Clinical trial NCT04252625
Conditions: Prostate Adenocarcinoma
Sponsor: University of Utah
Start date: 2022-11-14; Completion date: 2024-01-25
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the difference in prostatitis symptoms in men with localized prostate cancer following brachytherapy taking Q-Urol relative to placebo.

Detailed description:
This is a Phase 2, double-blinded, placebo-controlled trial assessing the safety of Q-Urol use after brachytherapy placement in patients with localized prostate cancer. Patients will be randomized in a 1:1 ratio to receive Q-Urol/Placebo twice daily for 6 weeks after brachytherapy placement. Questionnaires will be administered pre- and post-treatment to assess the change in prostatitis symptoms and quality of life measures. The mean values between groups will be compared.

Arms: arm 1: Patients will be randomized in a 1:1 ratio to receive Q-Urol, two capsules, twice daily for 6 weeks after brachytherapy placement.

Questionnaires will be administered pre- and post-treatment to assess the change in prostatitis symptoms and quality of life measures. The mean values between groups will be compared. arm 2: Patients will be randomized in a 1:1 ratio to receive Placebo, two capsules, twice daily for 6 weeks after brachytherapy placement.

Questionnaires will be administered pre- and post-treatment to assess the change in prostatitis symptoms and quality of life measures. The mean values between groups will be compared.
Interventions: intervention 1: Q-Urol intervention 2: Placebo
Intervention descriptions: intervention 1: Q-Urol is an over-the-counter herbal supplement manufactured by Farr Laboratories. It is a combination product composed of quercetin, pollen extract, bromelain, and papain. intervention 2: placebo capsule

Protocol documents:
Prot_SAP_000.pdf: 
Short Title: Q-Urol 
Version Date: 11APR2023 
Principal Investigator: Jonathan D. Tward, MD, PhD 
 
A Phase II Randomized Controlled Trial of a Supplement Containing Quercetin, 
Bromelain, Rye Flower Pollen, and Papain on Reducing the Severity of Radiation-Induced 
Prostatitis 
HCI# 129154 
Coordinating Center 
Huntsman Cancer Institute 
Principal Investigator 
Jonathan D Tward MD, PhD 
University of Utah 
Huntsman Cancer Institute 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Email: Jonathan.Tward@hci.utah.edu 
Statistician(s) 
Kenneth M. Boucher, PhD  
Research Associate Professor, Internal Medicine 
University of Utah 
Huntsman Cancer Institute 
2000 Circle of Hope Room 1710 
Email: Ken.Boucher@hci.utah.edu 
Medical Monitor 
Matthew Poppe, MD 
University of Utah 
Huntsman Cancer Institute 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Email: Matthew.Poppe@hci.utah.edu 
Drug Manufacturer  
Farr Labs, LLC 
Investigational agent(s) 
Q-Urol 
IND Number 
IND152781  
NCT Number (CT.gov) 
NCT04252625 
Historical Protocol Version Dates 
Version 1: 02DEC2020 
Version 2: 11APR2023 
 


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TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS ................................................................................................................ 2 
LIST OF ABBREVIATIONS ......................................................................................................... 5 
PROTOCOL SIGNATURE ............................................................................................................ 9 
STUDY SUMMARY.................................................................................................................... 10 
SCHEMA ...................................................................................................................................... 13 
1 
OBJECTIVES ....................................................................................................................... 14 
1.1 
Primary Objective .......................................................................................................... 14 
1.2 
Secondary Objective(s) .................................................................................................. 14 
2 
BACKGROUND .................................................................................................................. 14 
2.1 
Prostate Cancer and Brachytherapy Induced Prostatitis ................................................ 14 
2.2 
Rationale for Q-Urol ...................................................................................................... 15 
2.3 
Clinical Experience ........................................................................................................ 15 
2.4 
Effect of Antioxidants on Radiation efficacy ................................................................. 16 
2.5 
Rationale of definition of ½ standard deviation of the mean for clinically significant 
difference on the Patient-Reported Outcomes Measures: ......................................................... 17 
3 
DRUG INFORMATION ...................................................................................................... 17 
3.1 
Q-Urol ............................................................................................................................ 17 
4 
STUDY DESIGN.................................................................................................................. 18 
4.1 
Description ..................................................................................................................... 18 
4.2 
Randomization and Blinding .......................................................................................... 19 
4.3 
Number of Patients ......................................................................................................... 19 
4.4 
Number of Study Centers ............................................................................................... 19 
4.5 
Study Duration ............................................................................................................... 19 
5 
ELIGIBILITY CRITERIA.................................................................................................... 20 
5.1 
Inclusion Criteria ............................................................................................................ 20 
5.2 
Exclusion Criteria ........................................................................................................... 21 
5.3 
Recruitment Strategies ................................................................................................... 23 
6 
STRATIFICATION FACTORS ........................................................................................... 23 
7 
TREATMENT PLAN ........................................................................................................... 23 
7.1 
Administration Schedule ................................................................................................ 23 
7.2 
Q-Urol and Identical Placebo ......................................................................................... 23 


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7.3 
Concomitant Medications and Therapies ....................................................................... 24 
7.4 
Duration of Therapy ....................................................................................................... 25 
8 
TOXICITIES AND DOSE MODIFICATION ..................................................................... 26 
8.1 
Dose Modifications ........................................................................................................ 26 
8.2 
Supportive Care .............................................................................................................. 27 
8.3 
Contraception ................................................................................................................. 27 
9 
SCHEDULE OF EVENTS ................................................................................................... 27 
10 STUDY PROCEDURES ...................................................................................................... 31 
10.1 
Screening .................................................................................................................... 31 
10.2 
Treatment Period ........................................................................................................ 31 
10.3 
End of Treatment ........................................................................................................ 31 
11 STUDY ASSESSMENTS .................................................................................................... 31 
11.1 
Physical Examinations and Vital Signs ...................................................................... 31 
11.2 
Baseline Characteristics .............................................................................................. 31 
11.3 
Adverse Events ........................................................................................................... 32 
11.4 
Laboratory Assessments ............................................................................................. 32 
11.5 
Questionnaire administration ...................................................................................... 33 
11.6 
Dosing and Pain Diary ................................................................................................ 33 
12 CRITERIA FOR EVALUATION AND ENDPOINT .......................................................... 33 
12.1 
Safety .......................................................................................................................... 33 
12.2 
Efficacy ....................................................................................................................... 33 
12.3 
Population for analyses ............................................................................................... 34 
12.4 
Safety stopping rules .................................................................................................. 34 
13 STATISTICAL CONSIDERATIONS.................................................................................. 34 
13.1 
Statistical hypothesis .................................................................................................. 34 
13.2 
Statistical Analyses ..................................................................................................... 35 
14 REGISTRATION GUIDELINES ......................................................................................... 36 
15 DATA SUBMISSION SCHEDULE .................................................................................... 37 
16 ETHICAL AND REGULATORY CONSIDERATIONS .................................................... 37 
16.1 
Human Subject Protections ........................................................................................ 37 
16.2 
Institutional Review .................................................................................................... 37 
16.3 
Data and Safety Monitoring Plan ............................................................................... 37 
16.4 
Adverse Events and Serious Adverse Events ............................................................. 38 


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16.5 
SAE Reporting Requirements .................................................................................... 40 
16.6 
Reporting of Pregnancy .............................................................................................. 42 
16.7 
Protocol Amendments ................................................................................................ 42 
16.8 
Protocol Deviations .................................................................................................... 42 
16.9 
FDA Annual Reporting .............................................................................................. 43 
16.10 
Clinical Trials Data Bank ........................................................................................... 43 
16.11 
Record Keeping .......................................................................................................... 43 
17 REFERENCES ..................................................................................................................... 44 
 
List of Tables 
Table 1: Schedule of Events ......................................................................................................... 28 
Table 2: Laboratory Assessments ................................................................................................. 32 
Table 3: Operating Characteristics ................................................................................................ 34 
 
List of Appendances 
Appendix 1: National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) ...... 45 
Appendix 2: The Expanded Prostate Cancer Index Composite (EPIC) ....................................... 48 
Appendix 3: The International Prostate Symptom Score (I-PSS) ................................................ 57 
Appendix 4: Rectal Function Assessment Score  (R-FAS) .......................................................... 59 
Appendix 5: The Sexual Health Inventory for Men (SHIM) Questionnaire ................................ 61 
Appendix 6: Patient Dosing Diary ................................................................................................ 63 
Appendix 7: Pain Management Diary........................................................................................... 64 
Appendix 8: NCCN Risk Stratification ........................................................................................ 65 
Appendix 9 Baseline Characteristics ............................................................................................ 66 
Appendix 10: Charlson Comorbidity Index .................................................................................. 67 
Appendix 11: Eastern Cooperative Oncology Group Performance Status Criteria (ECOG) & 
Karnofsky Performance Scale Index (KPS) equivalency ............................................................. 68 
Appendix 12: Cautionary Medications ......................................................................................... 69 
 
List of Figures 
Figure 1 : Study Schema ............................................................................................................... 13 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D/C 
Discontinue 


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Abbreviation or Term1 
Definition/Explanation 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
Eg 
Exempli Gratia (for example) 
FACS 
Fluorescence-Activated Cell Sorting  
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LLQ 
The lower limit of quantitation 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MID 
minimal important difference 


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Abbreviation or Term1 
Definition/Explanation 
MRI 
Magnetic resonance imaging 
MRSD 
The maximum recommended starting dose 
MTD 
Maximum tolerated dose  
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
PCORI 
the Patient-Centered Outcomes Research Institute 
PD 
Pharmacodynamic(s) 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcome 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
RBC 
Red blood cell 
QD 
Once-daily 
QOL 
Quality of Life 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Fredericia equation 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 
TSH 
Thyroid-stimulating hormone 
ULN 
The upper limit of normal 
ULQ 
The upper limit of quantitation 
UV 
Ultraviolet 


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Abbreviation or Term1 
Definition/Explanation 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of nonchildbearing potential 
1 All of these abbreviations may or may not be used in the protocol.  
 


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PROTOCOL SIGNATURE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of the 
federal government. I will promptly submit the protocol to the IRB for review and approval. Once 
the protocol has been approved by the IRB, I understand that any modifications made during the 
course of the study must first be approved by the IRB prior to implementation except when such 
modification is made to remove an immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study treatment, the conduct of the study, and the obligations of 
confidentiality. 
Note: This document is signed electronically through submission and approval by the Principal 
Investigator in the University of Utah IRB Electronic Research Integrity and Compliance 
Administration (ERICA) system. 
 
 


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STUDY SUMMARY 
Title 
A Phase II Randomized Controlled Trial of a Supplement 
Containing Quercetin, Bromelain, Rye Flower Pollen, and 
Papain on Reducing the Severity of Radiation-Induced 
Prostatitis 
Short Title 
Q-Urol 
Protocol Identifiers (IRB – 
internal) 
129154 
Phase 
Phase II 
Design 
An asymmetric two-sided group sequential design will be 
used with an interim analysis for efficacy and futility.  
Study Duration 
Up to three years. 
Study Center(s) 
Huntsman Cancer Institute 
Objectives 
Primary Objective: 
To assess the difference in prostatitis symptoms in men with 
localized prostate cancer following brachytherapy taking Q-
Urol relative to placebo. 
Secondary Objectives: 
• To assess Health-Related Quality of Life (HRQOL) 
in the urologic, rectal, sexual, hormonal, mental and 
overall physical domains of men receiving either 
placebo or supplement after definitive brachytherapy. 
• To assess if the Q-Urol has any significant impact on 
serum biomarkers of inflammation relative to 
placebo. 
• To access if the addition of Q-Urol introduces any 
additional toxicity relative to placebo. 
Number of Subjects 
Up to 140, 70 per arm. 
Diagnosis and Main Eligibility 
Criteria 
Key Inclusion Criteria: 
• Male subjects aged ≥ 18 years. 
• Histologically proven prostate adenocarcinoma who 
have selected treatment with brachytherapy with or 
without external beam radiation, with or without 
androgen deprivation therapy. 
• Fluent in speaking and reading English. 
• ECOG Performance Status ≤ 1 
Key Exclusion Criteria: 
• Baseline AUA symptom scores > 15. 


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• Prior diagnosis of chronic prostatitis type II-IV.  
• The subject has received systemic therapy intended 
for the treatment of prostatitis (including herbal 
supplements) ≤ 14 days of starting study treatment. 
• The subject has received a fluoroquinolone antibiotic 
(e.g. ciprofloxacin, norfloxacin, ofloxacin 
levofloxacin, etc.) ≤ 3 days of starting study 
treatment. 
• The subject is actively on anti-inflammatory 
medications for other medical conditions, unless 
approved by PI.  
• The subject has undergone transurethral resection of 
the prostate (TURP). 
Study Product, Dose, Route, 
Regimen 
Q-Urol (proprietary blend 375 mg plus 37.5 mg calcium) 
two capsules taken twice daily. 
Duration of administration 
Six weeks after brachytherapy placement. 
Reference therapy 
Standard of care supportive therapy after brachytherapy 
placement. 
Statistical Methodology 
There are two planned analyses of the primary endpoint 
variable, an interim analysis at N1 = 21 patients per groups 
and a final analysis at N = 70 patients per group. Two sample 
t-tests will be used for both the analysis.  A single interim 
analysis is planned after N1= 21 subjects per group have 
outcome data. The interim and final analysis will compare 
the treatment and control means using nominal t statistics 
(control minus treatment). If the t statistic has a value less 
than -1.16 at the interim analysis the trial will be terminated 
for futility. If the t statistic has a value greater than 2.85 at 
the interim analysis the trial will be terminated for efficacy.   
If the study is not terminated for efficacy or futility at the 
interim analysis an additional N2 = 49 patients per group 
will be accrued for a total of N = 70 patients per group. If the 
interim analysis is done at the planned sample size (21 
patients per group) the treatment will be deemed efficacious 
at the final analysis if the t statistic has a nominal value 
greater than 1.67. 
 In addition to formal testing for a difference between 
groups, the mean change between groups and the mean 
change within each group together will be reported together 
with 95% confidence intervals.  
 


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SCHEMA 
 
 
Figure 1 : Study Schema 
 
 


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1 
OBJECTIVES 
1.1 
Primary Objective 
 To assess the difference in prostatitis symptoms in men with localized prostate 
cancer following brachytherapy taking Q-Urol relative to placebo. 
Primary Endpoint: The mean peak score of the National Institutes of Health‐
Chronic Prostatitis Symptom Index (NIH‐CPSI) measured at six weeks post 
brachytherapy. 
1.2 
Secondary Objective(s) 
 To assess Health-Related Quality of Life (HRQOL) in the urologic, rectal, 
sexual, hormonal, mental and overall physical domains of men receiving either 
placebo or supplement after definitive brachytherapy. 
Secondary Endpoint: Patient questionnaires administered pre- and post-study 
therapy: The Expanded Prostate Cancer Index Composite (EPIC), The 
International Prostate Symptom Score (I-PSS), The Rectal Function 
Assessment Score (R-FAS), and the Sexual Health Inventory for Men (SHIM). 
 To assess if the Q-Urol has any significant impact on serum biomarkers of 
inflammation relative to placebo. 
Secondary Endpoint: Inflammation markers pre and post brachytherapy: 
erythrocyte sedimentation rate, C-reactive protein, and prostate-specific antigen 
(PSA) 
 To access if the addition of Q-Urol introduces any additional toxicity relative 
to placebo. 
Secondary Endpoint: Frequency of adverse events (AEs) will be collected and 
characterized by type, severity (as defined by CTCAE, version 5.0), seriousness, 
duration, and relationship to study treatment. 
 To assess the effect on prostatitis-related pain in men with localized prostate 
cancer following brachytherapy taking Q-Urol relative to placebo. 
Secondary Endpoint: The number of days during the 28 days post-
brachytherapy that any medication is taken for the treatment of prostate-related 
pain. 
2 
BACKGROUND 
2.1 
Prostate Cancer and Brachytherapy Induced Prostatitis 
Prostate cancer is the most commonly diagnosed cancer in men with an estimated 174,650 
new cases and 31,620 deaths projected in 2019.1  At diagnosis, approximately 85% of men 


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will have disease localized to the prostate, and most will elect to have either surgical therapy 
or radiation treatment with curative intent.  
Brachytherapy (seed implant), either alone or combined with external beam radiation 
therapy, is an established care standard for localized prostate cancer.  The physical trauma of 
the procedure and the continuing exposure of the prostate tissue, neurovascular bundles, 
bladder neck, and anterior rectal wall over the ensuing 3‐6 months to radiation and its effects 
results in an inflammatory state with symptoms identical to chronic prostatitis type IIIA or 
IIIB.  Virtually 100% of subjects will experience these uncomfortable symptoms, with 
severity typically peaking around weeks 4-6 post-implant, before gradually improving over 
the ensuing 6‐12 months.  Like chronic prostatitis, the mainstay of comfort therapy for these 
subjects is the use of alpha‐blockers, NSAIDs, steroids, anticholinergics, antidiarrheals, and 
phosphodiesterase inhibitors.    
Prostatitis symptoms can result in significant distress, pain, nocturia related‐fatigue, loss of 
work and productivity.  Improving the side‐effect profile of brachytherapy without adding a 
significant risk of other toxicities or a decrease in oncologic efficacy is highly desirable.  
2.2 
Rationale for Q-Urol 
Q-Urol is a commercially available supplement whose key active ingredient is Quercetin. 
Quercetin has been shown to have the following biological properties: 
• A potent free radical scavenger2 and antioxidant.3 
• An anti-inflammatory agent, which reduces inflammation by inhibiting 
interleukin-6, interleukin 8, tumor necrosis factor, and NF-κB.4-7 
• In animal models of inflammatory pain, quercetin reduced pain, oxidative stress, 
and cytokine production.8 
• Patients with chronic prostatitis who report improvement with quercetin have a 
reduction in the oxidative stress metabolite F2-isoprostane in their expressed 
prostatic secretions (EPS). 9 
• Quercetin therapy reduces inflammation as measured by prostaglandin E2 levels 
in EPS, and increases the levels of prostatic β-endorphins.10 
• Side effects with quercetin therapy are rare.11 
We propose that the use of Q-Urol will be an effective therapy at reducing symptom 
burden and distress following prostate brachytherapy procedures due to radiation-induced 
prostatitis versus a comparator cohort receiving placebo without adding additional 
toxicity.  
2.3 
Clinical Experience 
In a prospective, randomized, double‐blind, placebo‐controlled trial of the bioflavinoid 
quercetin in men with chronic prostatitis, 20% percent of patients taking a placebo and 67% 
of patients taking the bioflavonoid had an improvement of symptoms of at least 25% as 
measured by the NIH chronic prostatitis symptom score. In an unblinded open-label follow 
up study, 82% of patients who received a formulation of quercetin, bromelain, papain and 


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zinc (Prosta‐Q, Farr labs) had at least a 25% improvement in symptom score9.  The 
treatment was well tolerated.  Out of 30 patients enrolled on the trial, the only adverse 
events reported were:   
• One patient taking placebo developed a rash that resolved when he stopped taking 
the capsules.  
• One patient taking quercetin developed a headache after the first few doses, which 
resolved 
• One patient taking quercetin noted mild tingling of the extremities after each dose. 
All these side effects resolved after cessation of therapy. 
2.4 
Effect of Antioxidants on Radiation efficacy 
The primary mechanism of antitumor activity from radiation therapy is via the production of 
chemical radicals perturbing DNA in cancer cells resulting in tumor cell death.  Some of the 
supplements being evaluated in this trial have antioxidant properties, and therefore one 
could hypothesize that they could produce antitumor activity.  In the most exhaustive meta-
analysis on the effect of antioxidant use with either chemotherapy or radiotherapy, 49 
randomized trials were identified that specifically addressed this concern.12 The authors 
determined the following: 
“ In 17 articles of 49 (approximately 35%) included in this study, effects on patient survival 
or clinical response during chemotherapy and/or radiotherapy were described. In 7 of 17 
RCTs using melatonin supplementation, 4 reported a significantly increased survival rate 
and 4 reported a significantly increased tumor regression rate. In addition, 1 trial each 
using vitamin A and multiple vitamins reported a significantly increased survival rate. On 
the other hand, 2 trials using multiple vitamins reported that there were no significant 
differences between supplementation and control groups, although the survival rates of the 
supplementation groups were slightly lower than those of the control groups. Two trials 
using vitamin E reported that there was no significant difference in clinical response 
between groups. Also, the RCT using ellagic acid reported that there were no significant 
differences between groups in survival rate and clinical response. Similarly, a trial using l-
arginine supplementation reported a significant increase in the pathological response. On 
the other hand, a trial using combination supplement (vitamins C and E and selenium) 
reported that there was no significant difference in clinical response.” 
With regard to toxicity, the same authors determined: 
“In total, 19 radiotoxicity prevention trials were investigated, which specifically aimed to 
reduce toxicities affecting the mucosa, skin, salivary glands, and taste. Four of 19 trials 
reported no significant differences in toxicity between groups. Antioxidant supplements such 
as vitamin E, multivitamin combination, polyphenol, and zinc were effective in preventing 
radiation-induced toxicities in the skin, mucosa, and salivary glands.” 
Patients currently undergoing radiation therapies for prostate cancer at the Huntsman Cancer 
Institute at the University of Utah are not currently counselled to stop antioxidants or 
supplements, but asked about supplementation use.  There is also no recommendation by the 
NCCN or any other prostate cancer treatment guideline that suggests antioxidants, 
phytochemicals, minerals or other supplements should be discontinued.  Given the 


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overwhelming amount of evidence from the randomized controlled trials in the 
contemporary Yasueda meta-analysis, and the current care standard of allowing antioxidant 
therapies during prostate cancer radiation therapy, the use of antioxidants and 
phytochemicals used in this study is considered safe by the best evidence available. 
 
2.5 
Rationale of definition of ½ standard deviation of the mean for clinically 
significant difference on the Patient-Reported Outcomes Measures: 
A ½ standard deviation from the mean at the baseline for each PRO-QOL measure or 
domain was specified as the minimal clinically important difference (MID), to be consistent 
with established convention and other PCa PRO-QOL outcome studies.13-17  Specifically, a 
½ standard deviation was defined as the MID on the landmark ProtecT randomized trial 
which randomized approximately 1800 men to radiation therapy, versus surgery, versus 
active surveillance using the same PRO forms (EPIC) used in this study.  Utilizing this 
convention will allow the investigators to compare their outcomes not only against the 
cohorts in this study, but to historical cohorts such as those in ProtecT, as well as studies 
funded by the Patient-Centered Outcomes Research Institute (PCORI) evaluating QOL in 
prostate cancer patients receiving radiation therapy.18, 19 
3 
DRUG INFORMATION 
3.1 
Q-Urol 
Q-Urol is an over-the-counter herbal supplement manufactured by Farr Laboratories 
claiming to have anti-inflammatory effects. It is a combination product composed of 
quercetin, pollen extract, bromelain, and papain.  
 Pharmacology 
Quercetin is a bioflavonoid found in plants such as onions, berries, green tea, and 
apples that has antioxidant and anti-inflammatory effects. It is thought to exert its anti-
inflammatory effects through mast cell stabilization leading to the inhibition of 
prostaglandin D2 formation and the inhibition of the release of histamine, interleukin-
8, and TNF.  
Rye Flower pollen extract comes from the pollen of rye grass and is often marketed 
under the name Cernilton. It is been used by men worldwide for the treatment of 
benign prostatic hyperplasia. Randomized controlled trials have demonstrated some 
moderate efficacy in the improvement of urological symptoms.20, 21 While the 
mechanism of action is not well understood, it is thought that the efficacy is related to 
anti-androgenic effects. Rye flower pollen may also act on α-adrenergic receptors to 
relax the sphincter muscles or by increasing bladder contraction by relaxing urethral 
smooth muscle tone. Bromelain is a mixture of enzymes found in the fruit and stem of 
the pineapple plant. Only a small amount of research has been done with bromelain in 
nasal swelling, inflammation, and the removal of dead skin after burns. Evidence does 
support its efficacy for relieving acute nasal and sinus inflammation symptoms when 
used in combination with standard of care medications.22 It is thought to exert its anti-


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inflammatory action by reducing leukocyte migration and through inhibition of COX2 
expression.23, 24 However, those sensitive or allergic to pineapples should not take 
bromelain. 
Papain is a protease isolated from papaya that mediates the hydrolysis of proteins. It is 
a common ingredient in many products, including toothpaste, contact lens cleaners, 
meat tenderizers, and meat products However, little research has been done to fully 
assess its efficacy as an anti-inflammatory. Caution should be taken when used 
concurrently with warfarin. 
 Clinical Safety 
In a prospective, placebo-controlled, randomized trial, 30 patients with category III 
chronic prostatitis were randomized to receive quercetin/placebo in a 1:1 ratio. 9 
Prosta-Q was then administered for 17 additional patients after completion of the 
randomized portion of the trial. Of the 15 patients randomized to receive quercetin, 
one experienced a headache after the first few doses and another patient noted mild 
tingling in the extremities after each dose. Both adverse events resolved on their own 
upon discontinuation of study therapy.  
The group randomized to receive quercetin reported a 35% improvement in the mean 
NIH symptom score vs. 7.2% reported by the placebo group. However, the 17 patients 
treated with Prosta-Q reported a mean improvement of 44%. 
139 men were treated in a prospective, placebo-controlled, randomized trial of pollen 
extract in patients with inflammatory chronic prostatitis and chronic pelvic pain 
syndrome. After 12 weeks of therapy, response (defined as a decrease of the NIH-
CPSI total score by at least 25% or at least 6 points) was seen in the pollen extract 
versus placebo group in 70.6% and 50.0% (p=0.0141). The pollen was well tolerated; 
two patients reported mild gastrointestinal disorders that caused a short treatment 
interruption and moderate pain (not otherwise specified) that caused discontinuation of 
treatment. 
4 
STUDY DESIGN 
4.1 
Description 
This is a Phase 2, double-blinded, placebo-controlled trial assessing the safety of Q-Urol use 
after brachytherapy placement in patients with localized prostate cancer. Patients will be 
randomized in a 1:1 ratio to receive Q-Urol/Placebo twice daily for six weeks after 
brachytherapy placement. Questionnaires will be administered pre- and post-treatment to 
assess the change in prostatitis symptoms and quality of life measures. The mean values 
between groups will be compared. 
Once 42 patients (21 to each arm) have been enrolled and treated on the study therapy, 
enrollment will be placed on hold and an interim analysis conducted. The interim analysis 
will be conducted for futility and efficacy and will be reviewed by the DSMC. If the analysis 
is favorable, as defined in the Statistical Analysis section, the trial will open to the 
enrollment of 98 additional subjects, 49 per arm. However, if the analysis does not 
demonstrate standards defined in the statistical analysis, the trial will be closed to accrual.  


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Safety monitoring will be overseen by the DSMC at HCI. See Section 12.4 for safety 
monitoring plan and early stopping rules.  
4.2 
Randomization and Blinding 
Patients who meet all criteria for enrollment will be randomly assigned to receive Q-Urol 
(Arm 1) or placebo (Arm 2). Patients will be randomized through the OnCore system in a 
1:1 ratio to Arm 1 or Arm 2 and stratified by dose level of brachytherapy used. 
To preserve the blind, only the Investigational Drug Services Pharmacy personnel and Data 
Safety Monitoring Committee (DSMC) at Huntsman Cancer Institute will know treatment 
assignments. Access to unblinded data/documents will be controlled by the pharmacy to 
ensure the blind is maintained. Every effort will be made to blind the patient, the 
investigator, and the study team to the treatment assignment, but the inadvertent unblinding 
of a patient may occur. If an investigator, site personnel, or patient is inadvertently 
unblinded, the unblinding will not be sufficient cause for the patient to be discontinued from 
study treatment or excluded from study analyses. Cases of accidental unblinding will be 
recorded in the applicable eCRF and evaluated by the DSMC for appropriateness of 
inclusion in the study analysis. 
In the case of an emergency, the treating investigator has the sole responsibility for 
determining if unblinding of a patient’s treatment assignment is warranted. Patient safety 
must always be the first consideration in making such a determination. If the treating 
investigator decides that unblinding is warranted, the investigator should contact the 
investigational pharmacy for treatment assignment. 
4.3 
 Number of Patients 
The trial will enroll up to 70 patients to each arm, 140 patients total. 
4.4 
Number of Study Centers 
This will be a single-center trial run at the Huntsman Cancer Institute at the University of Utah. 
4.5 
Study Duration  
The study is projected to last for 3 years from the first patient on to the last patient end of 
treatment visit. 
 
 
 


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5 
ELIGIBILITY CRITERIA 
This eligibility checklist is used to determine patient eligibility and filed with the enrolling 
investigator’s signature in the patient research chart.  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 
Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
 _____ Male subjects aged ≥ 18 years. 
 _____ Men with histologically proven localized prostate adenocarcinoma, 
stage I – III (as defined by AJCC 8th edition),  who have selected treatment 
with brachytherapy with or without external beam radiation, with or without 
androgen deprivation therapy. 
 _____ Fluent in speaking and reading English. 
 _____ ECOG Performance Status ≤ 1. 
 _____ Adequate organ function as defined as:  
• Hepatic:  
o Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) 
o AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN 
• Renal:  
o Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault 
formula:  
 Males: 
(140−𝑎𝑎𝑎𝑎𝑎𝑎)×𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡[𝑘𝑘𝑘𝑘]
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ቂ𝑚𝑚𝑚𝑚
𝑑𝑑𝑑𝑑ቃ×72 
 _____ Highly effective contraception for both male subjects and their female 
partners of childbearing potential throughout the study and at least 5 days after 
last study treatment administration if the risk of conception exists. 
 _____ Median life expectancy ≥ 5 years as calculated by the Lee and Shonberg 
Index (https://eprognosis.ucsf.edu/leeschonberg.php) 
 _____ Able to provide informed consent and willing to sign an approved 
consent form that conforms to federal and institutional guidelines. 
 


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5.2 
Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
 _____ Baseline AUA symptom scores > 15. 
 _____ Prior diagnosis of chronic prostatitis type II through IV.  
 _____ Subject has received systemic therapy intended for the treatment of 
prostatitis (including herbal supplements) ≤ 14 days of starting study treatment. 
 _____ Subject has received a fluoroquinolone antibiotic (e.g. ciprofloxacin, 
norfloxacin, ofloxacin levofloxacin, etc.) ≤ 3 days of starting study treatment. 
 _____ Subject is actively on anti-inflammatory medications for other medical 
conditions, unless approved by PI.  
 _____ Subject has undergone transurethral resection of the prostate (TURP). 
 _____ Patients with a prior or concurrent malignancy whose natural history or 
treatment has the potential to interfere with the safety or efficacy assessment of 
the investigational regimen. 
 _____ History of irritable bowel syndrome, chronic fatigue syndrome, 
fibromyalgia, and interstitial cystitis-bladder pain syndrome (IC/BPS). 
 _____ History of symptomatic hypotension, falls, or syncope 
 _____ Chronic hypoglycemia requiring hospitalization. 
 _____ Actively abusing alcohol or drugs 
 _____ The subject has uncontrolled, significant intercurrent, or recent illness 
including, but not limited to, the following conditions: 
• Congestive heart failure 
• Diabetes  
• Pulmonary artery hypertension 
• Any clinically significant condition that requires therapy with diuretic 
medications for any indication other than the management of 
hypertension. 
• Other clinically significant disorders that would, in the opinion of the 
treating investigator, preclude safe study participation. 


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 _____ Known prior severe hypersensitivity to investigational product or any 
component in its formulations (NCI CTCAE v5.0 Grade ≥ 3). 
 _____ Known allergy to pineapple or pineapple containing products. 
 ______ Subjects taking prohibited medications as described in Section 7.3 A 
washout period of prohibited medications for a period of at least 5 half-lives or 
as clinically indicated should occur prior to the start of treatment. 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto this 
study.  
______________________________ 
 
_________ 
_______ 
Investigator Signature  
 
 
 
Date  
Time 
 
 
 


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5.3 
Recruitment Strategies 
Potential patients will be identified by Investigators in the setting of their outpatient clinics. 
6 
STRATIFICATION FACTORS 
Patients will be stratified by prior use of alpha-blockers for prostate related condition (yes, no) 
and the dose of brachytherapy: high dose rate (HDR) or low dose rate (LDR). 
7 
TREATMENT PLAN 
7.1 
Administration Schedule 
Patients will undergo Low Dose Radiation (LDR) brachytherapy with or without External 
Beam Radiation Therapy (EBRT) or High Dose Radiation (HDR) brachytherapy with 
EBRT. When LDR is used as monotherapy the isotope will be PD-103 prescribed at 125 Gy, 
when used as a combined modality with EBRT, the LDR brachytherapy will precede the 
EBRT, the isotope used will be PD 103 prescribed at 100Gy. HDR monotherapy will not be 
performed.  The HDR + EBRT regimen will be a single fraction of Iridium-192 prescribed 
at 15Gy and will precede the EBRT. When EBRT is combined with LDR or HDR, the 
EBRT will only occur after the completion of the study drug regimen and toxicity 
evaluations for the primary endpoints. 
On the day of but after brachytherapy, patients will self-administer two Q-Urol or placebo 
capsules by mouth with food twice daily. Doses should be taken at about the same time 
every day (± 4 hours) and recorded on the patient's dosing diary. Doses missed outside of the 
dosing window should not be made up but rather patients should be instructed to take their 
next dose at their regularly scheduled time.  
7.2 
Q-Urol and Identical Placebo 
 How Supplied, Stored, Packaged, and Labeled 
Q-Urol will be provided by Farr Laboratories. Q-Urol will be provided as 375 mg 
proprietary blend and 37.5 mg calcium capsules for oral administration. They should 
be stored at room temperature, away from heat, moisture, and direct light. 
Placebo capsules, which do not contain the active ingredients of Q-Urol, will be 
compounded by the Investigational Drug Services Pharmacy at Huntsman Cancer 
Institute and will be identical in appearance to Q-Urol. 
The Investigator, or an approved representative, will ensure that all investigational 
products are stored in a secured area with controlled access under required storage 
conditions and in accordance with applicable regulatory requirements. 
According to Farr labs, the Q-Urol is manufactured in laboratories with Current Good 
Manufacturing Practice regulations enforced by the FDA.  In addition, Farr 
Laboratories ensures consistency and purity via the following measures: 


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• Ensures that the Certificates of Analysis (CofA’s) are in compliance with the 
United States Pharmacopeia (USP) standards on Identification and Purity 
Controls 
• Monitor manufacturing and quality control product documentation 
• Conduct laboratory testing on Finished products for Microbio, Heavy Metals, 
and Residual Solvents 
 Preparation and Administration 
Subjects will be provided enough Q-Urol/placebo for a full six weeks of treatment at 
the time of brachytherapy. Subjects will be instructed to self-administer the 
medication at home orally twice daily (every 12 hours ± 4 hours) with food. Subjects 
should begin dosing the evening after brachytherapy placement. Subjects should not 
take extra medication for any reason nor should they re-administer in the case of 
vomiting after administration. If a dose is missed outside of the dosing window, the 
dose should not be made up. 
 Accountability and Compliance 
Information pertaining to study drug compliance (i.e., date, time, and dose) will be 
recorded by patients on the drug diary (see Appendix 6) and recorded in the 
corresponding electronic case report form (eCRF) by the study team. A member of the 
study team will review patient drug compliance and provide patient re-education as 
required. Any reason for non-compliance will be documented in the subject’s research 
chart and the corresponding eCRF. At the discretion of the principal investigator, a 
subject may be discontinued from the trial for non-compliance with study visits or 
study drug. 
Subjects will be required to return any unused medication or empty bottles at the end 
of study therapy. Excess or unused study drug should be returned to the investigative 
site for accounting and destroyed in accordance with GCP after drug accountability 
has been performed. The total number of capsules dispensed, returned, and 
documented as taken will be reconciled to support drug accountability. Treatment 
compliance will be calculated and recorded for the study drug. It will be recorded as a 
percentage defined as the number of doses taken divided by the expected number of 
doses taken multiplied by 100%. 
7.3 
Concomitant Medications and Therapies 
Medications specifically prohibited in the exclusion criteria are not allowed during the 
active treatment period. Concomitant treatment considered necessary for the patient’s well-
being may be given at the discretion of the treating Investigator. 
 Allowed Therapy 
All supportive measures consistent with optimal patient care may be given throughout 
the study. Patients should receive appropriate supportive care measures as deemed 
necessary by the treating Investigator. 


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 Prohibited Therapy 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the active treatment period. Patients are prohibited from receiving the 
following therapies during the treatment phase of this trial:  
• Investigational agents, other than those utilized during study therapy.  
• Radiation therapy other than the brachytherapy conducted in conjunction with 
this study. 
• Herbal remedies, other than Q-Urol, defined as any substance derived from a 
botanical source, not prescribed by the physician that a patient is using without 
professional medical guidance with the intent of treating prostate specific 
conditions. 
• Cyclosporine 
• Digoxin 
• Warfarin 
• CYP2C8 substrates (e.g., repaglinide, paclitaxel, omeprazole, cisapride) 
 Allowed therapies to be used with caution and the discretion of the 
treating physician 
• While on study therapy, the use of anticoagulants should be used with 
caution.  
• Quercetin may have additive hypoglycemic effects when used with 
antidiabetic medications; use the combination with caution. 
• Quercetin may have varying effects on CYP3A4; substrates of CYP3A4 with 
a narrow therapeutic index should be used with caution (Appendix 12) 
• Quercetin may have additional blood pressure lowering effects when used 
with anti-hypertensive medications; use the combination with caution 
• Quercetin may have inhibitory effects on CYP2C9, CYP2D6, OATP1B1, and 
P-gp; substrates of these with narrow therapeutic indexes should be used with 
caution (Appendix 12). 
7.4 
Duration of Therapy 
Each patient will be on study therapy for six weeks starting with the day of brachytherapy. 
 Criteria for discontinuation of treatment (“off-treatment”) 
Patients may withdraw from treatment or the study overall at any time at their own 
request, or they may be withdrawn at the discretion of the Investigator or Sponsor for 
safety, behavioral reasons, or the inability of the patient to comply with the protocol-
required schedule of study visits or procedures. In addition to the drug-specific 
discontinuation criteria listed in Dose Modification Section, the following will result 
in treatment discontinuation: 


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• Unacceptable Toxicity 
• Subject requests to discontinue the study treatment and/or study procedures.   
• Non-compliance as defined as missing ≥ 30% of the required Q-Urol/placebo 
doses. At the discretion of the principal investigator, the subject may be 
permitted to continue on treatment after the first noted occurrence of non-
compliance if the subject is re-educated on treatment administration and 
compliance can be achieved within a reasonable timeframe.  
• Significant protocol violation 
• Study terminated by investigator sponsor 
• Lost to follow-up 
 Criteria for discontinuation of study (“off study”) 
Subjects will be taken off study for the following: 
• Completed study end of treatment visit. 
• Screen failure.  
• The subject is lost to follow-up. 
• If, in the investigator's opinion, the continuation of the trial would be harmful 
to the subject's well-being. 
• Development of intercurrent illness or situation which would, in the judgment 
of the investigator, significantly affect assessments of clinical status and trial 
endpoints. 
• Participant requests to be withdrawn from the study 
• Death 
8 
TOXICITIES AND DOSE MODIFICATION 
Every effort should be made to administer Q-Urol/Placebo at the planned dose and schedule. In 
the event of study treatment toxicity, dosing may be interrupted, delayed, and/or discontinued.  
In the event of multiple toxicities, treatment/dose modifications should be based on the worst 
toxicity observed (CTCAE v5.0) and/or the most conservative recommendation for any given 
toxicity.  Patients are to be instructed to notify Investigators at the first occurrence of any adverse 
symptom.  
All dose holds must be clearly documented in the patient's medical chart and in the CRF.  
Appropriate follow-up assessments should be done until adequate recovery occurs as assessed by 
the Investigator. 
8.1 
Dose Modifications 
While dose reductions are not permitted on trial, dose interruptions for study treatment-
related AEs are allowed as deemed necessary by the treating physician. Doses of Q-
Urol/Placebo that were not administered due to toxicity will not be replaced. If a toxicity-


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related dose delay extends over 12 days, treatment will be discontinued permanently and the 
patient should be removed from the study.  
Study therapy may be held for any treatment-related adverse events, grade ≥ 2 as deemed 
necessary by the treating investigator. Upon resolution of the treatment-related adverse 
event, study therapy may be resumed at the prior dose level and frequency.  
If a subject on study therapy experiences a grade ≥ 3 SAE attributed to study drug, study 
therapy will be discontinued. 
8.2 
Supportive Care 
All supportive measures consistent with optimal patient care may be given throughout the 
study. 
8.3 
Contraception 
Subjects will be instructed to abstain from sexual intercourse for the first two weeks after 
brachytherapy implantation. After the first two weeks, subjects may engage in sexual 
intercourse but should use a condom for the duration of study participation and for 5 days 
after the last dose of study therapy. In addition, female partners of childbearing potential 
should also use a highly effective contraceptive method during the same period.  
Acceptable highly effective contraceptive methods include: 
• Bilateral tubal occlusion 
• Intra-uterine devise (IUD) or hormone-releasing system (IUS) 
• Any hormonal (estrogen combined with progesterone or progesterone alone) 
contraception associated with inhibition of ovulation: implanted, oral, intravaginal, 
transdermal, or injectable 
• Spermicide in combination with a compatible barrier method (i.e. diaphragm, 
sponge, or male or female condoms) 
• Abstinence from heterosexual intercourse. 
9 
SCHEDULE OF EVENTS 
The Schedule of Events table provides an overview of the protocol visits and procedures.  Refer 
to the Study Procedures section of the protocol for detailed information on each assessment 
required for compliance with the protocol. The Investigator may schedule visits (unplanned 
visits) in addition to those listed in the Schedule of Events table in order to conduct evaluations 
or assessments required to protect the wellbeing of the patient. This Schedule of Events will be 
followed for the entire study. 
 
 


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Table 1: Schedule of Events 
Protocol Activities 
Screening 
On Treatment Period 
Post-Treatment Period 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
EOT  
(Day 43) 
30 days post 
EOT 
Visit Window 
(-90 days) 
 
(± 2 days) 
(± 2 days) 
(± 3 days) 
(± 3 days) 
(± 3 days) 
(+7 days) 
(± 7 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Baseline 
Characteristics1 
X 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Clinical Assessments 
Vital Signs2 
X 
X 
 
 
 
 
 
X 
 
Physical Exam 
X 
X 
 
 
 
 
 
X 
 
ECOG Score3 
X 
X 
 
 
 
 
 
 
 
NCCN Risk 
Stratification4 
X 
 
 
 
 
 
 
 
 
Charlson 
Comorbidity Index5 
X 
 
 
 
 
 
 
 
 
Phone Call6 
 
 
X 
X 
X 
X 
X 
 
X 
Adverse events  
 
X 
Concomitant 
Medications  
 
X 
 


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Protocol Activities 
Screening 
On Treatment Period 
Post-Treatment Period 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
EOT  
(Day 43) 
30 days post 
EOT 
Visit Window 
(-90 days) 
 
(± 2 days) 
(± 2 days) 
(± 3 days) 
(± 3 days) 
(± 3 days) 
(+7 days) 
(± 7 days) 
Laboratory Studies 
Hematology7 
X 
 
 
 
 
 
 
 
 
Chemistry8 
X 
 
 
 
 
 
 
 
 
Testosterone 
X 
 
 
 
 
 
 
X 
 
Inflammatory 
marker9 
X 
 
 
 
 
 
 
X 
 
Subject Materials  
Patient 
questionnaires10 
X 
 
 
 
 
 
 
X 
 
Q-Urol/Placebo 
dosing diary11 
 
X 
 
 
 
 
 
X 
 
Pain management 
diary12 
 
X 
 
 
 
 
 
X 
 
Study Therapy 
Q-Urol/Placebo13 
 
X 
 
Brachytherapy 
 
X 
 
 
 
 
 
 
 
1 Appendix 9. 
2 Vital signs to include weight and height (height will be measured at screening only), blood pressure, pulse rate and temperature. 
3 Appendix 11. 
                                                 


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4 Appendix 8. NCCN Risk Stratification may be taken from the initial consultation note where brachytherapy was recommended. 
5 Appendix 10. 
6 An appropriately trained and delegated study team member will contact subjects on treatment weekly to assess adverse event and concomitant 
medication information, to answer subject questions, and to ensure compliance with study medication and procedures. 30 days after the last dose 
of study drug, a study team member will contact subjects to assess adverse event information. 
7 CBC with differential and platelets. 
8 Complete Metabolic Panel including: Sodium, Potassium, Chloride, Carbon Dioxide, Alkaline Phosphatase, Aspartate Aminotransferase, 
Alanine Aminotransferase, Urea Nitrogen, Glucose, Creatinine, Calcium, Protein, Albumin, Bilirubin, Anion Gap. 
9 Inflammatory markers include: erythrocyte sedimentation rate, C-reactive protein, prostate‐specific antigen (PSA) 
10 Questionnaires include: National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), The Expanded Prostate Cancer Index 
Composite (EPIC), The International Prostate Symptom Score (I-PSS), Rectal Function Assessment Score (R-FAS),  The Sexual Health Inventory 
for Men (SHIM) Questionnaire. 
11 A Q-Urol/Placebo dosing diary will be dispensed on the day of brachytherapy and returned completed at the EOT visit (Appendix 6). 
12 Patients will be asked to maintain a diary of the daily use of medications taken for prostate pain for 28 days post-brachytherapy (Appendix 7). 
13 Q-Urol/Placebo will begin after brachytherapy placement. 


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10 STUDY PROCEDURES 
10.1 Screening 
For screening procedures see the Schedule of Events and the Assessments Section. 
Screening activities may only begin after a subject has signed consent. All screening 
activities must take place within 90 days prior to brachytherapy unless otherwise noted. 
10.2 Treatment Period  
Once a subject has completed screening, has been found to be eligible, and has been 
registered, treatment procedures may begin. On the same day, but after brachytherapy, 
patients will begin Q-Urol or placebo. Patients on treatment will be contacted weekly by a 
trained and delegated study member to assess adverse events, concomitant medications, and 
to answer questions to ensure protocol adherence. See the Schedule of Events and the 
Assessments Section for treatment period procedures.  
10.3 End of Treatment 
An End of Treatment visit will occur six weeks after brachytherapy. At this visit, the patient 
will discontinue Q-Urol, return any remaining medication, the pain medication diary, and 
the dosing diary for medication reconciliation. For End of Treatment procedures the 
Schedule of Events and the Assessments Section. 
11 
STUDY ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to perform 
the test. In these cases, the Investigator will take all steps necessary to ensure the safety and well-
being of the patient. When a protocol-required test cannot be performed, the Investigator will 
document the reason for this and any corrective and preventive actions that he or she has taken to 
ensure that normal processes are adhered to as soon as possible. 
11.1 Physical Examinations and Vital Signs 
Patients will have physical examinations to include major body systems, vital signs, 
assessment of ECOG performance status (see Appendix 1), weight and height (height will 
be measured at screening only) at the time points described in the Schedule of Events. If 
necessary to facilitate scheduling, the physical exam may occur one day prior to study 
treatment.  
Vital signs, including blood pressure, pulse rate, and temperature will be also recorded at the 
time points described in the Schedule of Events.   
11.2 
Baseline Characteristics 
The following baseline characteristics will be collected from patients at screening (see also 
Appendix 9): 


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• Does the patient have a history of Coronary Artery Disease? 
• Has the patient had bacterial prostatitis that went away with antibiotics? 
• Does the patient have any family history of prostatitis? 
• Alcohol history (never used alcohol, current alcohol user, former alcohol user) 
• Smoking history (never smoked, current smoker, former smoker) 
• Pack years (average number of packs per day and number of years smoked) 
• Current employment status (employed, retired, student, unknown, other) 
• Insurance status (private insurance, Medicare, Medicaid, VA, military, not 
insured, self-pay, unknown, other) 
• Prostate volume  
• Post-void residual urine volume if available 
• Prior use of alpha-blockers for symptoms 
• The extent of prostate cancer, including location of the cancer relative to the 
prostate gland capsule 
11.3 Adverse Events 
Adverse events experienced during trial participation will be collected per the Schedule of 
Events and Adverse Events Section. Each study participant will be questioned about the 
occurrence of adverse events in a non-leading manner. Should the treating investigator feel 
that the adverse event is attributed to study therapy, then dose modification guidelines in the 
Dose Modification Section will be followed.  
11.4 Laboratory Assessments 
Samples for all laboratory assessments will be drawn at the time points indicated in the 
Study Calendar and when clinically indicated. All safety laboratory analyses will be 
performed by the local laboratory. All safety laboratory assessments must be reviewed by 
the treating investigator prior to study drug administration.  
Table 2: Laboratory Assessments 
Laboratory Assessments 
CBC with Platelet Count and Differential 
• 
White Blood Cell Count 
• 
Hemoglobin 
• 
Platelets 
• 
Absolute Neutrophil Count 
• 
Absolute Lymphocytes 
Complete Metabolic Panel (Chemistry) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Carbon Dioxide 
• 
Alkaline Phosphatase 


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• 
Aspartate Aminotransferase 
• 
Alanine Aminotransferase 
• 
Urea Nitrogen 
• 
Glucose 
• 
Creatinine 
• 
Calcium 
• 
Protein 
• 
Albumin 
• 
Bilirubin 
Endocrine 
• 
Testosterone 
Inflammatory Markers 
• 
Erythrocyte sedimentation rate 
• 
C-reactive protein 
• 
Prostate-specific antigen (PSA) 
11.5 Questionnaire administration 
All questionnaires will be completed in the clinic by the patient prior to starting study 
therapy and after completing six weeks of daily Q-Urol/Placebo therapy.  
11.6 Dosing and Pain Diary  
Patients will be required to keep a diary of the Q-Urol/Placebo doses taken during the study. 
If a dose is missed or omitted, comments should be added to indicate why the dose was not 
taken.  
Patients will also be required to keep a diary of any medications used for pain management 
for 28 days after brachytherapy placement. On the diary, subjects will be asked to indicate 
yes/no if they took any medications for the management of prostate-related pain during the 
day. They will be asked to record this information daily for 28 days post-brachytherapy.  
12 CRITERIA FOR EVALUATION AND ENDPOINT 
12.1 Safety 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical laboratory 
test results. More frequent safety evaluations may be performed if clinically indicated or at 
the discretion of the investigator.  
12.2 Efficacy 
The primary outcome variable is the peak score of the National Institutes of Health‐Chronic 
Prostatitis Symptom Index (NIH‐CPSI) total score measured from baseline to six weeks post 
brachytherapy. Efficacy will be determined by the mean difference in outcome variable 
between the treatment and control groups. 
 


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12.3 Population for analyses 
 Evaluable for toxicity 
Subjects who have received one dose of Q-Urol will be evaluable for toxicity. 
 Evaluable for response 
A modified intent-to-treat data set will be used to assess efficacy. Subjects who have 
successfully undergone brachytherapy and received one dose of Q-Urol will be 
evaluable for response. Subjects who fail to undergo brachytherapy or begin Q-Urol 
therapy will be replaced. Those who do not complete the end of treatment patient 
questionnaires will be considered treatment failures.  
12.4 Safety stopping rules 
A 5% rate of grade ≥ 3 SAEs attributed as definitely or probably related to study drug is 
considered acceptable, and a 15% rate of grade ≥ 3 SAEs attributed as definitely or probably 
related to study drug is excessive. Excessive toxicity will be evaluated at 10, 21, 30, 40, 50, 
60, and 70 patients. Toxicity will be declared excessive if the number of patients with an 
SAE exceeds 2/10, 3/21, 3/30, 4/40, 5/50, 6/60, or 6/70. The stopping boundary was 
calculated using the “toxbdry” function in the R package “clinfun”.  
Table 3: Operating Characteristics 
Operating Characteristics of Strategy  
True Probability of 
SAE 
Probability the 
Boundary Will Be 
Crossed at Any Time 
Probability the Trial 
Will Stop Before the 
End 
Average Sample Size 
5% 
10.9% 
9.1% 
66.4 
7% 
29.4% 
24.0% 
60.9 
9% 
52.0% 
43.3% 
53.5 
11% 
71.8% 
62.2% 
45.6 
13% 
85.5% 
77.3% 
38.5 
15% 
93.4% 
87.6% 
32.6 
13 STATISTICAL CONSIDERATIONS 
13.1 Statistical hypothesis 
The primary outcome variable is the peak score of the National Institutes of Health‐Chronic 
Prostatitis Symptom Index (NIH‐CPSI) total score measured from baseline to six weeks post 
brachytherapy. The primary hypothesis is that the mean of the primary outcome variable 
will be ½ standard deviation lower in patients taking Q-Urol compared to placebo. 


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13.2 Statistical Analyses 
 Sample size determination 
The outcome for sample size determination is the primary endpoint variable, the peak 
of the National Institutes of Health‐Chronic Prostatitis Symptom Index (NIH‐CPSI) 
total score measured from baseline to six weeks post brachytherapy. The primary 
hypothesis is that the mean of the primary outcome variable will be ½ standard 
deviation lower in patients taking Q-Urol compared to placebo.  A single interim 
analysis is planned after N1= 21 subjects per group have outcome data. The interim 
and final analysis will compare the treatment and control means using nominal t 
statistics (control minus treatment). If the t statistic has a value less than -1.16 at the 
interim analysis the trial will be terminated for futility. If the t statistic has a value 
greater than 2.85 at the interim analysis the trial will be terminated for efficacy.   
If the study is not terminated for efficacy or futility at the interim analysis an 
additional N2 = 49 patients per group will be accrued for a total of N = 70 patients per 
group. If the interim analysis is done at the planned sample size (21 patients per 
group) the treatment will be deemed efficacious at the final analysis if the t statistic 
has a nominal value greater than 1.67.  
The above design was evaluated using 100,000 simulated data sets for both the null 
and alternative hypotheses.  There is 90% power at overall one-sided Type I error 
equal to 0.05 (one-sided) to detect a 0.5 standard deviation lower mean of the primary 
endpoint in the treatment group compared to the control group. The probability of 
early termination for futility under the null hypothesis is 12%. The probability of early 
termination for futility under the alternative hypothesis is 0.3%. The probability of 
early termination for efficacy under the alternative hypothesis is 12%.  
If the interim analysis or final analysis is performed at a sample size that is different 
than the planned sample size the final analysis will be adjusted to maintain an overall 
Type I error of no more than 0.05 (one-sided). 
 Primary endpoint  
There are two planned analyses of the primary endpoint variable: an interim analysis 
at N1 = 21 patients per group and a final analysis at N = 70 patients per group. Two 
sample t- statistics will be calculated and evaluated as described in 13.2.1.  
Multiple imputation will be used to replace missing end of treatment values of the 
National Institutes of Health‐Chronic Prostatitis Symptom Index (NIH‐CPSI) total 
score. A sensitivity analysis will replace missing values by the largest (i.e. worst) 
observed value.  
In addition to formal testing for a difference between groups, the mean change 
between groups and the mean change within each group together will be reported 
together with 95% confidence intervals. 


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 Secondary endpoint 
1.  Patient questionnaires administered pre- and post-study therapy: The 
Expanded Prostate Cancer Index Composite (EPIC), The International Prostate 
Symptom Score (I-PSS), The Rectal Function Assessment Score (R-FAS), and 
the Sexual Health Inventory for Men (SHIM). The change in questionnaire 
scores will be compared between groups using two-sample t-tests. If normality 
assumptions are violated, non-parametric Wilcoxon tests may be used. 
Confidence intervals for the mean change between and within groups will also 
be reported.  
2. Inflammation markers pre and post brachytherapy: erythrocyte sedimentation 
rate, C-reactive protein, and prostate-specific antigen (PSA). The change in 
inflammatory markers will be compared between groups using two-sample t-
tests. If normality assumptions are violated, non-parametric Wilcoxon tests 
may be used. Confidence intervals for the mean change between and within 
groups will also be reported. For laboratory markers that are known to be 
positivity skewed, such as CRP, the analyses will be based on the log-
transformed values. 
3. The frequency of adverse events (AEs) will be collected and characterized by 
type, severity (as defined by CTCAE, version 5.0), seriousness, duration, and 
relationship to study treatment. Counts and proportions of patients with 
adverse events will be tabulated and exact 95% binomial confidence intervals 
will be reported.  
4. The number of days during the 28 days post-brachytherapy that any medication 
is taken for the treatment of prostate-related pain will be summarized using the 
mean, median and interquartile range. A Wilcoxon test will be used to compare 
the arms.  
 Exploratory Analyses 
For the analyses involving score changes, the investigators will use ANCOVA in place 
of 2-sample t-tests, which has been found to be robust to violation of modeling 
assumptions. 
14 REGISTRATION GUIDELINES 
Study-related screening procedures can only begin once the patient has signed a consent form.  
Patients must meet all of the eligibility requirements listed in Section 5 prior to registration.  
Patients must be registered before receiving any study treatment and must begin treatment as 
soon as logistically possible after registration.  
To register eligible patients on study, complete a Clinical Trials Office Patient Registration Form and 
submit to CTORegistrations@hci.utah.edu. 


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15 DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each patient that provides 
a record of the data generated according to the protocol. CRF’s should be created prior to the study 
being initiated and updated (if applicable) when amendments to the protocol are IRB approved. 
These forms will be completed on an on-going basis during the study. The medical records will be a 
source of verification of the data. During the study, the CRFs will be monitored for completeness, 
accuracy, legibility and attention to detail by a member of the Research Compliance Office. The 
CRFs will be completed by the Investigator or a member of the study team as listed on the 
Delegation of Duties Log. The data will be reviewed no less than annually by the Data and Safety 
Monitoring Committee. The Investigator will allow the Data and Safety Monitoring Committee or 
Research Compliance Office personnel access to the patient source documents, clinical supplies 
dispensing and storage area, and study documentation for the above-mentioned purpose. The 
Investigator further agrees to assist the site visitors in their activities. 
Data capture should be restricted to endpoints and relevant patient information required for 
planned manuscripts. 
16 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 Human Subject Protections  
The study will be conducted in accordance with the appropriate FDA, IRB, ICH GCP, and 
other federal and local regulatory requirements, as applicable. Informed consent will be 
obtained from all research participants prior to performing any study procedures using the 
most recent IRB-approved version. All patients must be at least 18 years of age to 
participate. 
16.2 Institutional Review 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials (e.g., 
advertisements), and any other applicable patient-facing documents. The investigator should 
also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information. 
The investigator or designee should provide the IRB/IEC with reports, updates, and other 
information (e.g., expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures.  
16.3 Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman Cancer 
Institute (HCI) to ensure the well-being of patients enrolled on Investigator Initiated Trials 
that do not have an outside monitoring review. The roles and responsibilities of the DSMC 
are set forth in the NCI-approved Data and Safety Monitoring (DSM) plan. The activities of 
the committee include reviewing adverse events (including SAEs), deviations, important 
medical events, significant revisions or amendments to the protocol, and approving 
cohort/dose escalations. If the DSMC and/or the PI have concerns about unexpected safety 
issues or rising AE trends, the study will be stopped and an unplanned safety data analysis 


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may take place. Enrollment will not resume until the issues are resolved. The DSMC also 
reviews and approves audit reports generated by the Research Compliance Office. 
This is a Phase II study holding an IND and is classified as high risk per the NCI-approved 
DSM plan.  
Each high-risk study will be assigned a physician member of the DSMC as a medical 
monitor, or in rare cases, an external medical monitor. The medical monitor will be notified 
of all serious adverse events (SAEs). All serious adverse events (SAEs) occurring in patients 
treated at HCI or its affiliates will also be reviewed by the full DSMC monthly.  
Each high-risk study will also be assigned a dedicated research compliance officer who will 
monitor the trial. High-risk studies will be monitored by RCO personnel after the first 
patient is enrolled and every three months thereafter during active enrollment. The RCO 
monitor will review the study status and summarize enrollment, toxicities, SAEs, dose-
escalation, statistical endpoints (e.g., stopping rules), deviations, etc. for the full DSMC 
membership at the regularly scheduled meetings. Amendments that increase risk, change 
dosing, or impact study objectives will be reviewed by the DSMC and approved by the 
PRMC and IRB. High-risk trials will be formally reviewed by the DSMC after the first 
patient is enrolled and then quarterly thereafter. 
An initial audit of high-risk studies will be conducted by the RCO approximately one year 
after enrollment begins and annually thereafter. Audits of high-risk studies may be 
conducted more frequently as requested by the DSMC, IRB, PRMC, RCO management, or 
the PI.  
16.4 Adverse Events and Serious Adverse Events  
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for AE and SAE reporting.  
 Adverse Events (AEs) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not 
considered to be related to the study drug. For the purposes of this study, the terms 
toxicity and adverse event are used interchangeably. Medical conditions/diseases 
present before starting study drug are only considered adverse events if they worsen 
after starting the study drug. Abnormal laboratory values or test results constitute 
adverse events only if they induce clinical signs or symptoms, are considered 
clinically significant, or require therapy. 
The collection of adverse events will begin after the study drug has been started and 
end 30 days after the last dose study drug (or until new cancer treatment is initiated).  
Information about all adverse events, 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. 
 The adverse event should be evaluated to determine: 
1. The severity grade based on CTCAE v5.0 (grade 1-5) 


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2. Its relationship to the study drug, brachytherapy, and ADT (definite, probable, 
possible, unlikely, not related) 
3. Its duration (start and end dates or if continuing at the final exam) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse event; 
concomitant medication taken; non-drug therapy given; 
hospitalization/prolonged hospitalization) 
5. Whether it constitutes an SAE 
All adverse events will be treated appropriately. Such treatment may include changes 
in study drug treatment as listed in the dose modification section of this protocol (see 
section 8 for guidance). Once an adverse event is detected, it should be followed until 
its resolution, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about Q-Urol is described in 
the Drug Information (Section 3). This information will be included in the patient 
informed consent and will be discussed with the patient during the study as needed. 
All adverse events will be immediately recorded in the patient research chart.  
 Abnormal Test Findings 
Abnormal test finding, such as incidental image findings, should only be listed as an 
adverse event if it meets the following criteria: 
• Is associated with accompanying symptoms; and/or 
• Requires additional testing or intervention; and/or 
• Leads to changes in study therapy dosing; and/or 
• Leads to the addition or change of a concomitant medication or therapy; and/or 
• Is considered an adverse event by the treating investigator. 
An abnormal test considered to be an error should not be listed as an adverse event. 
Repeating a test due to an abnormal result in the absence of any of the criteria above 
does not require listing as an adverse event.  
 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded. A serious 
adverse event is an undesirable sign, symptom, or medical condition which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes 
listed above 


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• Causes congenital anomaly or birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition (procedures such as central line 
placements, paracentesis, pain control) 
o Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the start 
of the study drug 
o Treatment on an emergency outpatient basis for an event not fulfilling any 
of the definitions of an SAE given above and not resulting in hospital 
admission 
o Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
Collection of serious adverse events will begin with the initiation of Q-Urol and end 
30 days after the last dose study drug or upon initiation of new cancer treatment, 
whichever happens the soonest. 
Any death occurring after the SAE following-up period that is felt to be related to 
study therapy will be reported according to SAE reporting guidelines.  
Toxicities that fall within the definitions listed above must be reported as an SAE 
regardless if they are felt to be treatment-related or not. Toxicities unrelated to 
treatment that do NOT fall within the definitions above must simply be documented as 
AEs in the patient research chart.  
16.5 SAE Reporting Requirements 
All serious adverse events should be reported as soon as possible but no later than one 
business day after the Investigator becomes aware. All SAEs must be reported via the HCI 
CTMS (OnCore) and submitted to HCI-RCO@utah.edu and Farr Laboratories. The HCI 
Clinical Site Monitor will in turn, submit the report to the Medical Monitor. The RCO will 
summarize and present all reported SAEs according to the Data and Safety Monitoring Plan 
at the monthly DSMC meeting. 
At a minimum, initial SAE reports must include a description of the event, assessment of 
event causality, event grade, and the expectedness of the event. Although the Investigator 
may not know all the information at the time of the event, the available information should 
be reported. An SAE follow-up may be submitted at a later date once more information is 
known. It is required that follow-up reports be submitted until the SAE is resolved. 
Follow-Up Information 
It is recommended that follow-up reports be submitted as new information becomes 
available, however, a follow-up report should be submitted within 3 days of knowledge of 
event resolution. Follow-up information will be added to the SAE in OnCore and submitted 
to the DSMC via RCO. 


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 FDA Notifications 
Per 21 CRF 312.32 adverse events and serious adverse events will be reported on a 
MedWatch 3500A form to the FDA. Reportable events will be reported by the RCO 
according to the following guidelines: 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate participant demographic (Section A) and suspect 
medication information (Section C & D), the report should include the following 
information within the Event Description (Section B.5) of the MedWatch 3500A form: 
• 
Protocol number and title description 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics (Section B.6) 
• 
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
• 
Expectedness of the event (i.e., expected or unexpected event). 
FDA Reporting Timelines: 
• 
7 Calendar Day Report: 
Any event that is fatal or life-threatening, unexpected, and definitely, probably or 
possibly related to study medication will be reported to the FDA by telephone or fax 
within seven calendar days of first learning of the event. 
• 
15 Calendar Day Report: 
Any event that is serious, unexpected, and definitely, probably or possibly related to 
study medication will be reported to the FDA in an IND safety report within 15 calendar 
days of first learning of the event. 
In accordance with 21 CFR 312.32, an Analysis of Similar Events should be included in 
the IND Safety Report. All safety reports previously filed by the investigator with the 
IND concerning similar events should be analyzed and the significance of the new report 
in light of the previous, similar reports commented on. 
FDA fax number for IND Safety Reports: 
1 (800) FDA 0178 
 IRB Notification 
The University of Utah IRB requires any unanticipated problems that may increase the 
risk to research participants be promptly reported. All study-therapy related, unexpected 
adverse events whose nature, severity, or frequency is not consistent with either: 
• 
The unknown or foreseeable risk of adverse events that are described in the protocol 
related-documents, such as the IRB-approved research protocol, applicable 
investigator brochure, the current IRB-approved informed consent document, and/or 
other relevant sources of information, such as product labeling and package inserts; or 


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• 
The expected natural progression of any underlying disease or condition of the 
participant(s) experiencing the adverse event. 
Adverse events meeting this criterion must be promptly reported to the IRB within 10 
business days of awareness. 
16.6 Reporting of Pregnancy  
Although pregnancy is not considered an adverse event, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject, including 
the pregnancy of a male subjects’ female partner as an SAE. Pregnancies or lactation that 
occurs during the course of the trial or with 5 days of completing the trial or starting another 
new anticancer therapy, whichever is earlier, must be reported to the DSMC, IRB, FDA, and 
the sponsor as applicable. All subjects and female partners who become pregnant must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, fetal death, intrauterine death, miscarriage, and 
stillbirth must be reported as serious events.  
16.7 Protocol Amendments 
Any amendments or administrative changes to an IRB approved protocol will not be 
initiated without submission and approval from the IRB of record.   
These requirements for approval will in no way prevent any immediate action from 
being taken by the investigator in the interests of preserving the safety of all subjects 
included in the trial.  
Any amendments to the protocol that significantly affect the safety of subjects, the 
scope of the investigation, or the scientific quality of the study are required to submit 
the amendment for FDA review. 
16.8 Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and 
treatment plans as outlined in the protocol version submitted and previously approved by the 
IRB. Protocol deviations have the potential to place participants at risk and can also 
undermine the scientific integrity of the study thus jeopardizing the justification for the 
research. Protocol deviations are unplanned and unintentional events.  
Because some protocol deviations pose no conceivable threat to participant safety or 
scientific integrity, reporting is left to the discretion of the PI within the context of the 
guidelines below. The sponsor requires the prompt reporting to HCI RCO of protocol 
deviations which are: 
• 
Exceptions to eligibility criteria. 
• 
Intended to eliminate an apparent immediate hazard to a research participant or  
• 
Harmful (caused harm to participants or others, or place them at increased risk 
of harm - including physical, psychological, economic, or social harm), or  
• 
Possible serious or continued noncompliance  


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16.9 FDA Annual Reporting  
An annual progress report will be submitted to the FDA within 60 days of the anniversary of 
the date that the IND went into effect. (21 CFR 312.33).  
16.10 Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical Trials 
Reporting Program) by the Clinical Trials Office. 
16.11 Record Keeping 
Per 21 CFR 312.57, the Investigator records shall be maintained for a period of 2 years 
following the date a marketing application is approved; or, if no application is filed or the 
application is not approved, until 2 years after the investigation is discontinued and the FDA 
is notified. 
 


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1. 
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2. 
Balavoine GGA, Geletii YV. Peroxynitrite Scavenging by Different Antioxidants. Part I: Convenient Assay. Nitric 
Oxide. 1999;3(1):40-54. 
3. 
Terao J. Dietary Flavonoids as Antioxidants. 2009;61:87-94. 
4. 
Bobe G, Albert PS, Sansbury LB, Lanza E, Schatzkin A, Colburn NH, et al. Interleukin-6 as a Potential Indicator for 
Prevention of High-Risk Adenoma Recurrence by Dietary Flavonols in the Polyp Prevention Trial. Cancer Prevention Research. 
2010;3(6):764. 
5. 
Chuang C-C, Martinez K, Xie G, Kennedy A, Bumrungpert A, Overman A, et al. Quercetin is equally or more effective 
than resveratrol in attenuating tumor necrosis factor-α–mediated inflammation and insulin resistance in primary human 
adipocytes. The American Journal of Clinical Nutrition. 2010;92(6):1511-21. 
6. 
Huang R-Y, Yu Y-L, Cheng W-C, OuYang C-N, Fu E, Chu C-L. Immunosuppressive Effect of Quercetin on Dendritic 
Cell Activation and Function. The Journal of Immunology. 2010;184(12):6815. 
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Lee S, Kim YJ, Kwon S, Lee Y, Choi SY, Park J, et al. Inhibitory effects of flavonoids on TNF-alpha-induced IL-8 
gene expression in HEK 293 cells. BMB reports. 2009;42(5):265-70. 
8. 
Valério DA, Georgetti SR, Magro DA, Casagrande R, Cunha TM, Vicentini FTMC, et al. Quercetin Reduces 
Inflammatory Pain: Inhibition of Oxidative Stress and Cytokine Production. Journal of Natural Products. 2009;72(11):1975-9. 
9. 
Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis: a preliminary 
prospective, double-blind, placebo-controlled trial. Urology. 1999;54(6):960-3. 
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Shahed AR, Shoskes DA. Oxidative stress in prostatic fluid of patients with chronic pelvic pain syndrome: correlation 
with gram positive bacterial growth and treatment response. Journal of andrology. 2000;21(5):669-75. 
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Shoskes DA, Nickel JC. Quercetin for chronic prostatitis/chronic pelvic pain syndrome. The Urologic clinics of North 
America. 2011;38(3):279-84. 
12. 
Yasueda A, Urushima H, Ito T. Efficacy and Interaction of Antioxidant Supplements as Adjuvant Therapy in Cancer 
Treatment. Integrative Cancer Therapies. 2016;15(1):17-39. 
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Barocas DA, Alvarez J, Resnick MJ, et al. Association between radiation therapy, surgery, or observation for localized 
prostate cancer and patient-reported outcomes after 3 years. JAMA. 2017;317(11):1126-40. 
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Chen RC, Basak R, Meyer A, et al. Association between choice of radical prostatectomy, external beam radiotherapy, 
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Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable 
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Norman GR, Sloan JA, Wyrwich KW. The truly remarkable universality of half a standard deviation: confirmation 
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Lane A, Metcalfe C, Young GJ, Peters TJ, Blazeby J, Avery KNL, et al. Patient-reported outcomes in the ProtecT 
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Chen RC, Clark JA, Talcott JA. Individualizing Quality-of-Life Outcomes Reporting: How Localized Prostate Cancer 
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Oncology. 2009;27(24):3916-22. 
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Barocas DA, Alvarez J, Resnick MJ, Koyama T, Hoffman KE, Tyson MD, et al. Association Between Radiation 
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MacDonald R, Ishani A, Rutks I, Wilt TJ. A systematic review of Cernilton for the treatment of benign prostatic 
hyperplasia. BJU International. 2000;85(7):836-41. 
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Cai T, Verze P, La Rocca R, Anceschi U, De Nunzio C, Mirone V. The role of flower pollen extract in managing 
patients affected by chronic prostatitis/chronic pelvic pain syndrome: a comprehensive analysis of all published clinical trials. 
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Guo R, Cantery PH, Ernst E. Herbal Medicines for the Treatment of Rhinosinusitis: A Systematic Review. 
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Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain treatment decreases neutrophil migration to sites of 
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Bhui K, Prasad S, George J, Shukla Y. Bromelain inhibits COX-2 expression by blocking the activation of MAPK 
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Turnbull CJaBW, editor. Group Sequential Methods with Applications to Clinical Trials. 1 ed. Boca Raton: Chapman 
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Appendix 1: National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) 
Pain or Discomfort 
1. In the last week, have you experienced any pain or discomfort in the following areas? 
 
Area between rectum and testicles (perineum) 
 Yes 
 No 
 
Testicles 
 Yes 
 No 
 
Tip of the penis (not related to urination) 
 Yes 
 No 
 
Below your waist, in your pubic or bladder area 
 Yes 
 No 
2. In the last week, have you experienced: 
 
Pain or burning during urination? 
 Yes 
 No 
 
Pain or discomfort during or after sexual climax (ejaculation)? 
 Yes 
 No 
3. How often have you had pain or discomfort in any of these areas over the last week? 
0. Never 
1. Rarely 
2. Sometimes 
3. Often  
4. Usually 
5. Always 
4.  Which number best describes your AVERAGE pain or discomfort on the days that 
you had it over the last week? 
No Pain –   0       1       2       3       4       5       6       7       8       9       10   – 
Pain as 
bad as 
you can 
imagine 
Subject ID: 
 
 
Subject Initials: 
Date: 


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Urination 
5. How often have you had a sensation of not emptying your bladder completely after you 
finished urinating during the last week? 
0. Not at all 
1. Less than 1 time in 5 
2. Less than half the time 
3. About half the time 
4. More than half the time 
5. Almost always 
6. How often have you had to urinate again less than 2 hours after you finished urinating, 
over the last week? 
0. Not at all 
1. Less than 1 time in 5 
2. Less than half the time 
3. About half the time 
4. More than half the time 
5. Almost always 
Impact of Symptoms 
7. How much have your symptoms kept you from doing the kinds of things you would 
usually do, over the last week? 
0. None 
1. Only a little 
2. Some 
3. A lot 
8. How much did you think about your symptoms during the last week? 
0. None 
1. Only a little 
2. Some 
3. A lot 
Quality of Life 
9. If you were to spend the rest of your life with your symptoms just the way they have 
been during the last week, how would you feel about that? 
0. Delighted 
1. Pleased 
2. Mostly satisfied 
3. Mixed (about equally 
satisfied and 
dissatisfied) 
4. Mostly dissatisfied 
5. Unhappy 
6. Terrible 
 
 
 
____________________________________________ 
 
 
__________________ 
Patient Signature 
 
 
 
 
 
 
 
Date 
Subject ID: 
 
 
Subject Initials: 
Date: 


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For research team member use: 
Scoring 
Pain (total from questions 1, 2, 3 and 4; Yes = 1, No = 0) 
 
Urinary Symptoms (total of items 5 and 6) 
 
Quality of life impact (total of items 7, 8, 9) 
 
Pain and urinary score (total of items 1 through 6) 
 
Total Score: 
 
 
 
 
____________________________________________ 
 
 
__________________ 
Research Team Member Signature 
 
 
 
 
 
Date 
 
 
Subject ID: 
 
 
Subject Initials: 
Date: 


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Appendix 2: The Expanded Prostate Cancer Index Composite (EPIC) 
 
 
 
EPIC  
The Expanded Prostate Cancer Index Composite 
 
 
This questionnaire is designed to measure Quality of Life issues in patients with Prostate cancer. 
To help us get the most accurate measurement, it is important that you answer all questions 
honestly and completely.  
Remember, as with all medical records, information contained within this survey will remain 
strictly confidential.  
 
Date survey completed): Month ___________ Day ___________ Year___________ 
 
Subject number: _________________________________________________  
 
Subject initials: _______________________ 
 
 


Short Title: Q-Urol 
Version Date: 11APR2023 
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Subject ID: 
 
 
Subject Initials: 
Date: 


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Subject ID: 
 
 
Subject Initials: 
Date: 


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Subject ID: 
 
 
Subject Initials: 
Date: 


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Subject ID: 
 
 
Subject Initials: 
Date: 


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Subject ID: 
 
 
Subject Initials: 
Date: 


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Subject ID: 
 
 
Subject Initials: 
Date: 


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Subject ID: 
 
 
Subject Initials: 
Date: 


Short Title: Q-Urol 
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_____________________________________ 
 
 
 
________________ 
Patient Signature  
 
 
 
 
 
 
 
Date 
 
 
Subject ID: 
 
 
Subject Initials: 
Date: 


Short Title: Q-Urol 
Version Date: 11APR2023 
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Appendix 3: The International Prostate Symptom Score (I-PSS) 
 
Not at 
all 
Less 
than 1 
time in 5 
Less than 
half the 
time 
About 
half the 
time 
More 
than half 
the time 
Almost 
always 
Your 
Score 
1. Incomplete emptying – It does 
not feel like I empty my bladder all the 
way 
0 
1 
2 
3 
4 
5 
 
2. Frequency – I have to go again less 
than two hours after I finish urinating. 
0 
1 
2 
3 
4 
5 
 
3. Intermittency – I stop and start 
again several times when I urinate. 
0 
1 
2 
3 
4 
5 
 
4. Urgency – It is hard to wait when I 
have to urinate. 
0 
1 
2 
3 
4 
5 
 
5. Weak stream – I have a weak 
urinary stream. 
0 
1 
2 
3 
4 
5 
 
6. Straining – I have to push or strain 
to begin urination 
0 
1 
2 
3 
4 
5 
 
 
None 
1 time 
2 times 
3 times 
4 times 
5 times 
or more 
 
7. Nocturia – I get up to urinate after I 
go to bed until the time I get up in the 
morning. 
 
 
 
 
 
 
 
Which of the above do you regard as the most troublesome (1-7)?  
Total Score  
(to be completed by the research team) 
 
 
 
Quality of life due to urinary symptoms  
If you were to spend the rest of your life with your urinary condition just the way it is now, how 
would you feel about that? (Pick one) 
0. Delighted 
1. Pleased 
2. Mostly Satisfied 
3. Mixed – satisfied and 
dissatisfied 
4. Mostly dissatisfied 
5. Unhappy 
6. Terrible 
 
 
____________________________________________ 
 
 
__________________ 
Patient Signature 
 
 
 
 
 
 
 
Date 
 
 
 
Subject ID: 
 
 
Subject Initials: 
Date: 


Short Title: Q-Urol 
Version Date: 11APR2023 
Page 58 of 69 
 
American Urological Association Symptom (AUA) Score 
Mild = 0-7 
Moderate = 8-19 
Severe = 20-35 
 
 
 
____________________________________________ 
 
 
__________________ 
Research Team Member Signature 
 
 
 
 
 
Date 
 
 
Subject ID: 
 
 
Subject Initials: 
Date: 


Short Title: Q-Urol 
Version Date: 11APR2023 
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Appendix 4: Rectal Function Assessment Score  (R-FAS)
1. Frequency of stools per day: 
 0-1 stool per day 
 2 stools per day 
 3 stools per day 
 4 or more stools per day 
2. Consistency of stools: 
 All stools formed 
 Stools Formed and loose 
  Stools loose  
 Watery stools 
3. Urgency of stools: 
 No urgency 
 Somewhat urgent 
 Urgent  
 Very urgent 
4. Abdominal discomfort: 
 No discomfort 
 Mild to moderate discomfort 
 Somewhat severe discomfort 
 Very severe discomfort 
5. Hemorrhoid discomfort: 
 No discomfort 
 Required mild treatments (i.e. tucks, sitz baths) 
 Requires topical medication (i.e.Prep H, etc.) 
 Requires oral analgesics or narcotics for relief 
6. Rectal bleeding 
 No rectal bleeding 
 Blood on toilet paper: 1 time per week 
 2-3 times per week  
 ≥ 4 times per week 
7. Continence: 
 Normal continence; able to control stool movement at all times 
 Gas incontinence only; able to control stool movements but not gas 
 Minor spotting or leakage of stool (up to coin size) about once per week 
 Minor spotting or leakage of stool (up to coin sixe) more than once per week 
Subject ID: 
 
 
Subject Initials: 
Date: 


Short Title: Q-Urol 
Version Date: 11APR2023 
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 Significant leakage of stool (larger than coin size about once per week)  
 Significant leakage of stool (larger than coin size more than once per week 
8. Nighttime bowel movements (total number of nights in last week that you had to get up 
from bed to have a bowel movement): 
 0 
 
 
 
 1 
 2 
 3 
 4 
 More than 
9. Completeness of evacuation: 
 Complete evacuation (requires one movement to completely empty bowel or feel you’re 
“all done”) 
 Occasional multiple evacuations (about once a week feel like you’re not “all done” or it 
takes more than one movement to finish) 
 Frequent multiple evacuations (more than once a week feel like you’re not “all done” or 
it takes more than one movement to finish) 
 Requires enema to obtain complete emptying. 
10.  My Bowel Movements after radiation or implant are: 
 Better 
 Worse 
 Same 
 Not Applicable 
 
 
 
________________________________________________ 
  _______________________ 
Patient Signature  
 
 
 
 
 
 
   Date 
 
Subject ID: 
 
 
Subject Initials: 
Date: 


Short Title: Q-Urol 
Version Date: 11APR2023 
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Appendix 5: The Sexual Health Inventory for Men (SHIM) Questionnaire 
1. How do you rate your confidence that you could get and keep an erection? 
1. Very low 
2. Low 
3. Moderate 
4. High 
5. Very high 
2. When you had erections with sexual stimulation, how often were your erections hard 
enough for penetration (entering your partner)? 
0. No sexual activity 
1. Almost never or never 
2. A few times (much less than half the time) 
3. Sometimes (about half the time) 
4. Most times (much more than half the time) 
5. Almost always or always 
3. During sexual intercourse, how often were you able to maintain your erection after you 
had penetrated (entered) your partner? 
0. Did not attempt intercourse 
1. Almost never or never 
2. A few times (much less than half the time) 
3. Sometimes (about half the time) 
4. Most times (much more than half the time) 
5. Almost always or always 
4. During sexual intercourse, how difficult was it to maintain your erection to completion of 
intercourse? 
0. Did not attempt intercourse 
1. Extremely difficult 
2. Very difficult 
3. Difficult 
4. Slightly difficult 
5. Not difficult 
5. When you attempted sexual intercourse, how often was it satisfactory for you? 
0. Did not attempt intercourse 
1. Almost never or never 
2. A few times (much less than half the time) 
3. Sometimes (about half the time) 
4. Most times (much more than half the time) 
5. Almost always or always 
Subject ID: 
 
 
Subject Initials: 
Date: 


Short Title: Q-Urol 
Version Date: 11APR2023 
Page 62 of 69 
 
 
 
________________________________________________ 
  _______________________ 
Patient Signature  
 
 
 
 
 
 
   Date 
 
 
Total: _______________ 
 
SHIM Scores 
You may have . . . 
1-7 
Severe ED 
8-11 
Moderate ED 
12-16 
Mild to Moderate ED 
17-21 
Mild ED 
22-25 
No signs of ED 
 
 
 
________________________________________________ 
  _______________________ 
Research Team Member Signature   
 
 
 
Date  
 
 
Subject ID: 
 
 
Subject Initials: 
Date: 


Short Title: Q-Urol 
Version Date: 11APR2023 
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Appendix 6: Patient Dosing Diary 
Subject ID: __________________________  
Subject Initials:______________________ 
Week #: __________________________ 
 
Week Start Date: ____________________ 
Take two Q-Urol capsules with food twice daily at about the same time every day (± 4 hours). If 
a dose is missed or forgotten outside of the 4-hour window, it should not be made up but rather, 
the next dose should be taken at the regularly scheduled time.  
Date 
Time 
Number of 
capsules taken 
Comments 
 
: 
 
 
: 
 
 
 
: 
 
 
: 
 
 
 
: 
 
 
: 
 
 
 
: 
 
 
: 
 
 
 
: 
 
 
: 
 
 
 
: 
 
 
: 
 
 
 
: 
 
 
: 
 
 
 
: 
 
 
: 
 
 
 
: 
 
 
: 
 
 
 
: 
 
 
: 
 
 
 
 
______________________________________ 
 
 
 
_________________ 
Patient Signature  
 
 
 
 
 
 
    
Date 
 


Short Title: Q-Urol 
Version Date: 11APR2023 
Page 64 of 69 
Appendix 7: Pain Management Diary 
Subject ID: __________________________  
Subject Initials:______________________ 
Week #: __________________________ 
 
Week Start Date: ____________________  
Please record any use of medications intended for the management of prostate pain. 
Date 
Medication Taken 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
Have you taken any medication today for prostate pain? 
 □ Yes                              □ No 
 
 
__________________________________________ 
 
 
__________________ 
Patient Signature 
 
 
 
 
 
 
 
Date 
 
 


Short Title: Q-Urol 
Version Date: 11APR2023 
Page 65 of 69 
Appendix 8: NCCN Risk Stratification 
Risk Group 
Clinical Pathologic Features 
Very Low 
● T1c AND 
● Gleason Score ≤ 6/ grade group 1 AND 
● PSA < 10 ng/mL AND 
● Fewer than 3 prostate biopsy fragments/cores, positive, ≤ 50% 
cancer in each fragment/coreb AND 
● PSA density < 0.15 ng/mL/g 
Low 
● T1-T2a AND 
● Gleason score ≤ 6/grade group 1 AND 
● PSA < 10 ng/mL 
Favorable Intermediate 
● T2b – T2c OR 
● Gleason score 3 + 4 =7/grade group 2 OR 
● PSA 10-20 ng/mL 
AND 
● Percentage of positive biopsy cores < 50% 
Unfavorable Intermediate 
● T2b – T2c OR 
● Gleason score 3 + 4 = 7/grade group 2 or Gleason score 4 + 3 
= 7/grade group 3 OR 
● PSA 10-20 ng/mL 
High 
● T3a OR 
● Gleason score 8/grade group 4 or Gleason score 4 + 5 = 
9/grade group 5 OR 
● PSA > 20 ng/mL 
Very High 
● T3b – T4 OR 
● Primary Gleason pattern 5 OR 
● > 4 core with Gleason score 8-10/ grade group 4 or 5 
Regional 
Any T, N1, M0 
Metastatic 
Any T, Any N, M1 
 
 
 


Short Title: Q-Urol 
Version Date: 11APR2023 
Page 66 of 69 
Appendix 9 Baseline Characteristics 
1. Does the patient have a history of Coronary Artery Disease? Yes□ No□ 
2. Has the patient had bacterial prostatitis that went away with antibiotics? Yes□ No□ 
3. Does the patient have any family history of prostatitis? Yes□ No□ 
4. Alcohol history: 
 Never used alcohol 
 Current alcohol user 
 Former alcohol user  
5. Smoking history: 
 Never smoked 
 Current smoker  
• Average number of packs per day _____ 
• Number of years smoked _____ 
 Former smoker 
• Average number of packs per day________ 
• Number of years smoked ____ 
6. Employment status 
 Employed 
 Retired 
 Student 
 Unknown 
 Other 
7. Insurance status 
 Private insurance 
 Medicare 
 Medicaid 
 VA 
 Military 
 Not insured 
 Self pay  
 Unknown  
Other  
Subject ID: 
 
 
Subject Initials: 
Date: 


Short Title: Q-Urol 
Version Date: 11APR2023 
Page 67 of 69 
Appendix 10: Charlson Comorbidity Index 
 
Date of Assessment: _________________________ 
Study Patient ID: _______________ 
 
 
 
 
 
 
 
 
Study Patient Initials:____________ 
Instructions: Select one option per line. 
 
None 
Uncomplicated 
End-organ Damage 
Diabetes mellitus 
 
 
 
 
 
None Mild Moderate/Severe 
Liver disease 
 
 
 
 
 
None 
Leukemia, Lymphoma, 
or Localized Solid Tumor 
Metastatic 
Solid Tumor 
Malignancy – exclude basal cell carcinoma 
 
 
 
 
 
Yes 
No 
HIV or AIDS 
 
 
Moderate to severe chronic kidney disease 
 
 
Congestive heart failure 
 
 
Myocardial infarction 
 
 
Chronic obstructive pulmonary disease (COPD) 
 
 
Peripheral vascular disease 
 
 
Cerebrovascular accident (CVA) or transient ischemic attack (TIA) 
 
 
Dementia 
 
 
Hemiplegia 
 
 
Connective tissue disease 
 
 
Peptic ulcer disease 
 
 
Investigator Signature __________________________________ 
 
 
 


Short Title: Q-Urol 
Version Date: 11APR2023 
Page 68 of 69 
Appendix 11: Eastern Cooperative Oncology Group Performance Status Criteria 
(ECOG) & Karnofsky Performance Scale Index (KPS) equivalency 
ECOG Performance Status Scale1 
Karnofsky Performance Scale2 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease. 
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). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active 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. 
60 
Requires occasional assistance, but is able to 
care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization indicated.  
Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
1. Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol.1982;5:649-655. 
2. Karnofsky D, Burchenal J, The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C, ed. 
Evaluation of Chemotherapeutic Agents. New York, NY: Columbia University Press; 1949:191–205 
 
 


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Version Date: 11APR2023 
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Appendix 12: Cautionary Medications 
CYP3A4 substrates with a narrow therapeutic index 
Abiraterone 
Carbamazepine 
Fosphenytoin 
Tacrolimus 
Acenocoumarol 
Cisapride 
Isavuconazole 
Terfenadine 
Aminophylline 
Clozapine 
Phenprocoumon 
Theophylline 
Amiodarone 
Cyclosporine 
Pimozide 
Tianeptine 
Argatroban 
Digitoxin 
Quinidine 
 
Cabergoline 
Dofetilide 
Ruxolitinib 
 
Cabozantinib 
Dronedarone 
Sirolimus 
 
 
CYP2D6 substrates with a narrow therapeutic index 
Amiodarone 
Flecainide 
Procainamide 
Theophylline 
Dosulepin 
Pimozide 
Sotalol 
 
 
CYP2C8 substrates with a narrow therapeutic index 
Amiodarone 
Fosphenytoin 
Phenprocoumon 
Phenytoin 
 
OATP1B1 substrates with a narrow therapeutic index 
Cyclosporine 
Digoxin 
Levothyroxine 
Methotrexate 
 
P-glycoprotein substrates with a narrow therapeutic index 
Cyclosporine 
Digoxin 
Phenytoin 
Sirolimus 
Digitoxin 
Phenobarbital 
Quinidine 
Tacrolimus