseline 
exposure to anti-oxidant status and response to treatment with antioxidants.21  Additionally, 
higher levels of SOD have been found in prostate cancer patients compared to controls.56, 58, 59, 61-
63, 72 
 
2.4.3 Microbiome 
 
Microbiome – An emerging area of interest within oncology is the microbiome and its impact 
on the effectiveness of therapies.73, 74  Even with the prostate and the urine, once considered a 
“sterile” site, there are bacterial organisms that are theorized to contribute to the pathobiology of 
prostate cancer.75, 76  There are also differences described between the gut microbiome in men 
with prostate cancer compared to those without prostate cancer.77  A natural next question is if 
the microbiome can be altered in a way to diminish disease progression.  There has been some 
early evidence that intake of another antioxidant, pomegranate, alters the stool microbiome78, 79 
and stimulates the growth of Akkermansia muciniphila,80, 81 a potentially beneficial bacterium 
that has been associated with increased responsiveness to immunotherapy.74  In our study, we 
will characterize the stool microbiome via rectal swab at baseline and 12, 24, 48, 36 and 48 
weeks in the randomized patient population to determine whether MPX influences the 
composition of the gut microbiome.  
 
 
3. Eligibility Criteria 
3.1  Inclusion Criteria 
Patients meeting the following conditions are eligible for registration and participation in the 
study: 
 
1. Subject has histologically or cytologically confirmed adenocarcinoma of the prostate 
 
2. Subject has undergone definitive treatment (surgery, surgery with radiation therapy, 
cryotherapy, radiation therapy or brachytherapy) for the primary prostate tumor (prior 
chemotherapy is not allowed).  


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a. A subject with a rising PSA post-prostatectomy should consider radiation as a 
potentially curative alternative. If subject declines radiation or is not a candidate 
for radiation, he may be considered eligible in this setting.  
 
3. Subject has a rising PSA on a minimum of 3 time points (2 rises) within the 12 months prior 
to study initiation (this will include the PSA measurement taken at the screening visit, but not 
at the baseline day 0 study visit).  The three time points must be at least 21 days apart. Note: 
Fluctuations in PSA are allowed per Bubley et al 1999 working group criteria. 82  
4. For purposes of calculating PSADT: 
a) All PSA values used in the calculation should be ≥ 0.10 ng/ml and overall should 
follow a rising trend; 
b) Record every available PSA drawn within the last 12 months; 
c) The minimum requirement is 3 PSA values; 
d) For radiotherapy only patients, record PSA nadir value and collection date. 
 PSADT must be positive according to Memorial Sloan Kettering Cancer Center Prostate 
Cancer Nomograms under this link: 
http://www.mskcc.org/applications/nomograms/prostate/PsaDoublingTime.aspx    
 
5. At least 2 PSA rises need to be after a normal Testosterone for those patients who had prior 
hormone therapy. 
 
6. One of the following criteria must be met. 
a. Absolute level of PSA >0.2ng/mL following surgery. (surgery only) 
b. Absolute level of PSA >0.2ng/mL for subjects treated with multiple treatment 
modalities (e.g., surgery + radiation, surgery + cryotherapy, etc.).  
c. A rise by 2 ng/mL or more above the nadir PSA will be considered the standard 
definition for biochemical failure after radiation therapy with or without hormonal 
therapy. (radiation only) 
 
7. Subject is >18 years of age. 
 
8. Subject has life expectancy of greater than 12 months. 
  
9. Subject has ECOG performance status 0, 1 or 2  
 
10. Subject has testosterone level of ≥150 ng/dL at screening. 
 
11. Subject has normal organ and marrow function as defined below: 
a. Leukocytes 
 
 
>3,000/mcL 
b. absolute neutrophil count  
>1,500/mcL 
c. platelets  
 
 
>100,000/mcL 
d. total bilirubin   
 
<1.5 x upper limit of normal except for Gilberts  
                                                      <2.5 x upper limit of normal 
e. AST(SGOT)/ALT(SGPT)  
≤ 2.5 X upper limit of normal 
f. creatinine  
 
 
≤ 2.5 upper limit of normal 
 


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12. Subject agrees to abstain from other commercially available MuscadinePlus (MP) products 
(Vinetra, MPlus or MP capsules) while participating in this study.  
 
13. Subject’s use of other dietary/herbal supplements (e.g. saw palmetto, selenium, pomegranate 
juice or pills, acai concentrated extract, etc) has been stable for at least 2 months prior to 
screening and the subject agrees not to stop or change the dose(s) while participating in the 
study. 
 
14. Subject has signed a written informed consent document and agrees to comply with 
requirements of the study. 
 
15. CT or MRI chest/abdomen/pelvis and bone scan without evidence of metastatic disease as an 
inclusion (Chest X ray may be used instead of Chest CT scan).   
 
16. Subject agrees to genotyping of MnSOD2 gene.  Only those with AA genotype will be 
randomized.    
 
3.2  Exclusion Criteria 
 
Subjects meeting the following conditions are not eligible for participation in the study:  
  
1. Subject has known radiographic evidence of metastatic disease, except for presence of 
positive lymph nodes from the surgical pathology.  Pelvic/intraperitoneal lymph nodes less 
than 1.5 cm maybe considered nonspecific and the patient would be eligible (including those 
patients who were treated with radiation for oligometastatic disease).  If there is any clinical 
suspicion for metastatic disease, CT and Bone Scan must be performed to rule out metastatic 
disease, within the last three months, per standard of care. 
 
2. Subject has received any therapies that modulate testosterone levels (e.g., androgen 
ablative/anti-androgen therapy, 5 alpha reductase inhibitors) for a minimum of 12 months 
prior to study.  
 
3. Subject has had prior or concomitant treatment with experimental drugs, high dose steroids, 
or any other cancer treatment within 4 weeks prior to the first dose of the study product. 
 
4. Subject has consumed any Muscadine Plus over the past 2 months. 
 
5. Subject has a known allergy to muscadine grapes, ellagic acid or rice. 
 
6. Subject has uncontrolled concurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
or psychiatric illness/social situations that would limit compliance with study requirements. 
 
7. Subject has negative PSA doubling time (negative doubling time corresponds with 
decreasing PSA) Doubling time may be computed using the Sloan Kettering prediction tools 
posted at http://www.mskcc.org/applications/nomograms/prostate/PsaDoublingTime.aspx 


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3.3  Inclusion of Minorities 
Men of all races and ethnic groups are eligible for this trial.  
 
 
4. SUBJECT REGISTRATION AND DATA REPORTING 
4.1  Subject Registration 
After pre-screening, eligible patients with qualified AA genotype of SOD2 gene will be 
registered on study centrally at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) by 
the Coordinating Center Study Manager. 
  
To register a patient, the following documents must be completed and emailed to SKCCC Study 
Manager: 
 Signed patient consent form 
 Research authorization/HIPAA form 
 MAP Trial Registration Request Form 
 Copies of the following records required for assessment of eligibility: 
o Prostate cancer pathology report  
o Baseline laboratory studies including CBC with differential, liver and kidney 
function tests, testosterone, and PSA values  
o Other materials considered pertinent for confirming patient eligibility 
 
Upon receipt of complete packet, the Study Manager will confirm eligibility within 48 hours.  
Issues that would cause treatment delays should be discussed with the Protocol Chair and 
SKCCC Study Manager.   
  
Each participating institution will receive MPX/placebo investigational products (IP) through a 
designated distribution facility contracted by the study after confirmed site activation.  Shipping 
and order details are included in the study operations manual.   
 
Randomization 
Once eligibility is confirmed, patients will be randomized to a treatment group according to the 
randomization schedule.  Patients will be randomized to receive either placebo or MPX in a 1:1 
ratio.  
 
The investigators, study site personnel except designated pharmacy staff, and the subject will 
remain blinded to each subject’s treatment throughout the course of the study.   
 
Stratification 
Stratification will be by pretreatment PSADT (≤9 or >9 months) and Grade Groups (Grade 
Groups 1 and 2, equivalent to Gleason ≤ 3 +4, and Grade Groups 3, 4 and 5, equivalent to 
Gleason ≥ 4 +3).   


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4.2  Data Reporting and Regulatory Requirements 
 
All information will be collected on study-specific CRFs by study staff.  These data will be 
reviewed for completeness and accuracy by the Principal Investigator at each site and remote-
monitored by SKCCC Study Manager or Monitors. 
 
The Protocol Chair 
The Protocol Chair, Channing Paller, MD, 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 
 Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 
 Reviewing data from all sites 
 
Lead Center 
The Lead Center (SKCCC) is responsible for performing the following tasks: 
 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 AE’s and SAE’s 
to the Protocol Chair and all other applicable parties. 
 Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
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 to the Lead Center (SKCCC) 
 Registering all patients with the Lead Center (SKCCC) by submitting registration form, 
signed informed consent, and eligibility documentation 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 Center (SKCCC) 
 Collecting and submitting data according to the schedule specified by the protocol 
 
4.3  Data Management 
 
Electronic CRFs will be used to capture study results and data.  Staff at the SKCCC 
Coordinating Center will be responsible for the initial study configuration and setup of the 
database and for any future changes.  The site study coordinator or other authorized study 


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personnel will transcribe data from source documents onto the eCRFs.  Site Investigators will be 
responsible for ensuring that data entry into the eCRFs are kept up-to-date.  Before or between 
visits, the Protocol Chair, IND Sponsor, or designee may request copies of the source documents 
for preliminary medical review and quality assurance.  Once the eCRFs are complete and source-
verified, the investigator may sign and verify the accuracy of all data contained within the EDC.  
4.3.1 Case report forms completion 
eCRFs will be completed within 2 weeks of the patient coming to the clinic and all 
relevant supporting documentation such as scans, progress notes, nursing notes, blood 
work, pathology reports, etc., will be submitted via email to the SKCCC Coordinating 
Center Study Manager.  All patient names and other identifying information will be 
removed prior to being sent to the Coordinating Center or non-redacted source documents 
can be sent via a password-protected/ secured document transfer based on each 
institution’s guidelines.  
4.3.2 Source documents 
Source documentation will be maintained by site study staff to support the patient 
research record.  SKCCC Study Manager and/or Monitors will remotely review entries 
on the CRFs at regular intervals, comparing the content with source documents. 
4.3.3 Record retention 
The investigator will maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified.  After study 
closure, the investigator will maintain all source documents, study-related documents, 
and the CRFs.  Because the length of time required for retaining records depends upon a 
number of regulatory and legal factors, documents should be stored until the investigator 
is notified that the documents may be destroyed.  In this study, records are to be retained 
and securely stored for a minimum of 7 years after the completion of all study activities. 
4.4  Study Monitoring and Quality Assurance 
All clinical work conducted under this protocol is subject to Good Clinical Practice (GCP) 
guidelines. This includes inspection of study-related records by the lead site, investigator-
sponsor, its designee, or health authority representatives at any time. 
Remote data monitoring will occur on a regular basis with the frequency dependent on the rate of 
subject accrual and the progress of the study.  The protocol will be monitored internally at 
SKCCC by the SKCCC Clinical Research Office Quality Assurance Core (CROQA), and 
externally at participating institutions by the SKCCC Study Manager. 
Regularly scheduled reports will be generated from the eCRFs to monitor patient accruals and 
the completeness of research data.  Routine data quality reports will be generated to assess 
missing data and inconsistencies.  Accrual rates and the extent and accuracy of evaluations and 
follow-up will be monitored periodically throughout the study period, and potential problems 
will be brought to the attention of the principal investigator for discussion and action. 


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4.4.1 
Data and Safety Monitoring 
This is a JHU-investigator-sponsored IND trial.  Data and safety monitoring will follow 
DSMP Level 2 per the SKCCC Data Safety Monitoring Plan.  The PI shall internally 
monitor the progress of the trial, including review and confirmation of all safety/treatment-
related outcomes, response assessments, safety reports and/or any related source 
documentation.  PI shall also establish additional external data/safety monitoring oversight 
(DSMB, etc), if required by IND-sponsor and detailed within protocol. IND-sponsor is 
ultimately responsible for external monitoring of JHU site, and also all subsites if JHU is 
coordinating center.  Authorized representatives of the Coordinating Center may visit the 
satellite sites to perform audits or inspections, including source data verification.  The 
purpose of these audits or inspections is to systematically and independently examine all 
trial-related activities and documents to determine whether these activities were conducted 
and data were recorded, analyzed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), and any applicable regulatory requirements. 
 
The Data Safety Monitoring Board (DSMB) for this clinical study will contain a minimum 
of five members, including at least one oncologist, a statistician, and a lay representative.  
Members may not have a conflict of interest with any aspect of the clinical trial.  The 
DSMB will provide a written recommendation to the IND Sponsor and Protocol Chair after 
each meeting.  In turn, the study team will forward these summaries to the JHU IRB, and 
JHU SKCCC SMC.  The operating plan of the DSMB will be as follows:  
 Meetings will be held at least semi-annually, and potentially more frequently if 
needed.  
 Meetings will be conducted in-person or via video/teleconference, with a participant 
sign-in sheet collected at each meeting.  The Protocol Chair and study staff may 
attend the open portion of this meeting to review data and answer any question the 
DSMB might have). 
 Approximately one week prior to each DSMB meeting, the study team will submit 
the following items to DSMB members for review and discussion at the meeting:  
o A summary of the clinical trial’s progress to date;  
o The latest IRB-approved protocol and informed consent;  
o A summary of all adverse events, serious adverse events, deaths, and 
withdrawals to date; 
 
Note that the DSMB may recommend halting trial accrual or all study activity if, after 
review, serious safety concerns warrant this action.  If the DSMB recommends halting study 
accrual or all study activity, then the study team must notify the JHU SKCCC SMC, JHU 
IRB, and the FDA immediately.   
 
 
5. TREATMENT PLAN 
                                                                                                                                
This is a randomized, double-blind, placebo controlled multicenter study to compare the change 
in slope and PSADT from baseline between placebo and MDX treatment groups.  Approximately 
500 subjects will be registered and genotyped to find 80 men with AA genotype for enrollment.  


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Those with AA genotype will be enrolled and randomized 1:1 (40 to placebo and 40 to MPX). 
Treatment on study will last 48 weeks and will be administered on an outpatient basis.     
 
Appropriate dose delays and discontinuation recommendations for MPX are described in Section 
6.  Adverse event reporting requirements and potential risks are described in Section 7.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy. 
5.1  MPX Administration 
Each treatment cycle is 12 weeks (84 days).  Patients will take 8 MPX pills or 8 placebo pills 
daily, for once daily oral dosing of 4000 mg MPX.  Patients may continue to receive additional 
cycles of study drug and will be followed every 12 weeks with standard visits with their 
physician until completion of 48 weeks of study treatment, disease progression, or until they 
wish to discontinue the drug. 
 
Patients will self-administer the assigned number of capsules on a daily schedule.  Patients will 
return capsule containers and any unused study drug to the study coordinator or research nurse at 
each scheduled follow-up visits.  Returns will be documented on the drug accountability log by 
the pharmacist or pharmacist designee. 
 
Compliance with study product consumption will be evaluated by subject interview and by 
patient pill diaries (Appendix B) that will be collected at each visit.  Compliance will be recorded 
as a percent of scheduled intakes of study product consumed.  Non-compliance will be defined as 
consumption of <80% of the scheduled intakes of study product. 
 
Patients will be asked to refrain from adding other vitamin or herbal supplements during the 
study period and follow-up.  If a patient does not comply, he will first be counseled that he may 
be withdrawn from the study.  If he persists in taking vitamins or herbal supplements, he will be 
withdrawn from the study. 
 
Participants will be encouraged to administer the MPX capsules as follows: 
1) MPX Capsules must be swallowed whole 
2) MPX Capsules should be taken with water 
3) MPX capsules should be taken at least 60 minutes prior to eating or 2 hours after eating 
4) Ingestion of capsules may be spread out over 2 hours if necessary 
5) Vomited doses will not be made up. If the vomiting occurs after 3 sequential doses and is 
thought to be related to study drug, the patient should refrain from taking additional MPX 
capsules and report this to study team.  
6) If a dose is missed (forgotten at the usually administered time), it may be made up any 
time later that same day. 
 
 
5.2  Blinding  
 


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The double-blind portion of the study will end when every subject has either completed the 
study, been treated for 48 weeks, or discontinued the study.  A subject is considered to have 
completed the study if he experiences PSA progression as defined in section 5.4.  A subject will 
also be considered to have completed the study if they have not experienced PSA progression but 
remain on-study at the time the study ends at 48 weeks.  Patients will not be informed if they are 
on the MPX or placebo arm.  At protocol defined progression or completion of 48 weeks of 
treatment, patients will be offered an additional four 12-week cycles of MPX treatment, and will 
come for a visit every 12 weeks, without correlates but with PSA drawn every 12 weeks.  
Patients who come off study for any other reason will not be offered open label, extension MPX.  
Subjects will have an end of study visit and are required to have CT and bone scans prior to 
beginning the open label extension, and at discharge.   
 
Blind Breaking Procedures 
 
In the event of a medical emergency in which the investigator believes that knowledge of study 
drug treatment is required, the investigator should contact the Protocol Chair, Dr. Channing 
Paller (cpaller1@jhmi.edu), and the SKCCC Study Manager, Harry Cao (hcao7@jhmu.edu).  
Decision to break the blind will be made by the study medical monitor, Dr. Samuel Denmeade.  
For emergencies or complications: please call Dr. Paller’s cell phone at 410-627-9512. 
 
Every effort must be made to contact the Protocol Chair prior to breaking the blind.  The date 
and reason that the blind was broken must be conveyed to the lead site and recorded on the 
appropriate CRF if the blind is broken for a participant.  In the event the team should break the 
blind, the reason will be documented in a note for the study file and on the appropriate CRF. 
 
When the predetermined timing of the primary analysis has been reached, the double-blind 
treatment period of this study will end and the study blind will be broken. 
 
Patients will not be informed to which arm they were assigned.  Patients who complete all 
protocol requirements will be offered 48 additional weeks of MPX treatment and monitoring 
every 12 weeks. 
 
5.3  General Concomitant Medication and Supportive Care Guidelines 
 
Patients may not be taking any other medications for the goal of treating their prostate 
cancer.  If they are taking medications for other purposes, they may continue per the 
guidance of the doctor. 
 
Patients who have an on-going study drug-related serious adverse event upon study 
completion or at discontinuation from the study will be contacted by the investigator or 
his/her designee periodically until the event is resolved or determined to be irreversible. 
 
5.4  Definition of Treatment Response and Disease Progression 
 


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Objective Response (OR): Defined as a decrease of 50% or more in the PSA compared with the 
baseline level, confirmed by a second PSA at least 3-4 weeks later. 
 
Progressive Disease (PD): Defined as:    
 Radiographic Progression  
Radiographic progression for soft tissue lesions will be determined using RECIST 1.1. 
Radiographic progression for bone lesions will be determined by radionuclide bone scan 
using the consensus guidelines of the PCWG2 criteria, Or  
 Unequivocal clinical progression: physical symptoms felt to be cancer related (in the 
opinion of the investigator), Or 
 PSA Progression: Clinically significant increase in PSA as defined below. 
o For subjects whose PSA declined from baseline (week 1 day 0):  record time from 
start of therapy to first PSA increase that is ≥ 50% and ≥ 5 ng/mL above the nadir, 
and which is confirmed by a second value ≥ 3 weeks later. 
o For subjects whose PSA has not declined from baseline: PSA progression has 
occurred if both: 
There has been a > 50% increase over baseline (week 1 day 0), AND 
The value of PSA is > 5 ng/mL above the baseline (week 1 day 0) value after 12 
weeks 
 
If subject’s PSA progresses ≥ 50% and ≥ 5 ng/mL above the baseline (week 1 day 0) on Week 
12, repeat the PSA at Week 14-16 to confirm rise. Subjects should continue taking study drug 
during this period, until the rise is confirmed. Once confirmed, subjects should either schedule 
Discontinuation Visit or start Open Label Extension treatment. 
 
Stable Disease (SD):  Disease Assessment that does not qualify as either objective response or 
progressive disease. 
 
5.5  Duration of Therapy  
 
Patients may continue on blinded therapy for up to 48 weeks.  
 
Patients may be removed from the study if any of the following occurs. 
 Completion of 48 weeks of study therapy 
 Disease progression (see Section 5.4) 
 A new illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient’s condition that renders the patient 
unacceptable for further treatment in the judgment of the investigator 
 Noncompliance: Subjects who do not meet 80% dosing compliance will be counseled, if 
they are deemed non-compliant at their next visit they will be withdrawn from the study 
 
Patients who complete all protocol requirements will be offered an additional 48 weeks of MPX 
treatment and monitoring every 12 weeks as the Open Label Extension. 


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5.6  Duration of Follow-Up 
 
A single safety follow-up visit will be scheduled 4 weeks following last dose of study drug. 
 
 
6. DOSING DELAYS 
Criteria for Treatment Delays and Discontinuation Due to Toxicity 
Grade or Description of Toxicity 
Action 
Grade 1 treatment-related toxicity  
No dose modification 
Grade 2 treatment-related toxicity unresponsive to 
therapy 
Per investigator discretion, continue treatment with 
careful monitoring or withhold treatment until toxicity 
returns to ≤ grade 1.   
Grade 3 treatment-related toxicity unresponsive to 
therapy 
Withhold treatment until toxicity returns to ≤ grade 2 
Repeated grade 3 treatment-related toxicity within 3 
months, or multiple grade 3 treatment-related 
toxicities 
Discontinue Treatment 
Grade 4 treatment-related toxicity 
Discontinue Treatment 
Treatment delays > 2 weeks due to treatment-related 
toxicity 
Discontinue Treatment 
 
As this is a blinded study, there will be no dose reductions.  All treatment discontinuations due to 
toxicity will be documented in the patient’s medical record and case report form. 
 
 
7. ADVERSE EVENTS: List and Reporting Requirements 
 
This study will use the descriptions and grading scales found in the revised CTCAE version 5.0 
for AE reporting that can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed as appropriate.  
 
7.1       Definitions 
7.1.1  Adverse Event 
 
An AE is defined as any undesirable sign, symptom or medical condition occurring after 
starting the study drug (or therapy) even if the event is not considered to be related to the 
study.  An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 


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(e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram).  Medical conditions/diseases present before 
starting the study treatment are only considered AEs if they worsen after starting the study 
treatment (any procedures specified in the protocol).  New medical conditions / diseases 
occurring before starting the study treatment but after signing the informed consent form 
will not be recorded as AEs.  Additionally, expected progression of the disease being 
studied will not be recorded as an adverse event.  
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be 
recorded as pre-treatment signs and symptoms.  After study treatment administration, all 
grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
will be reported as AEs.  A grade 1 or 2 clinical laboratory abnormality should be reported 
as an AE only if it is considered clinically significant by the investigator (induce clinical 
signs or symptoms or require therapy). 
  
7.1.2  Serious Adverse Events 
  
A Serious Adverse Event (SAE) is an AE that meets one of the following criteria: 
 Results in death 
 Is immediately life threatening 
 Results in persistent or significant disability or incapacity 
 Requires inpatient hospitalization or prolongation of existing hospitalization for 
>24 hours 
 Is suspected of leading to a congenital anomaly or birth defect 
 Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above 
 
Events not considered to be SAEs are hospitalizations for:  
 Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  
 Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study.  Appropriate documentation is required 
in these cases.  
 Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative). 
7.2  Assessment of Adverse Events 
7.2.1  Severity / Grade 
The investigator will make an assessment of grade for each AE and SAE reported during 
the study, which will be recorded in the appropriate CRF.  The assessment will be based on 
the National Cancer Institute’s CTCAE (Version 5.0) which can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
When an AE becomes more severe, the worsening is considered a new AE, and must be 


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documented and recorded according to section 7.2, Documentation and Reporting, below. 
  
7.2.2  Relatedness / Causality 
  
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
 No (unrelated, not related, no relation): The time course between the administration 
of study drug and the occurrence or worsening of the adverse event rules out a 
causal relationship and another cause (concomitant drugs, therapies, complications, 
etc.) is suspected.  
 Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal 
relationship and no other cause (concomitant drugs, therapies, complications, etc.) 
can be identified.  
 
The following factors should also be considered:  
 The temporal sequence from study drug administration - The event should occur 
after the study drug is given.  The length of time from study drug exposure to event 
should be evaluated in the clinical context of the event.  
 Underlying, concomitant, intercurrent diseases - Each report should be evaluated in 
the context of the natural history and course of the disease being treated and any 
other disease the subject may have.  
 Concomitant medication - The other medications the subject is taking or the 
treatment the subject receives should be examined to determine whether any of 
them might be recognized to cause the event in question.  
 Known response pattern for this class of study drug - Clinical and/or preclinical 
data may indicate whether a particular response is likely to be a class effect.  
 Exposure to physical and/or mental stresses - The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.  
 The pharmacology and pharmacokinetics of the study drug - The known 
pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered.  
 
7.2.3 
Expectedness 
Unexpected AE: An AE, which varies in nature, intensity or frequency from information on 
the investigational drug/agent provided in the product IB, package insert or safety reports.  
Any AE that is not included in the IB, package insert, safety reports or informed consent is 
considered “unexpected”.  
 
Expected (known) AE: An AE, which has been reported in the IB, package insert or safety 
reports. An AE is considered “expected,” only if it is included in the IB document as a risk.  
Potential risks associated with the study product are nausea, vomiting, and allergic 
reactions. 


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7.3  Documentation and Reporting 
7.3.1 Prompting Subjects 
 
An AE may be detected by a physical examination or may be reported by a subject without 
having been prompted.  The investigator will also periodically prompt subjects with the 
following non-leading question: “How have you felt since your last visit?”  To avoid bias, 
it is important that the prompt be non-leading. 
  
7.3.2 All Adverse Events 
 
AEs will be defined with the NCI-CTCAE v5.0.  All AEs, both related and unrelated, will 
be recorded on the appropriate study-specific CRFs, including the following information: 
 Specific type of reaction in standard medical terminology 
 Severity  
 Relatedness 
 Duration, including onset, of the event 
 Description of treatment action or change in study drug administration or dose 
 Resolution 
  
Adverse events should be recorded from the start of treatment with MPX through one week 
following the last dose of study drug.  Details of changes in AEs should be recorded even if 
they occur after the protocol prescribed follow-up.  Investigators should follow-up subjects 
having serious or related AEs until the resolution of the event. Details of the resolution will 
be recorded in the CRF. 
  
7.3.3 Serious Adverse Events 
  
All SAEs (including deaths) occurring from the first dose of the study drug through 1 week 
after the last dose of study drug will be collected and reported.  
 
Subjects who have an ongoing SAE related to the study procedures and/or medication(s) 
may continue to be periodically contacted by a member of the study staff until the event is 
resolved or determined to be irreversible by the investigator. 
 
SAEs will be reported promptly to the IND Sponsor and SKCCC Study Manager 
within 24 hours of initial discovery of the SAE. If this falls on a weekend or holiday, an 
email notification is acceptable but must be followed by an SAE reporting form on the next 
business day. 
 
SAE reports and any other relevant safety information are to be sent to:  
Channing Paller, MD (IND Sponsor/Protocol Chair) 
Email: cpaller1@jhmi.edu  
Harry Cao (SKCCC Study Manager) 
Email: hcao7@jhmi.edu 
Fax: 410-614-7287 


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After the initial AE or SAE report, the investigator is required to proactively follow each 
subject and provide further information to the safety department in regards to the subject’s 
condition. 
 
All AE(s) and SAE(s) will be followed until: 
• 
Resolution 
• 
The condition stabilizes 
• 
The event is otherwise explained 
• 
The subject is lost to follow-up 
• 
Death 
 
As soon as relevant information is available, a follow-up SAE report will be submitted to 
the IND Sponsor and SKCCC Study Manager. 
 
7.3.4  
Institutional Review Board Reporting 
 
Investigators at each participating site will be responsible for reporting SAEs to their local 
IRB in a timely manner per institutional standards.  Follow-up information will also be 
provided to the local IRB per institutional standards as soon as relevant information 
becomes available. 
 
7.3.5  Food and Drug Administration (FDA) 
 
All reporting to the FDA will be completed by the IND Sponsor. 
 
7.3.5.1 Expedited IND Safety Reports 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
investigational agent.  Such reports are to be telephoned or faxed (301-827-9796) to 
the FDA within 7 calendar days of first learning of the event. Follow-up information 
will be submitted to the FDA as soon as relevant information is available.  
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any SAE that is unexpected and 
related to the investigational agent in a written IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed with 
the IND concerning similar events should be analyzed.  The new report should contain 
comments on the significance of the new event in light of the previous, similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA within 15 calendar days of first learning of the event.  Follow-up information 
will be submitted to the FDA as soon as relevant information is available. 


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7.3.5.2 IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the 
adverse events and progress of the investigation.  Please refer to Code of Federal 
Regulations, 21 CFR § 312.33 for a list of the elements required for the annual report.  
All IND annual reports will be submitted to the FDA by the IND Sponsor. 
 
8. PHARMACEUTICAL INFORMATION  
 
8.1 Muscadine Plus  
 
Chemical Names:   
Ellagic acid (2,3,7,8-Tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione), gallic acid 
(3,4,5-trihydroxybenzoic acid), trans resveratrol (trans-3,5,4'-Trihydroxystilbene), 
epicatechin ((2R,3S)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol), and 
other polyphenols including quercetin (2-(3,4- dihydroxyphenyl)- 3,5,7- trihydroxy- 4H- 
chromen- 4-one), myricetin (3,5,7-Trihydroxy-2-(3,4,5-trihydroxyphenyl)- 4-chromenone), 
and kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) 
 
Other Names:  MPX 
 
Classification:  Antineoplastic 
 
CAS Registry Number:N/A 
 
Molecular Formula (Ellagic Acid): C14H6O8  
  
M.W.: 302.197g/mol 
 
Description:  Investigation ongoing.  Probable mechanisms listed under modes of action.  
 
Mode of Action: The principal compounds in MPX have been found to use the following 
mechanisms: 
 
Ellagic acid inhibits DNA Methyltransferase.  DNA Methyltransferases (DNMTs) are a 
family of enzymes that regulate chromatin methylation and use S-adenosyl methionine (SAM) 
as the methyl donor.  Ellagic acid’s metabolite, urolithin-A inhibits the protein complex NF-
B, potentially leading to increased rates of apoptosis and decreases in cancer cell 
proliferation.  Extracts from Vitis rotundifolia have shown inhibition of the 
phosphatidylinsoitol 3-kinase-Akt pathway.  
 
How Supplied:  
Patients will take 8 MPX pills or 8 placebo pills daily.  MPX/Placebo (the form of 
Muscadine Plus to be used in this study) is supplied by Muscadine Naturals Inc. as a white, 


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opaque gelatin capsule, size 0, containing 500mg of brown fine powdered muscadine grape 
skins or matching placebo of rice powder.  
 
All study personnel will be blinded except designated pharmacy staff.  Investigational 
products will be packaged as follows: 
 
MPX/Placebo 500 mg capsules #180 per bottle 
 
Drug Ordering: Each participating institution will receive MPX/placebo investigational 
products through a designated distribution facility contracted by the study after confirmed 
site activation.  Shipping and order details are included in the study operations manual.   
 
Storage: Store MPX capsules at room temperature, 15 to 30 ºC (59 to 86 ºF).  Do not store 
above 30ºC. Avoid exposure to excessive moisture.  
 
Stability: Shelf life stability studies of the intact bottles are ongoing.  
 
Route of Administration: Orally  
Administration: MPX capsules must be administered whole.  It should be taken with 
water, 1 hr prior or 2 hrs after eating.  Patients may consume all capsules over a 2 hour 
period if needed.  If vomiting occurs during dosing then hold the remainder of the capsules 
and resume with the next scheduled dose.  If vomiting occurs after taking 3 sequential 
doses thought to be related to the study drug, then patient should stop from taking any 
additional capsules. 
 
Dispensing: Patient should take 8 capsules from the 180 count bottle once a day (total of 8 
capsules/day).  Four (4) bottles will be dispensed at each study visit, constitutes of 90-day 
supply. 
 
Potential Drug Interactions: No drug interactions have been documented.  
 
Special Handling: N/A  
 
Patient Care Implications:  N/A 
 
Drug Destruction: Patient returns may be destroyed per hospital policy, following 
documentation of returns per your IDS policy.  
8.2  Investigational Products Accountability and Destruction (MPX and Placebo) 
All investigational products (IPs) required for completion of this study will be 
manufactured and supplied by Muscadine Naturals Inc. and distributed to site pharmacy by 
a contracted distribution facility.   
 
The receiving site pharmacy will acknowledge receipt of IPs by reporting the appropriate 
documentation indicating shipment content and condition.  Damaged supplies will be 


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replaced.  Accurate records of all IPs received at, dispensed from, returned to and disposed 
of by the study site should be recorded by using the Investigational Drug Accountability 
Record Form.  Inspections of the study drug supply for inventory purposes and assurance 
of proper storage will be conducted as necessary.  Any significant discrepancy will be 
recorded and reported to SKCCC Study Manager and a plan for resolution will be 
documented. 
 
Investigational products will not be loaned or dispensed by the Investigator to another 
Investigator or site. 
 
Temperature records for MPX/placebo must be made available to the SKCCC Study 
Manager or other Sponsor nominated monitoring teams for verification of proper study 
drug storage. 
 
At the conclusion of the study, only completely unused IP bottles (MPX/placebo) should be 
retained by the site until notified by SKCCC Coordinating Center staff for return or on-site 
destruction.  Partially used and completely used bottles should be destroyed according to 
the site’s guidelines, and their disposition should be recorded on the Investigational Drug 
Accountability Record Form. 
 
9. CORRELATIVE/SPECIAL STUDIES  
 
Complete instructions for the collection processing, and shipment of correlative samples will be 
provided in a separate laboratory manual.  All specimens should be correctly labeled with patient 
initials, study-specific subject ID number, protocol number, and date of collection. 
9.1  Blood  
Blood will be collected at Pre-Screening Visit for SOD2 genotyping (see Study Calendar).  
Complete instructions for the collection processing, and shipment of samples will be provided in 
a separate laboratory manual. 
9.2    Serum 
Blood for measuring serum levels of antioxidants (selenium, lycopene, alpha-tocopheral) and 
oxidation marker MDA will be collected from the 80 randomized patients at Day 0 (prior to first 
dosing), 12-, 24-, 36-, 48-Week, and Primary Discontinuation (progression) Visits, see Study 
Calendar.  Baseline sample on Day 0 Visit should be collected before patient receiving study 
drug.  All other visits, blood samples should be drawn at least one hour post dose in the morning 
(preferably before noon).   
 
9.3  Urine 
 
Urine for measuring F2-Isoprostanes, 8-OHdG (markers of oxidative stress) and routine urine 
creatinine will be collected at Day 0, 12-, 24-, 36-, 48-Weeks, and Primary Discontinuation 
(progression) Visits, see Study Calendar.  Baseline sample on Day 0 Visit should be collected 


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before patient receiving study drug.  All other visits, urine sample should be collected at least 
one hour post dose in the morning (preferably before noon). 
 
9.4  Microbiome analysis  
 
Rectal swabs will be collected at Day 0, 12-, 24-, 36-, 48-Weeks, and Primary Discontinuation 
(progression) Visits, see Study Calendar.   
 
 
10. STUDY CALENDAR18 
 Treatment Period 
Pre-
Screen 
for AA 
Screen for 
Elig.1 
On Study Visits -Blinded 
Open Label 
Extension2,7 
28-Day 
Follow 
Up13 
 
Weeks 
 
Day -28 to 
day -1 
W 1 
day 0 
12 W 
+ 7 
days 
24 W 
+ 7 
days 
36 W 
+ 7 
days 
48 W or 
Primary 
DC3 
+ 7 days 
Q 12 
weeks  
+ 7 
days 
OLE 
DC 
Informed Consent 
√ 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria11 
 
√ 
 
 
 
 
 
 
 
 
Medical History6  
 
√ 
 
 
 
 
 
 
 
 
Pathology Review 
 
√ 
 
 
 
 
 
 
 
 
Complete physical 
examination 
 
√ 
 
 
 
 
√ 
 
√ 
 
Interval History and Brief 
physical examination10 
 
√ 
 
√ 
√ 
√ 
 
√ 
 
√ 
Vital Signs  (temperature, 
BP, heart rate) 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Weight  
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Height  
 
√ 
 
 
 
 
 
 
 
 
ECOG Performance status 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
CMP9 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
CBC w/diff. 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Urine Creatinine17 
 
 
√16 
√ 
√ 
√ 
√ 
 
 
 
PSA 
 
√4 
√4 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
CT/Bone Scan1 
 
√ 
 
 
 
 
√ 
 
√14 
 
Testosterone 
 
√ 
 
 
 
 
 
 
 
 
Blood for MnSOD 
genotyping8 
√ 
 
 
 
 
 
 
 
 
 
Serum Collection for 
Correlative Studies5 
 
 
√16 
√ 
√3 
√ 
√ 
 
 
 
Rectal Swab for Correlative 
Studies 
 
 
√16 
√ 
√ 
√ 
√ 
 
 
 
Urine Collection for 
Correlative Studies 
 
 
√16 
√ 
√3 
√ 
√ 
 
 
 
Adverse Event Assessment   
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 


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1 Screening window: Baseline evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  Scans are 
allowed within 90 days. CT of chest, abdomen and pelvis. With contrast preferred; but without contrast allowed. 
2 Open label extension: Patients on study drug who complete protocol requirements may choose to start MPX after completing 
48 weeks on the blinded portion of the study or after discharge with documentation of protocol defined progression (per Section 
5.4).  In order to remain a double-blinded trial, patients and investigators will not know to which arm they were assigned and thus 
it is patient and investigator judgement if they want to try unblinded MPX for up to an additional 48 weeks.  
3 Primary discontinuation reason and sampling: If patient leaves the study for any reason prior to 24 weeks but > 12 weeks on 
trial, please record whether DC reason was patient meeting protocol defined progression (defined in Sec. 5.4 of this protocol) or 
DC reason was investigator judgement. If reason was protocol-defined progression, record whether there was pain, metastases on 
bone or CT scan and/or PSA progression.  Also collect serum and urine for correlative studies, and perform CT and bone scans 
unless scans and patient samples have been collected in the past 8 weeks. 
4 Pre-trial PSA’s: It is important to have 3 pre-trial PSA values (please refer to inclusion criteria #3 and #4) prior to day 0 and to 
collect a day 0 PSA value for on-study calculations. 
5 Serum correlative samples: One tube at original screening of 500 patients; three tubes at baseline, 12 weeks, 24 weeks, 36 
weeks, 48 weeks and progression for patients on MAP trial.  
6 With medical history record prior prostatectomy, prior radiation (brachytherapy, SBRT, etc.) plus start and end dates of any 
prior hormonal therapy including name of drug. Please also state alcohol and smoking intake. 
7 Open label extension: For patients discharged prior to 48 weeks, open label MPX drug will be offered only to patients who 
meet protocol defined progression per Section 5.4, patients with radiographic progression (metastatic disease) are excluded. 
8 MnSOD2 sample: All 500 patients should get genotype (5ml blood). 
9 Comprehensive metabolic panel to include measurement of sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, total bilirubin, calcium, total protein, albumin, AST, ALT, and alkaline phosphatase 
10 Brief physical examination includes cardiovascular, pulmonary, abdominal and Symptom-directed; includes investigating any 
new abnormalities and weight. Interval history includes any hospitalizations, illnesses, changes in medication 
11 Eligibility: All inclusion/exclusion criteria should be assessed at screening and confirmed prior to randomization 
12 Drug compliance: Compliance will be assessed by reviewing both returned # of pills and pill diary 
13 Follow-up Visit: The last visit will be 28 days (± 3 days) following last dose of study drug.  
14 CT/Bone Scan is performed at Discontinuation/End of Treatment visit only if it was not performed within the previous 4 
weeks. 
15 Food Frequency Questionnaire and Dietary Supplement List will be collected at baseline, 12 weeks, 24 weeks. 36 weeks, 
48 weeks and at progression for patients on MAP trial.  Please educate patients to allow 15-20 minutes to complete the survey. 
16 Baseline/Day 0 correlative sampling: Baseline research serum, urine, and rectal swab samples should be collected before 
patient receive study drug on Day 0 Visit. 
17 Urine Creatinine needs to be collected prior to drug administration on Week 1 Day 0.  For  the on study time points including 
12 weeks, 24 weeks, 36 weeks, 48 weeks and progression, Urine creatinine will be collected at least one hour post drug 
administration for patients on the MPX trial. The goal is to collect Urine creatinine at the same time as the urine research 
samples. 
 18 In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in person clinical 
trial visits or portions of clinical trial visits where determined to be appropriate and where determined by the investigator not to 
increase the participants risks. Prior to initiating telemedicine for study visits the study team will explain to the participant, what a 
telemedicine visit entails and confirm that the study participant is in agreement and able to proceed with this method. 
Telemedicine acknowledgement will be obtained in accordance with the Guidance for Use of Telemedicine in Research. In the 
event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be conducted 
using HIPAA compliant method approved by the Health System and within licensing restrictions. 
Concomitant Medication 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Dispense Study Drug and 
Pill Diary 
 
 
√ 
√ 
√ 
√ 
 
√7 
 
 
Collect Returned Study 
Product and Pill Diary12 
 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
 
Food Frequency 
Questionnaire and Dietary 
Supplement List15 
 
 
√ 
√ 
√ 
√ 
√ 
 
 
 


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11. EVALUATION AND STATISTICAL METHODS 
 
Study design:  This is a multicenter, double-blind, randomized study to evaluate the benefit of 
MPX supplementation in the subset of men who display the AA genotype of MnSOD.  Based on 
a previous randomized phase II trial of MPX at Hopkins,1 PSA doubling time (PSA-DT) was 
prolonged in this subgroup of men.  
The primary objective of this trial will be to determine how the rate of change in PSA is affected 
by MPX supplementation and compare this treatment effect to a control arm given a placebo.  
The rate of change in PSA, before and during treatment, for each patient will be quantified using 
the log slope which is calculated from a regression model of the log of PSA values on time.  This 
quantity is the estimate directly used in the standardized method for the calculation of PSA-DT2 
(PSA-DT is calculated as the natural log of 2 divided by the log slope). 
 
Different PSA kinetic measurements have previously performed differently in different settings.3  
In a randomized clinical trial, it is convenient if the distribution of the outcome to be compared 
between groups is suitable for analysis with a parametric test.  The distribution of log slope, or 
the change in log slope, can reasonably be assumed to be approximately normal.  By comparison, 
PSA-DTs are problematic when PSA values are not increasing exponentially, as in the setting 
where treatment may result in a PSA-DT less than zero.  In this case the DT for the patient is 
assigned an arbitrary large value and any calculated changes in DT will necessarily involve this 
imputed value.  As a result, assumptions of normality for the distributions of DTs, and changes 
in DTs, are not be reasonable, and would preclude parametric analyses.  The log slope as a 
continuous quantity is therefore the chosen kinetic for this randomized clinical trial. 
 
We expect the average DTs of patients enrolling on this study to be in the range of 6 to 15 
months, which correspond to average log slopes of 0.1155 ng/mL/month and 0.0462 
ng/mL/month respectively.  The historical post-treatment average slope estimates from the 
previous Hopkins trial were 0.033 ng/mL/month (average PSA-DT of 21 months) on the MPX 
arm and 0.083 ng/mL/month (average PSA-DT of 8.4 months) on the control arm.  We have 
powered this study using the difference in these historical estimates as the clinically relevant 
post-treatment difference to be detected in this study: 0.05 ng/mL/month (or a PSA-DT 
difference of 12.6 months).  It should be noted that for the same log slope difference between 
treatment arms, if the average post-treatment PSA rates of change are greater (steeper slopes), 
the detectable difference in DTs would be smaller and if the rates of change are less (slopes are 
less steep) the detectable DT difference will be larger.   
 
Randomization:  Stratified randomization will be performed to maintain balance between the 
arms as much as possible.  Stratification will be by pretreatment PSADT (≤9 or >9 months) and 
Grade Groups (Grade Groups 1 and 2, equivalent to Gleason ≤ 3 +4, and Grade Groups 3, 4 and 
5, equivalent to Gleason ≥ 4 +3).  Block randomization, with varying block sizes, will be used to 
ensure reasonable balance between the arms.  Randomization assignments will be generated by 
the study statistician prior to initiation of the study using an R (version 3.4), and made available 
to the study team through the study electronic database. 
 


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End of Study: The date the study ends for the purpose of the final analysis is the date at which 
all randomized subjects have either completed the study or prematurely discontinued treatment 
and withdrew.  This date will be designated as the primary analysis date for data cutoff and for 
all statistical analyses of efficacy and safety.  Following the collection and adjudication of all 
data for all randomized subjects (follow-up up to and including the primary analysis date for data 
cutoff, the study blind will be broken (Section 5.2, Blinding). 
 
Primary Objective: Determine if men who display the AA genotype of MnSOD and supplement 
their diet with MPX have greater changes in PSA slope following treatment compared to men that 
do not supplement with MPX. 
 
Sample size and accrual:  This two arm randomized study will determine if there are 
differences in the change in PSA slope (post supplementation minus pre supplementation) 
between patients supplementing with MPX (Arm A) and patients that are not (Arm B).  The 
accrual rate for each site is expected to be 1 patient per month.  With 16 to 17 sites, is expected 
that we could accrue 500 patients over 4 years, for which we will have baseline MnSOD 
genotype and baseline antioxidant status, of which approximately 80 would be of the required 
AA genotype and eligible for randomization to MPX or placebo. Overall the study would take 4 
years of accrual and another year for follow-up.  PSA slope will be defined by the linear 
regression line of the natural log of PSA (in ng/mL) against time (in months).  The primary 
statistical analysis will be an analysis of covariance (ANCOVA) to compare the two arms at the 
final analysis, adjusting for baseline PSA slope.  Implications of the sample size are given based 
on simulations which include a single interim analysis for futility midway through the trial.  The 
predictive probability approach for the futility analysis is described in the interim analysis 
section below.  Based on the previous study of MPX at Hopkins, we conservatively estimate that 
the difference in the post-treatment PSA slope (MPX minus placebo), adjusting for pre-treatment 
PSA, in this group of patients with the AA genotype will be -0.05 with the MPX arm having 
lower post-treatment slopes (MPX slope 0.033 ng/mL/month versus untreated 0.083 
ng/mL/month).  Patients with the AA genotype will be randomized to MPX (Arm A) and 
placebo (Arm B) in a 1:1 ratio.  Using a two sided 5% type I error allowance, a sample size of 78 
(39 per arm), and minimal correlation between the pre and post treatment PSA slopes, this study 
will have 83% power to detect a difference in post-study PSA slope of -0.05.  Use of the 
ANCOVA design with covariate adjustment for pre-treatment PSA slope will tend to increase 
the power depending on the level of the correlation between paired PSA slope measurements 
(i.e., pre- and post-treatment).  As an example, for a correlation (ρ) of 0.30, the power would 
increase to 87%. 
  
Interim analysis for primary objective:  We plan to monitor the primary efficacy objective for 
futility once, after treating half the planned number of patients (i.e., 39), using a predictive 
probability approach.  The ANCOVA analysis for the primary objective is a linear regression 
using the post treatment PSA slope as the outcome and study arm and baseline PSA slope as 
covariates.  The monitoring plan is based on calculations of the likelihood of a significant result 
if the trial were to continue to the end.  At the time the trial is monitored, 100 simulations of the 
future results of the trial will be generated and analyzed.  If the probability that the trial would 
end with a significant result falls below a cut off value, the study will be stopped for futility.   In 
Bayesian linear regression, all the parameters are given a prior distribution.  A common objective 


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prior for linear regression is the g-prior of Zellner.2  This prior uses the covariate information in 
the data to specify the prior variance for the regression coefficients.  An inverse-gamma prior 
distribution is typically used for the residual variance, .2  We will use information obtained at 
the time of the interim analysis to describe the distributions of these parameters. 
 
The interim analysis will occur after 50% of the patients (m=39) have been treated and assessed 
for post-treatment PSA slope.  At this time the ANCOVA model will be fit and the variance of 
the residuals, SSRg, and the posterior distribution of the regression (ANCOVA) coefficients β 
will be calculated using the g prior with g = m.  From this information, we predict the results of 
the trial by simulating the remaining future patients’ data from the predictive distribution and 
performing an ANCOVA analysis on the combined interim data and simulated data.  We will 
base the predicted probability of ultimately finding a significant difference on 100 simulations. 
The following steps will be used to generate the ith simulated value.   
1. Generate () from its inverse-gamma posterior. 
2. Generate β(i) from its (conditional) posterior distribution. 
3. Generate 	 , j=1,…,n-m from N (Xj β(i), σ2(i)) 
4. Perform the final ANCOVA analysis based on the interim data and the predicted data. 
5. Repeat for the required number of simulations predicting the final outcome (100). 
6. Calculate the predicted probability of rejecting the null hypothesis at the end of the 
study. 
 
If interim analysis simulations indicate that the probability of a successful trial would be less 
than 10%, we will consider stopping the trial for futility.  The table below gives the operating 
characteristics of the monitoring plan based on 2000 simulations for different scenarios, each 
scenario corresponding to different treatment effects and different levels of correlation between 
the pre-treatment and post-treatment PSA slope.  The seventh row shows results using the 
hypothesized treatment effect of a mean difference of -0.05 with a standard deviation of 0.075, 
and minimal correlation.  We do expect some correlation between pre and post-treatment values, 
so power will tend to increase with increasing correlation.  The significance level for the final 
analysis is 0.05.  Scenarios 1-3 give operating characteristics under the null (no treatment effect).      
 
Table 1.  Operating characteristics of monitoring rule from 2000 simulated studies with one interim analysis based 
on 100 predicted study conclusions and final analysis based on an ANCOVA model.  Simulations use a g-prior with 
g=39 (i.e. the sample size at the time of the interim analysis).  All simulations assume the standard deviation of post-
treatment PSA slope is 0.075. 
 
Scenario 
Treatment 
Effect 
Correlation 
(pre- and 
post-
treatment 
measures) 
Stop for 
Futility % 
Would have 
stopped for 
Futility and 
would have 
Rejected % 
Overall 
studies 
rejecting Ho 
% 
1 
0.0 
0.1 
34.0% 
0.10% 
4.3% 
2 
0.0 
0.2 
33.5% 
0.35% 
5.6% 
3 
0.0 
0.3 
34.5% 
0.20% 
4.4% 
4 
-0.025 
0.1 
21.9% 
1.00% 
31.8% 
5 
-0.025 
0.2 
20.4% 
0.80% 
30.6% 
6 
-0.025 
0.3 
17.5% 
1.40% 
35.0% 
7 
-0.050 
0.1 
4.5% 
1.25% 
82.7% 
8 
-0.050 
0.2 
4.4% 
0.75% 
81.9% 


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9 
-0.050 
0.3 
3.0% 
0.95% 
87.3% 
10 
-0.075 
0.1 
0.4% 
0.30% 
98.8% 
11 
-0.075 
0.2 
0.4% 
0.20% 
99.1% 
12 
-0.075 
0.3 
0.2% 
0.15% 
99.7% 
  
Safety monitoring and early stopping rules for safety:  The toxicity in each arm of the study 
will be monitored after every patient.  The prior for this study will assume that 1 of 6 patients 
may experience grade 3-4 diarrhea.  The prior probability that the treatment is too toxic may 
therefore be taken to be a Beta distribution with parameters 1.5 and 5.5.  This distribution 
corresponds to assuming a 1 in 4 chance that the risk of toxicity is 30% or higher and 90% 
certainty that the risk is between 3% and 49%.  The stopping rule applies this prior distribution to 
the observed number of patients experiencing toxicity and computes the resulting probability of 
toxicity.  If the posterior certainty that toxicity is 30% or higher, based on Bayes rule and these 
assumptions, is 75% or higher (≥ 3:1 odds in favor of the treatment being too toxic), the study 
should stop.  The following tables show the resulting monitoring rule and operating 
characteristics.  For example, the rule will call for stopping the study if 5 patients out of the first 
8 experience toxicities.  The next table shows the percent of the time that the stopping rule will 
stop the study under different hypothetical risks of toxicity, along with the average sample size 
(based on 5000 simulations).  
Stop if DLTs 
3 
4 
5 
6 
7 
8 
9 
in N patients 
3-4 
5-7 
8-9 
10-12 
13-15 
16-18 
19-22 
 
10 
11 
12 
13 
14 
15 
23-25 
26-28 
29-31 
32-34 
35-37 
38-39 
 
Risk of AE 
0.10 
0.20 
0.25 
0.30 
0.35 
0.40 
0.45 
0.50 
% of Time Study Stops 
0.7% 
7.7% 
19.0% 
39.3% 
60.9% 
79.3% 
92.0% 
97.8% 
Expected Sample Size 
38.7 
36.9 
34.2 
29.6 
24.3 
19.4 
14.6 
11.2 
 
11. 1 Analysis Plans for Primary Objective 
  
PSA Slope: Eligible patients must have a rising PSA with a minimum of 3 time points but up to 
17 time points (2 rises at least 21 days apart) within the 12 months prior to study initiation (this 
could include the PSA measurement taken at the screening visit, but not at the baseline day 0 study 
visit).  The pre-treatment slopes will be calculated based on these data prior to baseline (day 0).  A 
minimum of three time points but up to five time points will be used for calculating on-study 
slopes: baseline, 12, 24, 36, and 48 week assessments.  All data points will be used unless an 
assessment is unavailable, in which case the remaining time points will be used.  There must be a 
minimum of three data points, and there will be no imputation of missing PSA values.  
 
The primary objective will be based on the intent-to-treat (ITT) population and assessed with an 
ANCOVA model, with post-treatment PSA slope as the independent variable and study arm and 
baseline PSA slope as covariates.  A two-sided t test at the 0.05 significance level will be used to 
determine if, adjusting for baseline, the post-treatment PSA slope has been reduced with MPX 
supplementation (Arm A).  Scatterplots of post treatment PSA slope by baseline slope will be used 
to visualize the fitted ANCOVA model.  Boxplots of the observed changes will also be used to 
visualize the results.   


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11.2 Secondary Efficacy Assessment 
 
PSA Doubling Time (PSADT): The PSADT will be calculated as ln(2) (=0.693)/ β (=slope of 
the linear regression fit to ln PSA vs. time in months).  If the patient’s slope is less than or equal 
to zero, we will assign them a PSADT of 100 months, which is consistent with the literature.48 
 
A secondary statistical test of the difference between the two groups will be assessed by a 
nonparametric Wilcoxon Rank Sum test of the percentage change in PSADT (logarithm of the 
ratio of PSADT on-study divided by the pre-treatment PSADT).  We will also analyze the log of 
the PSADT ratio by the analysis of variance (ANOVA) adjusted for the stratification factors. 
Confidence intervals (95%) for the change from baseline in PSADT will also be computed for 
the two dose groups.  The paired t-test (or Wilcoxon signed-rank test) will be used to assess the 
within treatment group differences of PSADT on study compared to the baseline.  Patients with 
negative slopes will be assigned PSADT of 100 months.  
 
PSA Reduction of >50% / Objective Response: An objective response (OR) is defined as a 
decrease in PSA by 50% or more after the start of treatment.  The objective response rate (ORR) 
is estimated as the fraction of men for whom an objective response is observed.  The time to 
objective response, defined as the time from start of treatment to an observed objective response, 
as well as the average duration of response, defined as the time from objective response to 
disease progression, will also be summarized and compared between groups.  To further 
summarize PSA responses, the percentage change in PSA from baseline at 24 and 48 weeks will 
be presented in the form of waterfall plots.   
 
PSA Progression: The distribution of time to PSA progression will be estimated using Kaplan- 
Meier method for both treatment groups combined and separately.  The stratified logrank test 
will be used to test the hypothesis that the time to PSA progression distributions for the 2 
treatment groups are the same.  The same stratification factors used for the randomization will be 
used to stratify the logrank test. 
 
Disease Progression (Metastatic disease): The distribution of time to disease progression will 
be estimated using Kaplan-Meier method for the treatment groups combined and separately.  The 
stratified logrank test will be used to test the hypothesis that the time to disease progression 
distributions for the 2 treatment groups are the same.  The same stratification factors used for the 
randomization will be used to stratify the logrank test. 
 
Toxicity Assessments: Safety analyses will be performed on all subjects that received at least 
one dose of MPX.  The proportion of toxicities by type and grade according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be reported with exact 
binomial 95% confidence intervals for each arm of the study.   
 
11.3 Correlative Studies 
 
Correlative studies seek to improve understanding patient response to MPX, as well as the 
biological mechanism or mechanisms of action.  Correlative studies include: (1) correlating PSA 


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response with antioxidant levels and (2) correlating PSA response with markers of oxidative 
stress.   
 
We will look at baseline (prior to drug administration on Week 1 Day 0), week 12, week 24, 
week 36, week 48 and progression levels of selenium, lycopene, and -tocopherol.  Three 
measures of oxidative stress (F2-Isoprostanes, 8-OHdG, and Malondialdehyde) taken at all three 
time points (baseline, week 12, week 24, week 36, week 48 and progression) will be compared 
by study arm for changes following treatment.  Comparisons will be visualized using boxplots of 
the raw data on a logarithmic scale. Analytic comparisons will be made with multivariable 
regression analysis using generalized estimating equations (GEE) to assess oxidative stress 
outcomes as a function of MPX treatment, time, and other factors such as Gleason score, 
baseline PSA, and age.  A compound symmetric covariance structure will be assumed for these 
regression models.  With sample sizes of 40 per group, a standardized effect size of 40% would 
be detectable with 85%-96% power assuming within-subject correlations of 0.10-0.30 and a two-
sided alpha of 0.10.  Although multiple generalized estimating equation models will be explored, 
one for each measure of oxidative stress, we will not adjust for multiple comparisons. 
 
11.4 Additional Analyses 
 
Baseline Characteristic Analyses: Qualitative baseline characteristics will be summarized with 
the number and percent of subjects in each treatment group with the characteristic.  Quantitative 
characteristics (e.g., age, height, and weight) will be summarized with the median, mean, 
standard deviation, minimum value, and maximum value.  Categorical characteristics will be 
tabulated. 
 
The number and percent of subjects, who are randomized, treated with randomized study drug, 
prematurely discontinued study drug, are lost to follow up, and completed four 12 week cycles of 
follow-up after randomization will be summarized.  
 
The number and percent of subjects with each medical history will be summarized.  Fisher’s 
exact test will be used to assess treatment group differences in the proportions of subjects with 
each medical history.  The number and percent of subjects that receive each medication that is 
not the study drug will be summarized.  
 
There will be no adjustment for multiple statistical comparisons.  We recognize that carrying out 
multiple significant tests increases the risk of false positive results among the collection of all 
analyses.  Therefore, except for the primary outcome, all other analyses are considered as 
secondary, tertiary, or exploratory.  
 
ECOG Performance Status: ECOG Performance Status will be captured as on a 6-point 
categorical scale from 0 (normal activity) to 5 (dead) and summarized using shifts from baseline 
to the 24-week and 48-week evaluations.  Baseline is defined as the last ECOG value prior to or 
on the date of randomization.  The percentage of patients with an increase of at least 1 point from 
baseline will be presented for each treatment group at both the 24-week and 48-week evaluation 
time points.   
 


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Adherence: Participants who completed 4 cycles of study and had at least 80% of intake of the 
planned consumption will be defined as study compliant.  An overall probability of study 
compliance will be estimated with a 95% confidence interval.  The difference in proportion of 
compliance between two groups will be tested using Fisher’s exact test at a two-sided alpha level 
of 0.05.  Summary statistics will also be provided for the time from the first dose to the last dose 
of study drug. 
 
Food Frequency Questionnaire and Dietary Supplement List: The categories of “how often 
you ate the food” on the food questionnaire will be summarized with frequencies and 
percentages for both treatment groups at baseline and at each visit (12, 24, 36, 48 weeks and 
progression).  A nutrient analysis by the Nutrition Assessment Shared Resource at the Fred 
Hutchinson Cancer Research Center will provide estimates of daily intake of key antioxidants 
over the course of the study and will be summarized descriptively by treatment group.  Baseline 
is defined as the last questionnaire completed prior to or on the date of randomization.  Provided 
missing data are minimal, a sensitivity analysis of the primary endpoint may done by adjusting 
for the estimated daily antioxidant intake of patients over the course of the study.  The dietary 
supplement list will be used to further document the comparability of the treatment arms.  The 
list of supplements was selected from the NIH.83 In case of a large discrepancy, this may also be 
used as a covariate in a sensitivity analysis. 
 


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APPENDIX A: ECOG PERFORMANCE STATUS SCALE  
 
 
Grade 
Descriptions 
0 
 Normal activity. Fully active, able to carry on all pre-
disease performance without restriction. 
1 
 Symptoms, but ambulatory. Restricted in physically 
strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
 In bed <50% of the time. Ambulatory and capable of 
all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking 
hours. 
3 
 In bed >50% of the time. Capable of only limited self-
care, confined to bed or chair more than 50% of 
waking hours. 
4 
 100% bedridden. Completely disabled. Cannot carry 
on any self-care. Totally confined to bed or chair. 
5 
  Dead 
 
 
 
 
 


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APPENDIX B: Study Drug Compliance - Pill Diary 
 
Patient should be provided with diary pages for 90 days, enough to log study drug compliance 
between study visits. 
 


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J1823 The MAP TRIAL: A Randomized Double-Blind, Placebo-Controlled Study of the 
Effects of MPX Capsules on Rising Prostate-Specific Antigen Levels in Alanine/Alanine 
SOD2 Genotype Men Following Initial Therapy for Prostate Cancer  
 
Name_______________    Subject’s ID #: __________ 
Study Weeks#________ 
 
 
Take 8 capsules whole from the bottle once every day with water.  
 
Your pills should be taken ONE hour before food or TWO hours after food.  You can take the 
capsules over a 2-hour period if needed. 
 
Bring your diary and pill supply with you to each clinic visit. Return all unused pills and 
empty bottles. 
 
Tell us the time of your last meal (CLINIC VISIT DAY ONLY): __________  
 
Cycle 
Day 
Date of 
Dosing 
Time of 
Dose  
# of  
Capsules 
Comments/Side Effects 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 


Protocol Version 6.0 Date: July 02, 2021 
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Cycle 
Day 
Date of 
Dosing 
Time of 
Dose  
# of  
Capsules 
Comments/Side Effects 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
29 
 
 
 
 
30 
 
 
 
 
31 
 
 
 
 
32 
 
 
 
 
33 
 
 
 
 
34 
 
 
 
 
35 
 
 
 
 
36 
 
 
 
 
37 
 
 
 
 
38 
 
 
 
 
39 
 
 
 
 
40 
 
 
 
 
41 
 
 
 
 
42 
 
 
 
 
43 
 
 
 
 
44 
 
 
 
 
45 
 
 
 
 
46 
 
 
 
 
47 
 
 
 
 
48 
 
 
 
 
49 
 
 
 
 
50 
 
 
 
 


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Cycle 
Day 
Date of 
Dosing 
Time of 
Dose  
# of  
Capsules 
Comments/Side Effects 
51 
 
 
 
 
52 
 
 
 
 
53 
 
 
 
 
54 
 
 
 
 
55 
 
 
 
 
56 
 
 
 
 
57 
 
 
 
 
58 
 
 
 
 
59 
 
 
 
 
60 
 
 
 
 
61 
 
 
 
 
62 
 
 
 
 
63 
 
 
 
 
64 
 
 
 
 
65 
 
 
 
 
66 
 
 
 
 
67 
 
 
 
 
68 
 
 
 
 
69 
 
 
 
 
70 
 
 
 
 
71 
 
 
 
 
72 
 
 
 
 
73 
 
 
 
 
74 
 
 
 
 
75 
 
 
 
 
76 
 
 
 
 
77 
 
 
 
 
78 
 
 
 
 
79 
 
 
 
 
80 
 
 
 
 


Protocol Version 6.0 Date: July 02, 2021 
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Cycle 
Day 
Date of 
Dosing 
Time of 
Dose  
# of  
Capsules 
Comments/Side Effects 
81 
 
 
 
 
82 
 
 
 
 
83 
 
 
 
 
84 
 
 
 
 
 
 
 
 
 
 
 
 
Subject’s signature: _______________________ 
 
 
Date: _________________ 
 
Reviewer’s signature: _________________________  
 
Date: _________________ 


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APPENDIX C: FOOD FREQUENCY QUESTIONNAIRE FOR FRUITS AND VEGETABLES 
 
 
Subject ID  __ __-__ __ __-__ __      Initials __ __ __     Study Weeks _________ 
 
Date of Visit: _____/_____/_____  (mm/dd/yy) 
 
 
 
Instructions: Answer each question as best you can – estimate if you are not sure. 
 
 
 
 
 
 
 
 
 
 
Amount 
 
Not in 
the last 
month 
1 per 
month 
2–3 
per 
month 
1–2 
per 
week 
3–4 
per 
week 
5–6 
per 
week 
1 
per 
day 
2+ 
per 
day 
Medium 
serving size 
S M L 
FRUITS 
Example: Rice 
◦ 
◦ 
◦ 
◦ 
◦ 
• 
◦ 
◦ 
¾ cup 
◦ • 
◦ 
Apples, 
applesauce 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
apple or ½ 
cup 
◦ ◦ 
◦ 
Apricots 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
2 medium 
fruit 
◦ ◦ 
◦ 
Bananas 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
fruit 
◦ ◦ 
◦ 
Cantaloupe 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ melon 
◦ ◦ 
◦ 
Cherries 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Grapefruit 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
fruit 
◦ ◦ 
◦ 
Grapes 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Honeydew melon ◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ melon 
◦ ◦ 
◦ 
Kiwi 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
fruit 
◦ ◦ 
◦ 
Limes or lemons 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 
lemon/lime 
◦ ◦ 
◦ 
Mango 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ mango 
◦ ◦ 
◦ 
Nectarines 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
fruit 
◦ ◦ 
◦ 
Oranges 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 orange 
◦ ◦ 
◦ 
Papaya 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ papaya 
◦ ◦ 
◦ 


Protocol Version 6.0 Date: July 02, 2021 
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Amount 
 
Not in 
the last 
month 
1 per 
month 
2–3 
per 
month 
1–2 
per 
week 
3–4 
per 
week 
5–6 
per 
week 
1 
per 
day 
2+ 
per 
day 
Medium 
serving size 
S M L 
Peaches 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
fruit or ½ 
cup 
◦ ◦ 
◦ 
Pears 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
fruit or ½ 
cup 
◦ ◦ 
◦ 
Pineapple 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ fruit 
◦ ◦ 
◦ 
Plums 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
fruit 
◦ ◦ 
◦ 
Raisins 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ cup or 
small pack 
◦ ◦ 
◦ 
Strawberries 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Berries 
(Excluding 
strawberries) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Tangerines 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 tangerine 
◦ ◦ 
◦ 
Watermelon 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ melon 
◦ ◦ 
◦ 
VEGETABLES 
Avocado 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ medium 
or ½ cup 
◦ ◦ 
◦ 
Broccoli 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Brussel sprouts 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Cabbage 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Carrots 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Cauliflower 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Celery 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Coleslaw 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Corn 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Greens (Swiss 
chard, kale, 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 


Protocol Version 6.0 Date: July 02, 2021 
J1823 Protocol – Phase III MPX in Prostate Cancer  
Page 49 of 58 
 
 
 
 
 
 
 
 
 
 
Amount 
 
Not in 
the last 
month 
1 per 
month 
2–3 
per 
month 
1–2 
per 
week 
3–4 
per 
week 
5–6 
per 
week 
1 
per 
day 
2+ 
per 
day 
Medium 
serving size 
S M L 
collard, turnip, or 
mustard greens) 
Spinach (cooked) ◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Spinach (raw) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Fresh tomatoes 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
or 4 slices 
◦ ◦ 
◦ 
Green beans 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Green peas 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Green pepper 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ cup 
◦ ◦ 
◦ 
Green salad 
(iceberg lettuce 
only) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Green salad 
(romaine or leaf 
lettuce) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Jalapeno, sweet 
red, or chili 
peppers 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ cup 
◦ ◦ 
◦ 
Mixed vegetables 
(frozen or 
canned) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Onions and leeks ◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Summer squash 
or zucchini 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Sweet potatoes 
or yams 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
CEREALS, GRAINS, NUTS, AND SNACKS 
Almonds 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ cup 
◦ ◦ 
◦ 
Peanuts 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ cup 
◦ ◦ 
◦ 
Other nuts (e.g., 
Brazil, pistachio) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
¼ cup 
◦ ◦ 
◦ 
Peanut butter 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
2 Tbsp. 
◦ ◦ 
◦ 


Protocol Version 6.0 Date: July 02, 2021 
J1823 Protocol – Phase III MPX in Prostate Cancer  
Page 50 of 58 
 
 
 
 
 
 
 
 
 
 
Amount 
 
Not in 
the last 
month 
1 per 
month 
2–3 
per 
month 
1–2 
per 
week 
3–4 
per 
week 
5–6 
per 
week 
1 
per 
day 
2+ 
per 
day 
Medium 
serving size 
S M L 
Cold cereal, 
fortified (e.g., 
Raisin Bran® 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Oatmeal 
(fortified, 
instant) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Whole wheat 
bread or rolls 
(enriched) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
2 slices or 1 
medium roll 
◦ ◦ 
◦ 
MEATS, EGGS, AND DAIRY PRODUCTS 
Liver (beef or 
chicken) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
4 ounces 
◦ ◦ 
◦ 
Fish 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
4 ounces 
◦ ◦ 
◦ 
Cheese 
(excluding 
cottage and 
cream cheese) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 slice, ¼ 
cup, 
shredded 
◦ ◦ 
◦ 
Cottage cheese 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Cream cheese 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
2 Tbsp. 
◦ ◦ 
◦ 
Eggs, whole 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 medium 
◦ ◦ 
◦ 
Fat-free milk 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Reduced-fat milk ◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Whole milk 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Soy milk 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
MIXED DISHES AND SOUPS 
Chili 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Macaroni and 
cheese 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Minestrone 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Pizza 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 slice of a 
12″ pizza 
◦ ◦ 
◦ 


Protocol Version 6.0 Date: July 02, 2021 
J1823 Protocol – Phase III MPX in Prostate Cancer  
Page 51 of 58 
 
 
 
 
 
 
 
 
 
 
Amount 
 
Not in 
the last 
month 
1 per 
month 
2–3 
per 
month 
1–2 
per 
week 
3–4 
per 
week 
5–6 
per 
week 
1 
per 
day 
2+ 
per 
day 
Medium 
serving size 
S M L 
Spaghetti, 
lasagna, and 
other pasta with 
tomato sauce 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Stews with 
tomatoes 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Tomato soup 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
Vegetable soup 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 cup 
◦ ◦ 
◦ 
SAUCES, CONDIMENTS, AND OILS 
Butter or 
margarine 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
2 pats or 2 
teaspoons 
◦ ◦ 
◦ 
Mayonnaise, 
including low-fat 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 Tbsp. 
◦ ◦ 
◦ 
Ketchup 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
2 Tbsp. 
◦ ◦ 
◦ 
Tomato sauce 
(excluding pasta 
sauce) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
½ cup 
◦ ◦ 
◦ 
Salsa 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 Tbsp. 
◦ ◦ 
◦ 
Olive oil 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 Tbsp. 
◦ ◦ 
◦ 
Safflower or corn 
oil 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 Tbsp. 
◦ ◦ 
◦ 
Soybean oil 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 Tbsp. 
◦ ◦ 
◦ 
Wheat germ oil 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
1 Tbsp. 
◦ ◦ 
◦ 
BEVERAGES 
Apple juice or 
cider 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Carrot juice 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Cranberry juice 
(or Cran-blend 
juice) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Grapefruit juice 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 


Protocol Version 6.0 Date: July 02, 2021 
J1823 Protocol – Phase III MPX in Prostate Cancer  
Page 52 of 58 
 
 
 
 
 
 
 
 
 
 
Amount 
 
Not in 
the last 
month 
1 per 
month 
2–3 
per 
month 
1–2 
per 
week 
3–4 
per 
week 
5–6 
per 
week 
1 
per 
day 
2+ 
per 
day 
Medium 
serving size 
S M L 
Fruit punch or 
lemonade 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Orange juice, 
unfortified 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Orange juice 
(Vitamin C-
fortified) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Orange juice 
(Fortified, other) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Pineapple juice 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Tea (Iced or Hot) 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Tomato juice or 
V-8 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
8 oz. glass 
◦ ◦ 
◦ 
Red Wine 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
5 oz. glass 
◦ ◦ 
◦ 
Please answer these two important questions. 
 
Never 
or less 
than 
once 
per 
week 
1–2 
per 
week 
3–4 
per 
week 
5–6 
per 
week 
1 per 
day 
2 per 
day 
3 
per 
day 
4 
per 
day 
5+ per day 
In summary, how 
often did you eat 
vegetables in the 
past month, not 
counting 
potatoes, salad, 
or beans? 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
In summary, how 
often did you eat 
fruits in the past 
month, not 
counting juices? 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 
◦ 


Protocol Version 6.0 Date: July 02, 2021 
J1823 Protocol – Phase III MPX in Prostate Cancer  
Page 53 of 58 
 
APPENDIX D: Dietary Supplement List 
 
 
Subject ID  __ __-__ __ __-__ __      Initials __ __ __     Study Weeks _________ 
 
Date of Visit: _____/_____/_____  (mm/dd/yy) 
 
 
Instructions: Please indicate whether or not you take each supplement listed.  If yes, please 
fill out the additional columns to the best of your ability.  If the supplement is not in the list, 
please indicate it in “Other” section below.  Thank you! 
 
Supplement 
No 
Yes 
Start date  
End date  
Brand 
Dose & Frequency 
Multivitamin 
 
 
 
 
 
 
Pomi-T 
 
 
 
 
 
 
Pomegranate 
 
 
 
 
 
 
Reishi Mushroom 
 
 
 
 
 
 
Grape Skin 
 
 
 
 
 
 
Grape Seed 
 
 
 
 
 
 
Resveratrol 
 
 
 
 
 
 
Quercetin 
 
 
 
 
 
 
Lycopene 
 
 
 
 
 
 
Beta-Carotene 
 
 
 
 
 
 
Selenium 
 
 
 
 
 
 
Alpha Tocopherol 
(Vitamin E) 
 
 
 
 
 
 
Vitamin D 
 
 
 
 
 
 
Vitamin C 
 
 
 
 
 
 
Green Tea 
 
 
 
 
 
 
Modified Citrus 
Pectin 
 
 
 
 
 
 
Other (please list) 
 
 
 
 
 
 
 


Protocol Version 6.0 Date: July 02, 2021 
J1823 Protocol – Phase III MPX in Prostate Cancer  
Page 54 of 58 
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