Clinical trial NCT03152786
Conditions: Prostate Carcinoma
Sponsor: Wake Forest University Health Sciences
Start date: 2019-01-15; Completion date: 2023-02-28
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized pilot clinical trial studies how well propranolol hydrochloride works in treating patients with prostate cancer who are undergoing surgery. When stressed, the body makes a molecule that may prevent tumor cells from dying, and propranolol hydrochloride may affect the signals in cells that cause tumor cells survival and death.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare activation of ADRB2/PKA/BAD signaling pathway in the prostate glands of men two hours after taking or not taking propranolol hydrochloride (propranolol) prior to prostatectomy, as indicated by phosphorylated CREB.

SECONDARY OBJECTIVES:

I. To compare activation of ADRB2/PKA/BAD signaling pathway in the prostate glands of men two hours after taking or not taking propranolol prior to prostatectomy as indicated by phosphorylated BAD.

II. To determine the difference in candidate transcript levels associated with ADRB2/PKA activation between individuals two hours after taking propranolol or not taking propranolol prior to prostatectomy.

III. To determine plasma propranolol levels in individuals taking propranolol two hours after administration prior to prostatectomy.

IV. To determine if plasma catecholamine levels in men with prostate cancer can be used as a biomarker to identify patients who show activation of ADRB2 signaling pathway in prostate tumors.

V. To determine perceived stress level differences in men with prostate cancer prior to surgery to examine possible association between perceived stress level and catecholamine levels in blood and activation of ADRB2 pathway in tumors.

VI. To determine perceived distress level differences in men with prostate cancer prior to surgery to examine possible association between distress level and catecholamine levels in blood and activation of ADRB2 pathway tumors.

OUTLINE: Patients are randomized into 1 of 2 groups.

GROUP I: Patients receive propranolol hydrochloride orally (PO) 2 hours prior to standard of care prostatectomy.

GROUP II: Patients receive no treatment prior to standard of care prostatectomy.

After completion of study treatment, patients are followed up for 30 days.

Arms: arm 1: Patients receive propranolol hydrochloride PO 2 hours prior to standard of care prostatectomy. arm 2: Patients receive no treatment prior to standard of care prostatectomy.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Propranolol Hydrochloride intervention 3: Questionnaire Administration intervention 4: Survey Administration
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Ancillary studies intervention 4: Ancillary studies

Protocol documents:
Prot_SAP_001.pdf: 
Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
 
 
 
 
 
 
 
 
 
 
IRB-APPROVED DATE: 5/24/2021 
NCT03152786 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
 
 
Principal Investigators:  
Ashok Hemal, M.D. 
 
 
 
 
 
Department of Surgery Urology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
ahemal@wakehealth.edu 
P 336-716-4131 
 
Co-Investigators:  
 
George Kulik, D.V.M., Ph.D 
 
 
 
 
 
Department of Cancer Biology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
 
 
 
P 336-713-7650 
 
 
 
Rhonda Bitting, M.D. 
 
 
 
 
 
Section on Hematology and Oncology 
 
 
 
 
 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
rbitting@wakehealth.edu 
336-716-0327 
 
Ronald L. Davis, III, M.D. 
Department of Surgery Urology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
rodavis@wakehealth.edu 
P 336-713-0322 
 
Gregory Kucera, PhD 
Section on Hematology and Oncology 
 
 
 
 
 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
gkucera@wakehealth.edu 
336-716-6348 
 
Ram Pathak, MD 
Department of Surgery Urology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
rpathak@wakehealth.edu 
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
 
 
 
Chuanya Tong, MD 
Anesthesiology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
ctong@wakehealth.edu 
P 336-716-3014 
 
Biostatistician: 
 
 
Ralph B. D’Agostino Jr, PhD 
Wake Forest Baptist Comprehensive Cancer Center 
Wake Forest School of Medicine 
Medical Center Blvd 
Winston-Salem, NC 27157 
rdagosti@wakehealth.edu 
P 336-716-9410 
 
Procurement Officer: 
Libby McWilliams 
Wake Forest Baptist Comprehensive Cancer Center 
Wake Forest School of Medicine 
Medical Center Blvd 
Winston-Salem, NC 27157 
lmcwilli@wakehealth.edu 
P 336-716-5355 
 
Study Coordinator: 
 
Danita Washington 
Wake Forest Baptist Comprehensive Cancer Center 
Medical Center Blvd 
Winston-Salem, NC 27157 
dwashing@wakehealth.edu 
P 336-713-6627  
 
Data Manager: 
 
 
Deanna Hissim 
Wake Forest Baptist Comprehensive Cancer Center 
Medical Center Blvd 
Winston-Salem, NC 27157 
dehissim@wakehealth.edu 
P 336-713-6986 
 
Jasmine Bonapart 
Wake Forest Baptist Comprehensive Cancer Center 
Medical Center Blvd 
Winston-Salem, NC 27157 
jbonapar@wakehealth.edu 
P 336-713-9890 
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
 
 
 
Regulatory Contact: 
 
Cindy Miller 
Wake Forest Baptist Comprehensive Cancer Center 
Medical Center Blvd 
Winston-Salem, NC 27157 
cytmill@wakehealth.edu 
P 336-713-6770 
 
 
Participating Institution(s): 
Wake Forest Baptist Comprehensive Cancer Center 
(WFBCCC) 
 
 
Version Date: 07/21/2017  
Amended: 
  05/19/2021 
 
 
Confidential


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
Protocol version date 05/19/21 
 
 
 
 
 
 
Page 5 of 48 
 
Table of Contents 
Table of Contents 
SCHEMA ....................................................................................................................................... 7 
1.0 
Introduction and Background ............................................................................................ 8 
2.0 
Objectives ......................................................................................................................... 9 
2.1 
Primary Objective .............................................................................................................. 9 
2.2 
Secondary Objectives ....................................................................................................... 9 
3.0 
Study Population ............................................................................................................. 10 
3.1 
Inclusion criteria: ......................................................................................................... 10 
3.2 
Exclusion criteria: ........................................................................................................ 10 
3.3 
Inclusion of Women and Minorities ............................................................................. 10 
3.4 
Accrual ............................................................................................................................ 11 
4.0 
Methods .......................................................................................................................... 11 
4.1 
Registration Procedures .............................................................................................. 11 
4.2 
Methods....................................................................................................................... 12 
5.0 
Treatments ...................................................................................................................... 16 
5.1 
Treatments Administered ............................................................................................ 16 
6.0 
Dose Modifications .......................................................................................................... 16 
6.1 
Definition of a Safety Concern ..................................................................................... 16 
6.2 
Dose Reduction ........................................................................................................... 16 
7.0 
Outcome Measures ......................................................................................................... 17 
7.1 
Primary Outcome ........................................................................................................ 17 
7.2 
Secondary Outcomes .................................................................................................. 17 
8.0 
Analytic Plan ................................................................................................................... 17 
8.1 
Power Calculation/Sample size ................................................................................... 17 
8.2 
Primary Objective ........................................................................................................ 17 
8.3 
Secondary Objective ................................................................................................... 18 
8.4 
Interim Analysis ........................................................................................................... 18 
8.5 
Accrual Rate ................................................................................................................ 19 
9.0 
Data Management ........................................................................................................... 19 
10.0 
Confidentiality and Privacy .............................................................................................. 20 
11.0 
Data Safety and Monitoring ............................................................................................. 20 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
Protocol version date 05/19/21 
 
 
 
 
 
 
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12.0 
Reporting of Unanticipated Problems, Adverse Events or Deviations ............................ 20 
13.0 
Adverse Events List and Reporting Requirements ......................................................... 21 
13.1 
Adverse Event List for Propranolol .............................................................................. 21 
13.2 
Adverse Event Characteristics .................................................................................... 21 
13.3 
DSMC SAE Reporting Requirements .......................................................................... 22 
13.4 
WFBH IRB AE Reporting Requirements ..................................................................... 22 
14.0 
Pharmaceutical Information ............................................................................................ 23 
14.1 
Pharmaceutical Accountability .................................................................................... 23 
14.2 
Propranolol .................................................................................................................. 23 
References .................................................................................................................................. 24 
Appendix A – Subject Eligibility Checklist ................................................................................... 26 
Appendix B – Protocol Registration Form ................................................................................... 27 
Appendix C – Perceived Stress .................................................................................................. 28 
Appendix D – Distress Thermometer .......................................................................................... 29 
Appendix E – Adverse Events Log ............................................................................................. 30 
Appendix F – Mandatory DSMC SAE Reporting Guidelines ...................................................... 31 
Appendix G - Baseline Medical History ....................................................................................... 38 
Appendix H – Tissue Collection .................................................................................................. 40 
Appendix I – Blood Collection ..................................................................................................... 41 
Appendix J: CREB Phosphorylation ........................................................................................... 43 
Appendix K: BAD Phosphorylation ............................................................................................. 44 
Appendix L: Plasma Outcomes ................................................................................................... 46 
Appendix M: RNA Analysis ......................................................................................................... 47 
Appendix N: Surgery Day Worksheet ......................................................................................... 48 
 
 
 
 
 
 
 
 
 
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
Protocol version date 05/19/21 
 
 
 
 
 
 
Page 7 of 48 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
Eligibility and Consent 
Randomization 
Group 2: No drug + prostate 
biopsy 
Group 1: Propranolol (p.o. 
40mg) + prostate biopsy 
Administer Propranolol (40mg 
po x1) 2 hours prior to biopsy 
No drug 
Stress surveys and blood draw for stress hormones 
and propranolol levels  
Prostate biopsy or surgery, Tissue collection and 
Storage  
Day of Biopsy/Surgery 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
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Page 8 of 48 
1.0 
Introduction and Background 
 
Increased levels of epinephrine induced by stress inhibit apoptosis and accelerate 
tumor progression in mouse models of prostate cancer via β2-adrenergic 
receptor (ADRB2)/ cAMP-dependent protein kinase (PKA)/ BCL2-associated death 
promoter (BAD) signaling pathway 1. Furthermore, analysis of 20 prostate biopsies 
showed significant positive correlation between increased blood epinephrine levels and 
activation of the ADRB2/PKA/BAD signaling pathway in the prostate gland of men 2.  
Because PKA can phosphorylate several substrates in addition to BAD, it is beneficial to 
analyze phosphorylation of both S75 BAD and S133 CREB to increase assay 
specificity.  Further, antibodies to pS133CREB may be more sensitive compared to 
pS75 BAD-specific antibodies. 
 
To further improve the specificity and sensitivity of measuring activation of ADRB2 
signaling pathway, we have compared mRNA profiles in prostate cancer C42 cells 
exposed to vehicle or epinephrine using Affimetrix arrays.  This comparison identified 
several transcripts induced by activation of ADRB2 pathway.  Should the specificity of 
these induced transcripts be confirmed, the analysis of these transcripts in collected 
prostate tissues will also be conducted.   
 
Recently, in a breast cancer mouse model, it has been shown that chronic stress 
promotes metastasis and that treatment with a beta-blocker can prevent metastasis 3.  
Similarly, an association between dysregulation of stress-related signaling pathways, 
especially the adrenergic pathway and lethal prostate cancer has been reported 4. 
These data suggest that stress and ADRB2/PKA/BAD signaling may play an important 
role in prostate cancer pathophysiology.   
 
In patients with advanced prostate cancer who experience increased stress, elevated 
epinephrine levels may contribute to inhibition of apoptosis and, hence, therapeutic 
resistance. Conversely, inhibiting the ADRB2/PKA/BAD signaling pathway by ADRB2-
selective beta blockers could be a therapeutic option for patients with increased 
epinephrine levels 5. Several epidemiological studies have addressed a potential 
correlation between the use of beta blockers and prostate cancer incidence and 
mortality, but they reached contradictory conclusions 6-15. The results of the most recent 
studies suggest that activation of ADRB2 is likely to contribute to prostate cancer 
progression but does not increase prostate cancer incidence. Likewise improvement in 
overall survival was recently reported for ovarian cancer patients who took beta-
blockers 16.  Most patients in these studies took β1-selective blockers, which are poor 
inhibitors of ADRB2 signaling. A recent study that focused on patients who took 
propranolol that inhibits ADRB2 signaling reported significant decrease in incidence of 
several cancers including prostate cancer 15.  Furthermore, our data from preclinical 
models of prostate cancer suggest that not all patients will respond to therapy with β2-
selective blockers due to compensatory signaling pathways that inhibit apoptosis 
despite of the inactivation of ADRB2/PKA axis. Thus, patients in whom ADRB2/PKA is 
the major pathway that controls BAD phosphorylation and apoptosis are likely to benefit 
from ADRB2-selective blockers. In contrast, for patients with multiple redundant 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
Protocol version date 05/19/21 
 
 
 
 
 
 
Page 9 of 48 
pathways that converge on BAD, the ADRB2-selective blockers will likely need to be 
given in combination with inhibitors of other signaling pathways. 
 
Beta blockers are commonly administered in the perioperative period.   Perioperative 
beta blocker use has been associated with lower 30-day mortality rates, although the 
benefit is stronger for those undergoing cardiovascular surgery, and the benefit in the 
setting of non-cardiac surgery remains controversial 17.  In a 1991 study of women in the 
perioperative period, a one-time preoperative dose of oral propranolol of 80 mg was 
well-tolerated and resulted in less anesthetic use 18. In a more recent randomized study, 
perioperative doses of 20mg or 40mg were used to reduce anxiety among surgery 
patients19. With the administration of 20mg of oral propranolol, there was a significant 
decrease in anxiety with fewer cardiovascular effects than the 40mg dose.  In the 
current study, the use of propranolol will be continuously monitored for safety events. 
Any safety concerns that arise as defined in the protocol will trigger a dose reduction for 
subsequent patients. Additionally, an interim analysis will assess safety. 
2.0 
Objectives 
2.1 
Primary Objective  
2.1.1 To compare activation of ADRB2/PKA/BAD signaling pathway in 
the prostate glands of men two hours after taking or not taking 
propranolol prior to prostate biopsy or prostatectomy, as indicated 
by phosphorylated CREB. 
2.2 
Secondary Objectives  
2.2.1 To compare activation of ADRB2/PKA/BAD signaling pathway in 
the prostate glands of men two hours after taking or not taking 
propranolol prior to prostate biopsy or prostatectomy as indicated 
by phosphorylated BAD. 
 
2.2.2 To determine the difference in candidate transcript levels 
associated with ADRB2/PKA activation between individuals two 
hours after taking propranolol or not taking propranolol prior to 
prostate biopsy or prostatectomy. 
 
2.2.3 To determine plasma propranolol levels in individuals taking 
propranolol two hours after administration prior to prostate biopsy 
or prostatectomy.  
 
2.2.4 To determine if plasma catecholamine levels in men with prostate 
cancer can be used as a biomarker to identify patients who show 
activation of ADRB2 signaling pathway in prostate tumors. 
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
Protocol version date 05/19/21 
 
 
 
 
 
 
Page 10 of 48 
2.2.5 To determine perceived stress level differences in men with 
prostate cancer prior to prostate biopsy or prostatectomy to 
examine possible association between perceived stress level and 
catecholamine levels in blood and activation of ADRB2 pathway in 
tumors 
 
2.2.6 To determine perceived distress level differences in men with 
prostate cancer prior to prostate biopsy or prostatectomy to 
examine possible association between distress level and 
catecholamine levels in blood and activation of ADRB2 pathway in 
tumors.  
3.0 
Study Population 
 
Patients recruited will be individuals scheduled for prostate biopsy or 
prostatectomy. For this study, 60 individuals will be recruited.  Patients will be 
randomized to receive the treatment (or not) for a total of 30 patients receiving 
propranolol prior to biopsy or prostatectomy and 30 patients receiving no 
treatment.  It is expected that approximately 10 (5 patients in each group) may 
have non-evaluable tumor tissue.  In case the number of evaluable tumors will be 
less than 25 for each group, more patients will be recruited to accumulate 25 
evaluable samples for each group. 
3.1 
Inclusion criteria: 
1) Men >18 years of age  
2) Patients undergoing  prostate biopsy or prostatectomy 
3) Individuals able to understand and willing to sign an IRB-approved 
informed consent document 
3.2 
Exclusion criteria: 
1) Men taking propranolol daily for any reason are excluded 
2) Men with baseline SBP <120 or HR <63 
3) Men unable to swallow pills 
4) History of current or past medical or psychiatric illness that would 
make participation difficult or not feasible at the discretion of the 
principal investigator or co-investigators. 
 
3.3 
Inclusion of Women and Minorities 
Men of all races and ethnicities who meet the above-described eligibility 
criteria are eligible to participate.  Due to the sex specific nature of 
prostate cancer, women will not be included in this study. 
 
Based on WFBCCC population estimates and based on the sample size of 
60 patients total for this study, we plan to enroll approximately 15% Black 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
Protocol version date 05/19/21 
 
 
 
 
 
 
Page 11 of 48 
or African American (N=9). Given the low rates and/or population statistics 
in our catchment area we expect no or very low accruals within the Asian, 
American Indian, or Pacific Islander populations.  Additionally, we may 
expect approximately 5% of the sample to be Hispanic, which may 
account for an N = 3 Hispanic individuals. Should we not meet or exceed 
these estimates, the PI will engage the Cancer Center Health Equity 
Advisory Group to discuss strategies to enhance recruitment in these 
target populations. 
3.4 
Accrual 
 
Five (5) individuals per month for one year 
4.0 
Methods 
 
4.1 
Registration Procedures 
All patients entered on any WFBCCC trial, whether treatment, companion, 
or cancer control trial, must be  registered,  within 24 hours of Informed 
Consent, into WISER. Patients must be registered prior to the initiation of 
treatment.   
 
You must perform the following steps in order to ensure prompt 
registration of your patient: 
 
1. Complete the Eligibility Checklist (Appendix A) 
2. Complete the Protocol Registration Form (Appendix B) 
3. Alert the Cancer Center registrar by phone, and then send the signed 
Informed Consent Form, Eligibility Checklist and Protocol Registration 
Form to the registrar, either by fax or e-mail. 
 
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
            
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-
Friday. 
 
4. Fax/e-mail ALL eligibility source documents with registration. Patients 
will not be registered without all required supporting documents. 
Note: If labs were performed at an outside institution, provide a printout of 
the results. Ensure that the most recent lab values are sent. 
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
Protocol version date 05/19/21 
 
 
 
 
 
 
Page 12 of 48 
To complete the registration process, the Registrar will:   
 
• assign a patient study number 
• Randomized Group Assignment  
• register the patient on the study 
 
4.2 
Methods  
Compare activation of ADRB2/PKA/BAD signaling pathway in the prostate 
glands of men who take or do not take ADRB2-selective beta blockers 
 
Patients scheduled for prostate biopsy. 
 
The research staff screens the OR and clinic schedules for potential patients and 
provides a list to the investigator.  Dr. Hemal or co-Investigator will discuss the study 
with the patient and inform the research nurse or coordinator (research staff) about the 
patients who agreed to participate in the study.   Research staff will inform Tissue 
Procurement Lab (Director Dr. Kucera; Libby McWilliams, Tumor Procurement 
Coordinator) and courier about the scheduled date and time when prostate samples will 
be collected. 
 
On the day of sample collection Dr. Kucera’s lab will prepare box with dry ice for 
prostate biopsy samples, a box with wet ice for blood samples as well as 2 ml cryovials 
(Corning, cat#430488) to collect biopsies and tubes to collect blood (Na heparin, green-
capped tube, 10 ml total blood volume).  
 
Courier will pick up boxes from Tissue Procurement Lab (Director Dr. Kucera; Hanes 
Building Rm 4032, tel 336-716-3721) and deliver to research staff at Charlois clinic (140 
Charlois Boulevard, Winston-Salem, 27103). 
 
Recruited patients scheduled for prostate biopsy will be randomized into two groups.  
Group one will receive 40 mg propranolol given by research nurse 2 hours prior to 
prostate biopsy.  The research nurse should withhold drug and contact treating 
physician if SBP <120 or HR < 63.  Group two will receive no treatment.   
 
All patients will fill out stress surveys on the biopsy day.   
 
All patients will give approximately 10 mL of blood  approximately  20 min prior to 
prostate biopsy to test plasma catecholamine levels (collected in 10 mL green top tube 
(sodium heparin) and sent on ice within 1 hour to clinical lab for processing)and 
propranolol level (collected in 10 mL green top tube (sodium heparin) and sent on ice to 
The Tissue Procurement lab for processing and storage as described below).  For 
group one that takes propranolol, this blood sample will be drawn at 1.5 -2 hours after 
taking the propranolol tablet.  
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
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Page 13 of 48 
For the biopsy, at least 1 core of the prostate specimen is to be flash frozen (on dry ice -
80C) for laboratory analysis.  Each biopsy sample will be collected into separate 
cryovials. The samples will be picked up by courier at Charlois clinic and delivered to 
Tissue Procurement laboratory..   The tissue samples will be frozen at -80 C. 
 
At Tissue Procurement Lab, the blood sample will be centrifuged to prepare plasma.  
Plasma will be transferred into cryovials and stored at -80 C.   
 
Patients scheduled for prostatectomy. 
 
Research staff will inform Tissue Procurement Lab (Director Dr. Kucera; Libby 
McWilliams, Tumor Procurement Coordinator) about the scheduled date and time when 
samples from prostate cancer patients will be collected at OR.  Prior to the day of 
sample collection at specified time Dr. Kucera’s lab will provide vials and freezing media 
to collect prostatectomy samples and plasma samples (Na heparin, green cup).  
 
Recruited patients scheduled for prostatectomy will be randomized into two groups.  
Group one will receive 40 mg propranolol given by research staff 2 hours prior to 
prostatectomy.  The research staff should withhold drug and contact the study physician 
performing the procedure and/or the anesthesiologist if SBP <120 or HR < 63.  Group 
two will receive no treatment.  All patients will fill out stress surveys prior to 
prostatectomy.    
 
 
Research staff will collect stress questionnaire and will collect blood into the vials with 
Na heparin that will be stored on ice (+4C).    All patients will give approximately 10 ml 
of blood  approximately 20 min prior to prostatectomy to test plasma catecholamine 
levels and propranolol level.  For group one that takes propranolol, this blood sample 
will be drawn at 1.5 -2 hours after taking the propranolol tablet.  Blood will be collected 
into two 10 mL green top (sodium heparin) tubes.  One tube will sent on ice within 1 
hour to the clinical lab for processing of fractionated catecholamines.   The other tube 
will be sent on ice to The Tissue Procurement lab for processing and storage.  The 
plasma will be separated, transferred to cryovials, and stored in -80C at the Tissue 
Procurement Lab   
 
Prior to anesthesia patient will be evaluated by anesthesiologist for hypotension and 
bradycardia.  Prostatectomy samples will be collected by Tissue Procurement 
Coordinator and placed into cryovials and flash-frozen.  At least 3 vials with the prostate 
specimens will be flash frozen (on dry ice -80C) for laboratory analysis and stored at the 
Tissue Procurement Lab.    
 
 
Prostate samples will be analyzed for the overall status of prostate tissue (by 
pathologist) and for activation of ADRB2/PKA signaling pathway 2,20-22.   
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
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Page 14 of 48 
Analysis of ADRB2/PKA signaling pathway will be conducted by two methods: 1) 
western blotting to measure phosphorylation of CREB and BAD; 2) analysis of mRNA 
expression signature that reflects activation of ADRB2/PKA signaling pathway. 
Methods related to western blotting of material and RNA analysis will be per 
manufacturer’s instructions with modifications to adapt the protocol to the particular 
conditions of the experiments and will be kept in laboratory notebooks in the analyzing 
laboratory. Results will be kept in laboratory notebooks, but will also be recorded on 
the associated data collection forms (Appendices J-M) where appropriate and will 
ultimately be entered into a REDCap database. 
 
Experimental plan (Kulik laboratory):  
1. Test whether LCM can be used to excise epithelial cells from frozen sections 
of prostate tissue for analysis of CREB and BAD phosphorylation by Western 
blotting, and for the analysis of mRNA by qPCR or RNA seq.  
 
2. Recruit patients prior to prostate biopsy or prostatectomy. We plan to recruit 
60 patients to this study and expect that 10 patients may not have evaluable 
tumor tissue. Patients will provide medical history and pre-study blood 
samples. On the day of prostate biopsy, the patients will fill out two stress 
surveys, being given propranolol or no treatment approximately 2 hours prior 
to biopsy or surgery, give blood, have prostate biopsy/prostatectomy, at which 
point prostate sample will be collected.  
 
3. Compare CREB phosphorylation, BAD phosphorylation in prostates of men 
who took and who did not take propranolol.  Based on our recent study of 
activation of ADRB2/PKA pathway in prostate biopsies we anticipate that in ~ 
20% patients (10 of 50) ADRB2 pathway will be activated 2. If the selective 
beta blocker propranolol inhibits ADRB2/PKA pathway, then we will not see 
CREB and BAD phosphorylation in prostates of patients who take 
propranolol.  In the no treatment group, patients are expected to show 
elevated BAD and CREB phosphorylation in their prostates.  The levels of 
CREB and BAD phosphorylations will be determined by probing Western 
blots with antibodies to pS133CREB and total CREB; pS112BAD and total 
BAD.  Ratios of signals from pS133CREB/total CREB and pS112BAD/total 
BAD will be used to compare CREB and BAD phosphorylations in prostate 
tissue samples.  
 
4. Free plasma propranolol (pharmacologically active) will be measured at The 
Proteomics and Metabolomics Shared Resource (Dir. Dr. Cristina Furdui) 
using chromatographic separation and fluorometric detection (linear detection 
range 5-400 µg/L) as described in 20-22. 
 
5. Using prostate cancer cell models and tissues from the tumor bank, we will 
test if there is an mRNA signature of activation of ADRB2/PKA signaling 
pathway.  
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU # 85716 
 
 
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Page 15 of 48 
6. Compare mRNA signature of activation of ADRB2/PKA signaling pathway in 
prostates samples of men who take propranolol versus those who take 
nothing. Analysis of forskolin-induced genes using Affimetrix platform has 
been reported for HEK293T, MIN6 cell lines and primary hepatocytes and 
identified respectively 6, 14 and 17 mRNA transcripts induced over 3 fold 23. 
These results suggest that it would be possible to identify transcripts induced 
by ADRB2/PKA signaling in prostate cells as well. Our pilot studies identified 
8 transcripts induced in prostate cells by epinephrine. Experiments to confirm 
the specificity of these transcripts for ADRB2/PKA signaling pathway are 
currently ongoing.   
 
Results of these experiments will inform whether blood epinephrine levels can 
be determined above which ADRB2/PKA pathway is activated in prostate 
cells; whether beta blockers inhibit activation of ADRB2/PKA pathway in 
prostates and which method of monitoring activation and inhibition of 
ADRB2/PKA pathway is most adequate for analysis of clinical samples.  
 
Experimental plan (clinical): 
Prior to prostate biopsy or prostatectomy, a complete history and physical will be 
performed per standard of care; this can be completed during the initial consult. 
The necessary clinical information, including most recent PSA and testosterone if 
available (per standard-of-care) will be retrospectively obtained from what is 
charted and recorded per Appendix G.    
 
Study related activities for the day of prostate biopsy or prostatectomy should be 
recorded on the Surgery Day Worksheet (Appendix N). Patients will fill out both 
the perceived stress24 form (Appendix C) and the Distress Thermometer 
(Appendix D)25. Patients will receive either propranolol 40mg po x1 or no 
treatment 2 hours prior to prostate biopsy or prostatectomy. Approximately 20 
minutes prior to prostate biopsy or prostatectomy, Group 1 will have 
approximately 10 mL of blood collected into two green top (sodium heparin) 
tubes. Group 2 will have the same amount of blood collected into two green tops. 
There will be no time limit prior to the biopsy or prostatectomy. Plasma will be 
separated and stored for future analysis of propranolol levels.  
 
Epinephrine (fractionated catecholamines) levels will be performed per standard 
clinical laboratory procedures on all patients. 
 
Information regarding tissue and plasma collection will be recorded on the Tissue 
Collection Form (Appendix H) or the Blood Collection Form (Appendix I). 
All stored plasma or tissue will be stored in the Tumor Tissue Core. 
Tumor Tissue Core 
Wake Forest Baptist Comprehensive Cancer Center 
Tumor Tissue Core Facility 
Care of Dr. Greg Kucera 
Hanes Building Rm 4049  


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Medical Center Blvd 
Winston-Salem NC 27157  
 
 
5.0 
Treatments 
 
Study treatment is defined as any investigational treatment(s), marketed 
product(s), placebo, or medical device(s) intended to be administered to a study 
participant according to the study protocol. 
 
Clinical supplies [study treatment(s) provided by the Sponsor] will be stored as a 
stock bottle at the Urology clinic in a locked area, accessible to only study staff.  
Supplies at the main facility will be obtained from the IDS pharmacy. 
5.1 
Treatments Administered 
5.1.1 The study treatment(s) to be used in this trial are outlined in section 
4.2. 
 
6.0 
Dose Modifications 
 
Modifications to the dose will be made if Safety Concerns as outlined in 5.1.1 
arise in the propranolol/surgery group. 
6.1 
Definition of a Safety Concern  
6.1.1 Safety Concerns in this study will include bradycardia or 
hypotension requiring intervention by the anesthesiologist beyond 
standard interventions to mitigate the condition (CTCAE grade 3 or 
greater), or any adverse event attributable to propranolol that 
results in a prolonged stay in post anesthesia care unit. If any event 
of this nature occurs during the study, the dose will be reduced as 
described in Section 5.2.1 for subsequent patients. 
6.2 
Dose Reduction 
6.2.1 If a subject has CTCAE grade 3 hypotension or bradycardia (as per 
section 5.1.1), the dose of propranolol will be reduced to 20 mg for 
subsequent patients.  The study will be terminated if there is an 
additional CTCAE grade 3 event at the lowest dose of 20mg.  
  
6.2.2 For any CTCAE grade 4 or 5 hypotension or bradycardia 
attributable to pre-operative propranolol dosing, the study will be 
terminated.    
 
 


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7.0 
Outcome Measures 
7.1 
Primary Outcome 
7.1.1 CREB phosphorylation determination by western blot in prostate 
tissue from men two hours after taking or not taking propranolol 
prior to prostate biopsy. 
7.2 
Secondary Outcomes 
7.2.1 BAD phosphorylation by western blot in prostate tissue from men two 
hours after taking or not taking propranolol prior to prostate biopsy 
7.2.2 Difference in levels of transcripts that reflect ADRB2/PKA activation 
as measured by real-time PCR in prostate tissue from men two 
hours after taking or not taking propranolol prior to prostate biopsy 
or prostatectomy. 
 
7.2.3 Plasma propranolol levels as measured by fluorometric detection from 
men two hours after taking or not taking propranolol prior to prostate 
biopsy or prostatectomy. 
7.2.4 Plasma catecholamine levels (including epinephrine) measured by 
ELISA from men two hours after taking or not taking propranolol 
prior to prostate biopsy or prostatectomy. 
 
7.2.5 Self-perceived stress as measured by The Perceived Stress 
Questionnaire (Appendix C) from men on the day of surgery before 
taking propranolol, prior to prostate biopsy or prostatectomy. 
 
7.2.6 Distress score as measured by The Distress Thermometer 
(Appendix D) from men on the day of surgery before taking 
propranolol, prior to prostate biopsy or prostatectomy. 
8.0 
Analytic Plan 
8.1 
Power Calculation/Sample size 
Based on the preliminary data, the baseline level of CREB phosphorylation was 
0.73 with a standard deviation of 0.26 2. Using these values, we determined that 
there is 80% power to detect a difference of 0.21 between groups using a 2-
sample t-test (alpha=0.05, 2-sided). Thus, if the control group has a value of 0.73 
(based on the preliminary data) then we would be able to detect a difference if 
the value of CREB phosphorylation is below 0.52. Based on the preliminary data, 
this effect size is 0.81, and would correspond to a 29% relative change in CREB 
phosphorylation.  This calculation is based on have 25 patients in each group 
being evaluable (i.e., having tumor tissue available to be evaluated). 
8.2 
Primary Objective 
Since this is a randomized trial, the two groups can be compared for CREB 
phosphorylation levels using a two-sample t-test.  In addition to the 2-sample t-


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test, descriptive statistics will be calculated for this primary outcome within each 
group.  These statistics include n, mean, standard deviations and 95% 
confidence intervals.  
 
Based on the preliminary data, the baseline level of CREB phosphorylation was 
0.73 with a standard deviation of 0.26 2. Using these values, we determined that 
there is 80% power to detect a difference of 0.21 between groups using a 2-
sample t-test (alpha=0.05, 2-sided). Thus, if the control group has a value of 0.73 
(based on the preliminary data) then we would be able to detect a difference if 
the value of CREB phosphorylation is below 0.52. Based on the preliminary data, 
this effect size is 0.81, and would correspond to a 29% relative change in CREB 
phosphorylation.  This calculation is based on have 25 patients in each group 
being evaluable (i.e., having tumor tissue available to be evaluated).  Sixty 
patients are to be enrolled to allow up to 10 patients (5 per group) to possibly not 
have evaluable tissue available at the time of analyses.  
8.3 
Secondary Objective 
There are 6 secondary objectives; each of these is focused on comparing the 
levels of a potential biomarker in patients.  These measures are activation of 
ADRB2/PKA/BAD signaling pathway in the prostate glands, transcripts levels 
associated with ADRB2/PKA activation, plasma propranolol levels, plasma 
catecholamine levels, perceived stress levels, and distress levels.  For each of 
these measures 2-sample t-tests will be calculated to compare the groups who 
were randomized to receive propranolol (yes/no).  In addition to the 2-sample t-
tests, descriptive statistics will be calculated for each measure within each group.  
These statistics include n, mean, standard deviations and 95% confidence 
intervals.  
8.4 
Interim Analysis 
An interim analysis will occur after 10 patients (5 in each group) are recruited to 
determine if dosing or administration route of propranolol needs to be adjusted.  
This interim analysis will not include any statistical testing, but rather will be used 
to assess the safety of the trial.  
 
If CREB phosphorylation will be observed in patients with epinephrine blood 
levels over 1nM who took propranolol, the dose of propranolol will be increased 
to 80mg.  Exclusion criteria for this dose will be reviewed based on interim 
analysis.  
 
 
 


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Safety Review 
Safety will be addressed on a per patient basis as described in Section 5.0 and 
as reiterated below.  Because this pilot study involves only 1 dose of medication 
(initially 40mg; if 40mg is not effective in inhibiting CREB phosphorylation dose 
will be increased to 80mg) with a peak effect expected in 1-4 hours and a half-life 
of 3-6 hours, the safety assessment window will be in the perioperative period for 
up to 4 hours after dosing.  Blood pressure will be monitored at 3h and 4h after 
the propranolol is taken.  Patients will be allowed to leave if SBP >90.  If blood 
pressure not acceptable after 4 hours, the patient will continue to be monitored 
and may receive IV fluids  if SBP/DBP <90/60 after 6h post dose.  
 
If there is CTCAE grade 3 bradycardia or hypotension, then the dose for 
subsequent patients will be modified per section 5.2.  The study will be 
terminated if grade 4 or 5 cardiac events attributable to propranolol dosing occur.   
While safety will be addressed promptly on a per patient basis, a review of all 
AEs will occur at the safety interim analysis after 10 patients have been accrued 
(5 in each group).   If other safety events are identified by the investigators at this 
interval analysis, then the propranolol dosing may be modified for subsequent 
subjects as directed by Section 5.2 or in a manner designated by the PI to 
ensure safety of the patients.  
 
Finally, if a safety event as described in Section 5.1.1 occurs, the study will be 
locked and all activities suspended for 24 hours to further evaluate patient 
recovery and to monitor for other potential events. If patient recovery is deemed 
acceptable by the PI, the trial will be unlocked with subsequent patients following 
the modified dose reduction plan as described in Section 5.2. 
 
Occurrence of an SAE other than those listed above will be addressed following 
the SAE protocol (Appendix F). 
  
8.5 
Accrual Rate 
The accrual rate is anticipated to be 5 per month, thus recruitment should be 
complete within 12 months. Since analysis will occur on the samples that are 
taken during prostate biopsy, the overall length of this study is anticipated to be 
less than 18 months (allowing for the possibility that accrual goes slower than 
predicted or that time for lab analyses takes some time to be performed).  
9.0 
Data Management 
 
Informed consent document  
 
Subject Eligibility Checklist  (Appendix A) 
 
Protocol registration form (Appendix B) 
WISER 
Perceived Stress Form (Appendix C) 
REDCap 
Distress Thermometer (Appendix D) 
REDCap 
Adverse Events Log (Appendix E) 
WISER 


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Baseline Medical History Form (Appendix G) 
WISER 
Tissue Collection Form (Appendix H) 
 
Blood Collection Form (Appendix I) 
 
Data Collection Form (prostate pCREB and pBAD) 
(Appendix J and K) 
REDCap 
Plasma Outcomes Form (Appendix L) 
REDCap 
RNA Data Collection Form (Appendix M) 
REDCap 
Surgery Day Worksheet (Appendix N) 
 
 
 
10.0 Confidentiality and Privacy 
 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that 
could directly identify subjects, and maintaining all study information in a secure 
manner. To help ensure subject privacy and confidentiality, only a unique study 
identifier will appear on the data collection form. Any collected patient identifying 
information corresponding to the unique study identifier will be maintained on a linkage 
file, store separately from the data. The linkage file will be kept secure, with access 
limited to designated study personnel. Following data collection subject identifying 
information will be destroyed (state the anticipated time the data will be destroyed, e.g. 
three years after closure of the study, and the method of destruction), consistent with 
data validation and study design, producing an anonymous analytical data set. Data 
access will be limited to study staff. Data and records will be kept locked and secured, 
with any computer data password protected. No reference to any individual participant 
will appear in reports, presentations, or publications that may arise from the study. 
11.0 Data Safety and Monitoring 
 
The principal investigator will be responsible for the overall monitoring of the data and 
safety of study participants. The principal investigator will be assisted by other members 
of the study staff. 
12.0 Reporting of Unanticipated Problems, Adverse Events or 
Deviations 
 
Any unanticipated problems, serious and unexpected adverse events, deviations or 
protocol changes will be promptly reported by the principal investigator or designated 
member of the research team to the IRB and sponsor or appropriate government 
agency if appropriate. 


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13.0 Adverse Events List and Reporting Requirements 
 
13.1 Adverse Event List for Propranolol 
Cardiovascular: Bradycardia; congestive heart failure; intensification of AV block; 
hypotension; paresthesia of hands; thrombocytopenic purpura; arterial 
insufficiency, usually of the Raynaud type.  
 
Central Nervous System: Light-headedness, mental depression manifested by 
insomnia, lassitude, weakness, fatigue; catatonia; visual disturbances; 
hallucinations; vivid dreams; an acute reversible syndrome characterized by 
disorientation for time and place, short-term memory loss, emotional lability, 
slightly clouded sensorium, and decreased performance on neuropsychometrics. 
For immediate-release formulations, fatigue, lethargy, and vivid dreams appear 
dose-related.  
 
Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, 
diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis.  
 
Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid 
reactions, pharyngitis and agranulocytosis; erythematous rash, fever combined 
with aching and sore throat; laryngospasm, and respiratory distress.  
 
Respiratory: Bronchospasm.  
 
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic 
purpura.  
 
Autoimmune: Systemic lupus erythematosus (SLE).  
Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal 
necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, 
alopecia, SLE-like reactions, and psoriasiform rashes. Oculomucocutaneous 
syndrome involving the skin, serous membranes and conjunctivae reported for a 
beta blocker (practolol) have not been associated with propranolol.  
 
Genitourinary: Male impotence; Peyronie's disease. 
 
13.2 Adverse Event Characteristics 
• 
CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 


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• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 
above) for expedited reporting purposes only.   
 
• 
Attribution of the AE: 
 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
13.3 DSMC SAE Reporting Requirements 
The Data and Safety Monitoring Committee (DSMC) is responsible for reviewing SAEs 
for WFBCCC Institutional studies as outlined in Appendix F. DSMC currently requires 
that all unexpected 4 and all grade 5 SAEs on these trials be reported to them for 
review. All WFBCCC Clinical Research Management (CRM) staff members assisting a 
Principal Investigator in investigating, documenting and reporting an SAE qualifying for 
DSMC reporting are responsible for informing a clinical member of the DSMC as well as 
the entire committee via the email notification procedure of the occurrence of an SAE.  
13.4 WFBH IRB AE Reporting Requirements 
Any unanticipated problems involving risks to subjects or others and adverse events 
shall be promptly reported to the IRB, according to institutional policy. Reporting to the 
IRB is required regardless of the funding source, study sponsor, or whether the event 
involves an investigational or marketed drug, biologic or device. Reportable events are 
not limited to physical injury, but include psychological, economic and social harm. 
Reportable events may arise as a result of drugs, biological agents, devices, procedures 
or other interventions, or as a result of questionnaires, surveys, observations or other 
interactions with research subjects. 
 
All members of the research team are responsible for the appropriate reporting to the 
IRB and other applicable parties of unanticipated problems involving risk to subjects or 
others. The Principal Investigator, however, is ultimately responsible for ensuring the 
prompt reporting of unanticipated problems involving risk to subjects or others to the 
IRB. The Principal Investigator is also responsible for ensuring that all reported 
unanticipated risks to subjects and others which they receive are reviewed to determine 
whether the report represents a change in the risks and/or benefits to study participants, 
and whether any changes in the informed consent, protocol or other study-related 
documents are required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a site 
where the study has been approved by the WFBH IRB (internal events) must be 
reported to the WFBH IRB within 7 calendar days of the investigator or other members 
of the study team becoming aware of the event. 
 
Any unanticipated problems involving risks to subjects or others occurring at another site 
conducting the same study that has been approved by the WFBH IRB (external events) 
must be reported to the WFBH IRB within 7 calendar days of the investigator or other 
members of the study team becoming aware of the event. 


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Any event, incident, experience, or outcome that alters the risk versus potential benefit 
of the research and as a result warrants a substantive change in the research protocol or 
informed consent process/document in order to insure the safety, rights or welfare of 
research subjects. 
14.0 Pharmaceutical Information 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 12.1. 
 
14.1 Pharmaceutical Accountability 
Propranolol will be provided by the study as per section 5.0. 
14.2 Propranolol  
 
Product description:  Propranolol hydrochloride is a stable, white, crystalline 
solid  available in 10, 20, 40, 60 and 80 mg tablets. For this study, 40 mg tablets 
will be used. 
 
Solution preparation:  NA 
Storage requirements:  Store at room temperature. Protect from light 
Stability:  Propranolol is stable. 
Route of administration:  Take by mouth 2 hours before prostate biopsy 
Disposal:  Dispose of any unused tablets in line with local and institutional 
regulations. 
 
 


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References 
1. 
Hassan S, Karpova Y, Baiz D, et al. Behavioral stress accelerates prostate 
cancer development in mice. The Journal of clinical investigation. 
2013;123(2):874-886. 
2. 
Hassan S, Karpova Y, Flores A, et al. A pilot study of blood epinephrine levels 
and CREB phosphorylation in men undergoing prostate biopsies. International 
urology and nephrology. 2014;46(3):505-510. 
3. 
Le CP, Nowell CJ, Kim-Fuchs C, et al. Chronic stress in mice remodels lymph 
vasculature to promote tumour cell dissemination. Nature communications. 
2016;7:10634. 
4. 
Lu D, Sinnott JA, Valdimarsdottir U, et al. Stress-Related Signaling Pathways in 
Lethal and Nonlethal Prostate Cancer. Clinical cancer research : an official 
journal of the American Association for Cancer Research. 2016;22(3):765-772. 
5. 
Kulik G. Targeting psychoemotional stress to treat prostate cancer. Asian journal 
of andrology. 2013;15(3):362-363. 
6. 
Armaiz-Pena GN, Allen JK, Cruz A, et al. Src activation by beta-adrenoreceptors 
is a key switch for tumour metastasis. Nature communications. 2013;4:1403. 
7. 
Braadland PR, Ramberg H, Grytli HH, Tasken KA. beta-Adrenergic Receptor 
Signaling in Prostate Cancer. Frontiers in oncology. 2014;4:375. 
8. 
Cardwell CR, Coleman HG, Murray LJ, O'Sullivan JM, Powe DG. Beta-blocker 
usage and prostate cancer survival: a nested case-control study in the UK 
Clinical Practice Research Datalink cohort. Cancer epidemiology. 
2014;38(3):279-285. 
9. 
Grytli HH, Fagerland MW, Fossa SD, Tasken KA. Association between use of 
beta-blockers and prostate cancer-specific survival: a cohort study of 3561 
prostate cancer patients with high-risk or metastatic disease. Eur Urol. 
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10. 
Grytli HH, Fagerland MW, Fossa SD, Tasken KA, Haheim LL. Use of beta-
blockers is associated with prostate cancer-specific survival in prostate cancer 
patients on androgen deprivation therapy. Prostate. 2013;73(3):250-260. 
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Perron L, Bairati I, Harel F, Meyer F. Antihypertensive drug use and the risk of 
prostate cancer (Canada). Cancer causes & control : CCC. 2004;15(6):535-541. 
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Rodriguez C, Jacobs EJ, Deka A, et al. Use of blood-pressure-lowering 
medication and risk of prostate cancer in the Cancer Prevention Study II Nutrition 
Cohort. Cancer causes & control : CCC. 2009;20(5):671-679. 
13. 
Shah SM, Carey IM, Owen CG, Harris T, Dewilde S, Cook DG. Does beta-
adrenoceptor blocker therapy improve cancer survival? Findings from a 
population-based retrospective cohort study. British journal of clinical 
pharmacology. 2011;72(1):157-161. 
14. 
Wang HM, Liao ZX, Komaki R, et al. Improved survival outcomes with the 
incidental use of beta-blockers among patients with non-small-cell lung cancer 
treated with definitive radiation therapy. Annals of oncology : official journal of the 
European Society for Medical Oncology / ESMO. 2013;24(5):1312-1319. 
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Chang PY, Huang WY, Lin CL, et al. Propranolol Reduces Cancer Risk: A 
Population-Based Cohort Study. Medicine. 2015;94(27):e1097. 


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16. 
Watkins JL, Thaker PH, Nick AM, et al. Clinical impact of selective and 
nonselective beta-blockers on survival in patients with ovarian cancer. Cancer. 
2015;121(19):3444-3451. 
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London MJ, Hur K, Schwartz GG, Henderson WG. Association of perioperative 
beta-blockade with mortality and cardiovascular morbidity following major 
noncardiac surgery. Jama. 2013;309(16):1704-1713. 
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Dyck JB, Chung F. A comparison of propranolol and diazepam for preoperative 
anxiolysis. Canadian journal of anaesthesia = Journal canadien d'anesthesie. 
1991;38(6):704-709. 
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Khadke VV, Khadke SV, Khare A. Oral propranolol--efficacy and comparison of 
two doses for peri-operative anxiolysis. Journal of the Indian Medical Association. 
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20. 
Ray K, Trawick WG, Mullins RE. Assay of total and free propranolol in plasma by 
liquid chromatography with fluorometric detection. Clinical chemistry. 
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Salman SA, Sulaiman SA, Ismail Z, Gan SH. Quantitative determination of 
propranolol by ultraviolet HPLC in human plasma. Toxicology mechanisms and 
methods. 2010;20(3):137-142. 
22. 
Sood SP, Green VI, Mason RP. Routine methods in toxicology and therapeutic 
drug monitoring by high-performance liquid chromatography. IV. A rapid 
microscale method for determination of propranolol and 4-hydroxypropranolol in 
plasma. Therapeutic drug monitoring. 1988;10(2):224-230. 
23. 
Zhang X, Odom DT, Koo SH, et al. Genome-wide analysis of cAMP-response 
element binding protein occupancy, phosphorylation, and target gene activation 
in human tissues. Proceedings of the National Academy of Sciences of the 
United States of America. 2005;102(12):4459-4464. 
24. 
Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. 
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25. 
Donovan KA, Grassi L, McGinty HL, Jacobsen PB. Validation of the distress 
thermometer worldwide: state of the science. Psycho-oncology. 2014;23(3):241-
250. 


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Appendix A – Subject Eligibility Checklist  
IRB Protocol No.  00043227 
WFBCCC Protocol No. 8 5 7 1 6  
Study Title: Evaluating the effect of the ADRB2 blockers on PKA/BAD/CREB signaling in the 
prostate gland 
 
Principal Investigator:  Ashok Hemal, M.D., George Kulik, D.V.M, Ph.D. 
 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab 
results) 
Men > 18 years of age 
□ 
□ 
 
Patients undergoing prostate biopsy or 
prostatectomy 
 
□ 
□ 
 
Individuals able to understand and willing to sign 
an IRB-approved informed consent document 
□ 
□ 
 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab 
results) 
Men taking propranolol daily for any reason are 
excluded 
□ 
□ 
 
Men with baseline SBP <120 or HR <63 
□ 
□ 
 
Men unable to swallow pills 
□ 
□ 
 
History of current or past medical or psychiatric 
illness that would make participation difficult or not 
feasible at the discretion of the principal 
investigator or co-investigators 
□ 
□ 
 
 
This subject is      
 eligible /  ineligible     for participation in this study. 
 
WISER Assigned PID: __________________ 
 
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility:_______________________  
Date: _______________ 
 
Signature of Treating Physician**:  _____________________________________  
Date:  _______________ 
 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing 
the source, specifically state which document in the medical record was used to assess eligibility. Also 
include the date on the document. Example: “Pathology report, 01/01/14” or “Clinic note, 01/01/14” 
 
**Principal Investigator signature can be obtained following registration if needed 
 
 


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Appendix B – Protocol Registration Form  
DEMOGRAPHICS 
Patient: Last Name: _____________________ First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
ZIPCODE:  ___ ___ ___ ___ ___ 
 
 
 
 
Ethnicity (choose one):   Hispanic 
Non-Hispanic 
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
 
 
 
 
Primary Diagnosis: ____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
 
Randomization 
This patient has been randomly assigned to the following treatment arm (Check one): 
 
_______ Propranolol and Prostate biopsy or prostatectomy (Group 1) 
 
_______ Prostate biopsy or prostatectomy only (Group 2) 
 
Randomization Recorded by: ________________ Date___ ___ / ___ ___ / ___ ___Time______ 
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, Monday – Friday. 
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, faxed or e-mailed to 
the registrar at 336-7136772 or registra@wakehealth.edu. 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to 
registration) 
 YES   NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
PID # (to be assigned by WISER): 
___ ___ ___ ___ ___ ___ ___ ___ 


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Appendix C – Perceived Stress  
Perceived Stress Scale – 4* 
 
To be filled out by clinical staff 
 
WISER PID: __ __ __ __ __ __ __ __ 
Date Completed: __ __ / __ __ / __ __ 
 
PI: Ashok Hemal, M.D., George Kulik, D.V.M., Ph.D.  Study Number: 8_ 5_ 7_ 1_ 6_ 
 
 
To be filled out by the patient: 
Instructions: This set of questions asks about your feelings over the LAST 2 WEEKS.  
Please indicate how often you have felt this way. 
Questions 
1. In the last 2 weeks, how often have you felt that  
☐0 = Never 
you were unable to control the important things in  
☐1 = Almost Never 
your life?  
 
 
 
 
 
 
☐2 = Sometimes 
☐3 = Fairly Often 
☐4 = Very Often 
 
2. In the last 2 weeks, how often have you felt   
☐0 = Never 
confident about your ability to handle your personal  
☐1 = Almost Never 
problems?   
 
 
 
 
 
☐2 = Sometimes 
☐3 = Fairly Often 
☐4 = Very Often 
 
3. In the last 2 weeks, how often have you felt that  
☐0 = Never 
things were going your way?  
 
 
 
☐1 = Almost Never 
☐2 = Sometimes 
☐3 = Fairly Often 
☐4 = Very Often 
 
4. In the last 2 weeks, how often have you felt   
☐0 = Never 
difficulties were piling up so high that you could  
☐1 = Almost Never 
not overcome them?  
 
 
 
 
☐2 = Sometimes 
☐3 = Fairly Often 
☐4 = Very Often 
*Modified from: 
Cohen, S., Kamarck, T, and Mermelstein, R. "A Global Measure of Perceived Stress." Journal of 
Healthand Social Behavior, Vo. 24, No. 4 (Dec.,1983) 


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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
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Protocol version date 12/26/18  
 
 
 
 
 
Page 29 of 48 
 
Appendix D – Distress Thermometer 
 
 
WISER PID: __ __ __ __ __ __ __ __ Date Completed: __ __ / __ __ / __ __ 
 
PI: Ashok Hemal, M.D., George Kulik, D.V.M., Ph.D.  
 
Study Number:_8_ _5_ _7_ _1_ _6_ 
 


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Appendix E – Adverse Events Log 
WFBCCC 85716 Adverse Event (AE) Log 
PI: Ashok Hemal, MD; 
George Kulik, DVM, PhD 
 
PID: __ __ __ __ __ __ __ __ 
 
MRN: __ __ __ __ __ __ __ __ 
 
 
 
 
Date: __ __/__ __/__ __ 
 
 
 
 
 
 
Adverse 
Event CTC 
Term 
Value 
(-5 if non-
numeric) 
Grade 
(0-5) 
per 
CTC 
Start 
Date 
Attribution 
1=Related 
2=Probably 
3=Possible 
4=Unlikely 
5=Unrelated 
Treating MD 
Initials/Date 
End 
Date 
Expected 
1=Yes       
0=No 
*Serious 
Adverse 
Event 
(SAE)   
1=Yes 
0=No 
Dose 
Limiting 
Toxicity 
(DLT) 
1=Yes 
0=No 
Action 
Taken 
1=None    
2=Tx 
withheld 
3=Tx D/C   
4=Tx 
adjusted 
5=Other 
Reportable?  
1=IRB 
2=DSMC 
3=FDA 
4=Sponsor 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
*Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening; Death. 
CTCAE Version 4 - http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 


 
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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
WFBCCC # 85716 
 
 
Appendix F – Mandatory DSMC SAE Reporting Guidelines 
 
Data and Safety Monitoring Committee 
(DSMC) Serious Adverse Event (SAE) 
Notification SOP 
Date: 02/11/2021 
 
Mandatory DSMC SAE Reporting Requirements in WISER 
This document describes reporting requirements of adverse events from WFBCCC 
Investigator Initiated interventional trials to the Data and Safety Monitoring Committee 
(DSMC). A trial is considered a WFBCCC Investigator Initiated interventional trial if the 
following criteria are met: 
 
1) The Principal Investigator (PI) of the trial is a member of a department at the 
Wake Forest University Baptist Medical Center. 
2) WFBCCC is considered as the primary contributor to the design, implementation 
and/or monitoring of the trial. 
3) The trial is designated as “Interventional” using the Clinical Research 
Categories definitions provided by the NCI in the Data Table 4 
documentation. 
(https://cancercenters.cancer.gov/GrantsFunding/DataGuide#dt4) 
 
There are two distinct types of WFBCCC Investigator Initiated interventional trials based 
on where patient enrollment occurs.  These include: 
 
1) Local WFBCCC Investigator Initiated interventional trials defined as trials where all 
patients are enrolled from one of the WFBCCC sites. These include the main 
outpatient Cancer Center clinics (located in Winston-Salem) as well as WFBCCC 
affiliate sites located in Bermuda Run (Davie Medical Center), Clemmons, 
Lexington, High Point, or Wilkesboro. 
2) Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials 
where patients are enrolled from other sites in addition to WFBCCC sites.   
There are three types of trials that are included in this category: 
a. Trials sponsored by the NCI Community Oncology Research Program 
(NCORP) that are conducted at multiple sites where the PI is a member of a 
department at the Wake Forest University Baptist Medical Center. 
b. Trials sponsored by Industry that are conducted at multiple sites and the 
PI is a member of a department at the Wake Forest University Baptist 
Medical Center. 
c. Trials sponsored by WFBCCC that are conducted at multiple sites and the 
PI is a member of a department at the Wake Forest University Baptist 
Medical Center. 


 
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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
WFBCCC # 85716 
 
 
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients 
enrolled on WFBCCC Investigator Initiated Interventional trials must be entered into the 
WISER system. The only exception to this requirement is for patients enrolled on NCORP 
trials at non- WFBCCC sites. AEs and SAEs for NCORP patients enrolled at WFBCCC sites 
must be entered into the WISER system. Once these AEs and SAEs are entered in WISER, 
certain actions must be taken regarding the reporting of specific Adverse Events to the 
DSMC. 
 
All Adverse Events that occur during protocol intervention (defined below) and are coded 
as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours 
(regardless of grade), or grade 5 (death) must be reported to the DSMC using the using 
the SAE console in WISER. 
 
A research nurse or clinical research coordinator when made aware that an adverse event 
meets one of the above criteria has occurred on a WFBCCC Investigator Initiated 
interventional trial, is responsible for informing a clinical member of the DSMC by phone 
(or in-person) about the adverse event. The nurse/coordinator should contact the treating 
physician prior to calling the DSMC clinical member to obtain all details of the SAE, as well 
as all associated toxicities to be recorded along with the SAE. In addition, this nurse or 
coordinator is responsible for entering the adverse event information into the SAE console 
in WISER.  Once the adverse event has been entered into the SAE console an email 
informing the entire DSMC will be generated. 
 
THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a 
WFBCCC Institutional Interventional trial. Ultimately, the protocol PI has the primary 
responsibility for AE identification, documentation, grading and assignment of attribution 
to the investigational agent/intervention. However, when an AE event as described above 
is observed, it is the responsibility of the person who observed the event to be sure that it 
is reported to the DSMC. 
 
What is considered during protocol intervention? 
During protocol intervention is considered to be the time period while a patient is on study 
treatment or during the time period within 30 days of last study treatment (even if patient 
begins a new (non-study) treatment during the 30 days). This window of 30 days should be 
the standard window to be used in all protocols unless a specific scientific rationale is 
presented to suggest that a shorter window can be used to identify events. If it is a trial 
sponsored by Industry and the sponsor requires a longer window for monitoring of SAEs, 
then the longer window of time specified by the sponsor should be followed. 
 
What is considered as an Unexpected Grade 4 event? 
Any grade 4 event that was not specifically listed as an expected adverse event in the 


 
Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate 
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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
WFBCCC # 85716 
 
 
protocol should be considered as unexpected. A grade 4 adverse event can be considered to 
be unexpected if it is an event that would not be expected based on the treatment being 
received or if it is unexpected based on the health of the patient. In either case, if there is 
any uncertainty about whether a grade 4 adverse event is expected or unexpected it should 
be reported to DSMC. 
 
DSMC notification responsibilities of the person (e.g., nurse) handling the 
reporting/documenting of the SAE in WISER: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the 
DSMC according to the schedule as listed below (page if necessary). 
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in 
WISER WITHIN 24 HOURS of first knowledge of the event. Information can be 
entered and saved, but the DSMC members will not be notified until a date is 
entered into the  DSMC Notification Date Field. This will ensure that all persons that 
need to be made aware of the event (i.e., PI, study team members and DSMC 
members) will be notified; remember to file a copy of the confirmation. 
3. Document that the appropriate person(s) on the DSMC has been contacted. Indicate 
the name of the DSMC clinician that was contacted and the date and time contacted 
in the Event Narrative field in the SAE console of the particular subject. 
4. Document whether or not the protocol should be suspended based on the 
discussion with the DSMC clinician. This is the major function of the email 
notification. Enter whether the protocol should be suspended in the Event Narrative 
Field. 
5. Follow up/update the clinical member(s) of DSMC regarding any new developments 
or information obtained during the course of the SAE investigation and reporting 
process. 
 
Elements needed to complete the SAE form in the Subject Console in WISER (see Screen Shot 
3): 
1. Event Date 
2. Reported Date 
3. Reported by 
4. If Grade 5, enter Death Date 
5. If Grade 5, enter Death occurred: within 30 days 
6. Event Narrative: Brief description (include brief clinical history relevant to this event, 
including therapies believed related to event). Begin narrative with the DSMC clinician 
who was notified and Date/Time notified. In addition, state attribution by DSMC 
clinician as either “Unrelated”, “Unlikely”, “Possibly”, “Probably”, or “Definitely”.  
Always include the following here: 
i. DSMC clinician name, date/time contacted and comments 
ii. Date of last dose before the event 


 
Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate 
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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
WFBCCC # 85716 
 
 
iii. Is suspension of the protocol needed? Y/N 
7. Treating Physician comments 
8. PI comments, if available 
9. Protocol Attribution after discussion with DSMC clinician 
10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, Not Recovered/Not 
Resolved, Recovered/Resolved with Sequelae, Recovered/Resolved without Sequelae, 
Recovering and Resolving) 
11. Consent form Change Required? Y/N 
12. SAE Classification *This is required in order for the email notification to be sent* 
13. Adverse Event Details – Enter all details for each AE associated with the SAE. 
a. Course start date 
b. Category 
c. AE Detail 
d. Comments 
e. Grade/Severity 
f. Unexpected Y/N 
g. DLT Y/N 
h. Attributions 
i. Action 
j. Therapy 
k. Click ADD to attach the AE Detail to the SAE. 
14. Enter Date Notified DSMC -- *This is required for the email notification to be sent* 
15. Click Submit. The auto-generated notification email will disseminate within 5 minutes. 
If you do not receive an email within 5 minutes, check that you have entered the 
“Date Notified DSMC” and the “SAE Classification”. If these have been entered and 
the email still has not been received, take a screen shot of the SAE in WISER and 
immediately email it out to all of the DSMC members listed in this SOP. In the subject 
line, indicate that this is a manual transmission of the SAE in lieu of the auto-
generated email. It is required that a notification goes to the DSMC members 
immediately so that their assessment can be obtained within the 24 hour period 
requirement. Contact the Cancer Center Programmer/Analyst to alert that there is an 
issue with the auto-generated email. 
 
The Clinical Members of DSMC to Notify by Phone or Page: 
 
Monday 
Tuesday 
Wednesday Thursday 
Friday 
Saturday Sunday 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 


 
Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate 
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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
WFBCCC # 85716 
 
 
Glenn Lesser, MD – Hematology Oncology 6-9527 / 6-7972 / Pager 336-806-8397  
Mercedes Porosnicu, MD-- Hematology Oncology 6-7980 / 6-0230 / Pager 336-806-9150 
Ryan Hughes, MD – Radiation Oncology 3-3600 / Pager 336-806-9865 
Michael Goodman, MD -- Hematology Oncology 6-7970 / Pager 336-806-7283 
Daniel Reed, MD -- Hematology Oncology 3-3841 / Pager 336-806-0637 
Mary Beth Seegars, MD -- Hematology Oncology 6-4815 / Pager 336-806-9948 
 
 
Definition of Unavailable: 
As a general guideline if the first clinician that is contacted does not respond to the phone 
call or page within 30 minutes, then initiate contact with the next DSMC clinician listed in the 
table above on the particular day the SAE is being reported. Allow up to 30 minutes for the 
new DSMC clinician to respond to a phone call or page before contacting the next member in 
the table. These times (30 minutes) are a general guideline. Best judgment as a clinical 
research professional should be used giving considerations of the time of day, severity of the 
SAE, and other circumstances as to when it is appropriate to contact backup clinicians. If the 
event occurs near the end of day, then leave messages (voice or email) as appropriate and 
proceed with submitting the DSMC notification form. It is important to take reasonable steps 
and to document that some type of contact has been initiated to one or more of the clinical 
members of DSMC. 
 
DSMC CLINICAN RESPONSIBILITY: 
It is the responsibility of the DSMC clinician to review all reported events, evaluate the events 
as they are reported; and communicate a response to the Investigator, event reporter and 
the members of DSMC. The review will include but not be limited to the information 
reported; there may be times when additional information is needed in order for an 
assessment to be made and further communication directly with the investigator may be 
warranted. DSMC reserves the right to disagree with the Investigator's assessment. If DSMC 
does not agree with the Investigator, DSMC reserves the right to suspend the trial pending 
further investigation. If there is any immediate danger or harm that could be present for a 
future patient based on the information provided in the DSMC report then an immediate 
suspension of enrollment should be considered. 
 
 
AMENDMENTS TO PREVIOUS REPORTS 
If all pertinent information is unavailable with the initial submission, once the additional 
information is available do not submit a new report. Rather, go to the original email that 
was sent to the DSMC and using that email “reply to all”. Entitle this new email 
“Amendment for (list date of event and patient ID)” this will avoid duplications of the same 
event. List the additional information being reported. This information needs to be entered 
into WISER as well. To do this, go to the Subject console and click SAEs on the left column. 
Click on the appropriate SAE number that needs updating. Then click Update. This will allow 


 
Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate 
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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
WFBCCC # 85716 
 
 
additional  information to be added. 
 
Acronyms 
AE – Adverse Event 
DSMC-Data and Safety Monitoring Committee 
SAE-Serious Adverse Event 
WFBCCC – Wake Forest Baptist Comprehensive Cancer Center 
NCI-National Cancer Institute 
WISER –Wake Integrated Solution for Enterprise Research 
 
Screen Shots: 
 
The following screen shots come from the SAE Console within the Subject Console in WISER. 
Screen Shot 1: 
 
Screen Shot 2:
 


Evaluating the effect of ADRB2 blockers on PKA/BAD/CREB signaling in the prostate gland  
Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
 
 
WFBCCC # 85716 
 
Protocol version date 05/19/21 
 
 
 
 
 
 
Page 37 of 48 
 
Screen Shot 3: 
 
 
 
Screen Shot 4: 
 
 
 
 
 


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Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) 
 
 
WFBCCC # 85716 
 
Protocol version date 05/19/21 
 
 
 
 
 
 
Page 38 of 48 
 
Appendix G - Baseline Medical History 
 
Baseline Medical History and Data Collection Form 
WISER PID: _______________________ Date Completed: __ __ / __ __ / __ __ 
 
PI: Ashok Hemal, M.D. and, George Kulik, D.V.M., Ph.D.  
 
Study Number: CCCWFU 85716 
 
  
 
 
 
 
 
1. Oncologic history 
 
1. Prior prostate cancer therapies: 
 chemotherapy   
 radiation   
 surgery   
 hormone  
 other: 
__________________ 
 
 None 
 
 
 
Regimen Name 
Total # of Treatments 
Date of Last Treatment, or 
‘ongoing’ for certain HT 
1. 
 
 
2. 
 
 
3. 
 
 
4. 
 
 
5. 
 
 
Site of RT 
Total Dose in Gy 
Date of Last Treatment 
1. 
 
 
2. 
 
 
3. 
 
 
Type of surgery 
Date of surgery 
1. 
 
2. 
 
 
Hormone Therapy Name 
Dose 
Date of Last Treatment 
1. 
 
 
2. 
 
 
 
Other 
Dose 
Date of Last Treatment 
1. 
 
 
2. 
 
 
 
 
 
 


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2.   Concurrent medications and supplements 
a. List all prescription and over-the-counter medications (includes prescription supplements)     
Medication Name 
Is it PRN? 
Medication Name 
Is it PRN? 
1. 
yes         
no 
11. 
yes         
no 
2. 
yes         
no 
12. 
yes         
no 
3. 
yes         
no 
13. 
yes         
no 
4. 
yes         
no 
14. 
yes         
no 
5. 
yes         
no 
15. 
yes         
no 
6. 
yes         
no 
16. 
yes         
no 
7. 
yes         
no 
17. 
yes         
no 
8. 
yes         
no 
18. 
yes         
no 
9. 
yes         
no 
19. 
yes         
no 
10. 
yes         
no 
20. 
yes         
no 
 
3.   Vital signs: 
a. HR_________ 
b. BP____ /____ 
c. RR_________ 
d. Temp _______(°F) 
e. Weight ______(kg) 
 
 
4.   Blood Draws 
 
a.   Cancer-specific tumor marker measurement (if available): 
 
Prostate cancer: 
Testosterone,  Date __ __ /__ __ / __ __  Value: _______________ 
 
PSA,   
Date __ __ /__ __ / __ __ Value: _______________ 
 
 
 
 
Signature of research professional:_______________________ Date: __ __ / __ __ / __ __ 
 
 
 
 


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Page 40 of 48 
 
Appendix H – Tissue Collection 
 
TISSUE COLLECTION FORM 
This form is for the collection of core samples of prostate tissue. 
Sample Handling: Tubes used for collecting sample should be labelled with the patient 
study number (Patient ID), initials and date. Samples should be frozen in liquid nitrogen 
and stored in the Tumor Tissue Core at -80 until use. 
 
Tumor Tissue Core 
Wake Forest Baptist Comprehensive Cancer Center 
Tumor Tissue Core Facility 
Care of Dr. Greg Kucera 
Hanes Building Rm 4049 
Medical Center Blvd 
Winston-Salem NC 27157 
 
WISER PID: __ __ __ __ __ __ __ __ Date Completed: __ __ / __ __ / __ __ 
 
PI:, Ashok Hemal, M.D., George Kulik, D.V.M., Ph.D.  
 
Study Number:  CCCWFU 85716 
 
Drug Received 
Propranolol □ Yes 
 
□ No  
 
 
 
 
Tissue Sample 
Sample ID: _________________ 
Tissue pathology:___________________ 
Time of Collection 
Time Sample Collected __________am/pm  
Time in storage _______am/pm 
Location of Sample 
Freezer ID: _____________   Shelf: ________________  Box:______________ 
Person Collecting Tissue____________________________ Date__ __ / __ __ / __ __ 
 
 


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Deviations or notes regarding sample collection 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix I – Blood Collection 
 
BLOOD/PLASMA COLLECTION FORM 


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This form is for the collection of research blood samples to be stored for future use.  
Sample Handling: Plasma should be aliquoted in cryotubes or equivalent tubes and 
labelled with the patient study number (Patient ID), pre or post draw, initials and date. 
Samples should be frozen and stored in the Tumor Tissue Core at -80 until use. 
 
Tumor Tissue Core 
Wake Forest Baptist Comprehensive Cancer Center 
Tumor Tissue Core Facility 
Care of Dr. Greg Kucera 
Hanes Building Rm 4049 
Medical Center Blvd 
Winston-Salem NC 27157 
 
WISER PID: __ __ __ __ __ __ __ __ Date Completed: __ __ / __ __ / __ __ 
 
PI: Ashok Hemal, M.D., George Kulik, D.V.M., Ph.D.  
 
Study Number: CCCWFU 85716 
 
 
Drug Received 
Propranolol □ Yes 
 
□ No  
 
 
 
 
Plasma Sample 
Sample ID: _________________ 
Time of Collection 
Time Draw Collected __________am/pm 
Time 1 tube sent to clinical lab for catecholamine processing _______am/pmTime 
plasma was separated _______am/pm 
Time plasma placed in storage _______am/pm 
Location of Sample 
Freezer ID: _____________   Shelf: ________________  Box:______________ 
Person Processing plasma ____________________________Date__ __ / __ __ / __ __ 
Freeze Thaw Cycles (note tube number, date and amount of sample used) 


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____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________ 
Deviations or notes regarding collections and use 
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________ 
 
 
 
 
 
 
 
 
Appendix J: CREB Phosphorylation 
DATA COLLECTION FORM 
WISER PID: __ __ __ __ __ __ __ __ Date Completed: __ __ / __ __ / __ __ 
 


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PI: Ashok Hemal, M.D., George Kulik, D.V.M., Ph.D.  
 
Study Number: CCCWFU 85716 
 
Prostate CREB Phosphorylation Worksheet 
Densitometric Values 
Sample ID 
Date 
pCREB 
panCREB 
Normalized pCREB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix K: BAD Phosphorylation 
DATA COLLECTION FORM 
WISER PID: __ __ __ __ __ __ __ __ Date Completed: __ __ / __ __ / __ __ 
 
PI: Ashok Hemal, M.D., George Kulik, D.V.M., Ph.D.  
 


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Study Number:  CCCWFU 85716 
Prostate BAD Phosphorylation Worksheet 
Densitometric Values 
Sample ID 
Date 
pBAD 
panBAD 
Normalized pBAD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix L: Plasma Outcomes 
DATA COLLECTION FORM 
WISER PID: __ __ __ __ __ __ __ __ Date Completed: __ __ / __ __ / __ __ 
 
PI: Ashok Hemal, M.D., George Kulik, D.V.M., Ph.D.  
 
Study Number: CCCWFU 85716 
 
Sample ID 
Date 
Propranolol 
levels 
(ng/ml) 
Epinephrine 
(ng/ml) 
Initials 
Notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix M: RNA Analysis 
 
 
WISER PID: __ __ __ __ __ __ __ __ Date Completed: __ __ / __ __ / __ __ 
 
PI: Ashok Hemal, M.D., George Kulik, D.V.M., Ph.D.  
 
Study Number:  CCCWFU 85716 
 
 
 
 
 
 
 
 
RT-PCR Worksheet 
Sample ID or PID 
Date 
Transcript 
Relative expression  
Initials 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Appendix N: Surgery Day Worksheet  
SURGERY DAY WORKSHEET 
WISER PID: __ __ __ __ __ __ __ __ Date Completed: __ __ / __ __ / __ __ 
 
PI: Ashok Hemal, M.D., George Kulik, D.V.M., Ph.D.  
 
Study Number:   CCCWFU 85716 
 
Propranolol Administration 
 
Group Assignment (Randomization Assignment on Protocol Registration Appendix B) 
 
□ Group 1 (Propranolol) □ Group 2 (no Drug) 
□ Yes 
□ No  
Time:_______ 
Dose:__________ Initials__________ 
 
Post-randomization Activities (1-2hr Post-Drug if randomized to Group 1) 
 
 Blood Draw: □ Yes      □ No   Time________    Initials__________ 
 
Perceived Stress Survey: □ Yes 
□ No  
Time:______ Initials__________ 
Score__________________ 
 
Distress Thermometer Survey: □ Yes      □ No 
 Time ______ Initials__________ 
Score__________________ 
 
 
 
 
 
 
 
 

ICF_000.pdf: 
Official Title: Evaluating the Effect of ADRB2 Blockers on PKA/BAD/CREB Signaling 
in Patients Undergoing Prostatectomy  
IRB-Approved Date: 4/19/21
NCT03152786


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Department/Section of Hematology and Oncology
EVALUATING THE POTENTIAL OF ADRB2 BLOCKERS AS 
THERAPY FOR PROSTATE CANCER
Informed Consent Form to Participate in Research
Ashok Hemal, M.D, and George Kulik, D.V.M, Ph.D., Principal Investigators
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you are having a prostate biopsy or prostatectomy as a part of your normal care as 
indicated by your doctor. Your participation is voluntary. Please take your time in making your 
decision as to whether or not you wish to participate. Ask your study doctor or the study staff to 
explain any words or information contained in this informed consent document that you do not 
understand. You may also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to find out how reducing stress by using medication 
changes your cancer cells. Epinephrine, a molecule your body makes when you are stressed, can 
prevent cancer cells from dying in laboratory experiments. The study is designed to determine 
how the signals in cells that cause survival and death are affected by certain drugs like 
propranolol.  Propranolol is FDA approved for use in hypertension, angina and anxiety. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
About 60 people will take part in this study. The study will be conducted only at Wake Forest 
Baptist Medical Center and all 60 people will take part at this location.
WHAT IS INVOLVED IN THE STUDY?
You will be randomized into one of the study groups described below. Randomization means 
that you are put into a group by chance. It is like flipping a coin.  Group 1 will involve taking 
propranolol prior to prostate biopsy or Group 2 will involve prostate biopsy only.  You will have 
an equal chance of being placed in any group as a part of the research study, when you come to 
the clinic or hospital for your prostate biopsy or prostatectomy, you will fill out 2 stress surveys 
so we can assess how you are feeling and depending on which group you are randomized to, you 
may be asked to take a propranolol tablet (40 mg) 2 hours before you have your procedure.  You 
will also provide approximately 2 teaspoons of blood prior to your procedure to test plasma 
epinephrine level and propranolol level.  You will remain at the facility 4 hours post the dose of 
propranolol, to make sure your blood pressure is not too low.  The prostate biopsy itself and any 
biopsy -related procedure outside of those mentioned above, are not a part of the research. This is 
a part of your care. However, a small sample of your prostate tissue will be used for research.
If you take part in this study, you will have the following tests and procedures:
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00043227
Meeting Date Approved 4/19/2021          
Version Valid Until: 4/18/2022


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Prostate biopsy or prostatectomy will be performed as a normal part of your care (standard of 
care). Your doctor would have already recommended this procedure, and you should be 
scheduled or will be scheduled to have it done. 
On the day of your procedure, approximately 2 teaspoons of blood will be taken for research. 
You may be asked to take a medication called propranolol, a 40mg tablet, by mouth, one time, 2 
hours before your procedure. This is a part of the research study. 
Storage of Biological Tissue
If you agree to participate in this study, we will draw two teaspoons of blood and use some of the 
removed prostate tissue for future research. This sample will be kept, used for this study and 
remaining portions may be used in future research to learn more about other diseases.  Your sample 
will be obtained at the Comprehensive Cancer Center at Wake Forest University Baptist Medical 
Center. The sample will be stored In the Tumor Tissue Core Laboratory and it will be given only 
to researchers approved by Ashok Hemal, M.D. or George Kulik, D.V.M, Ph.D.  
Tumor Tissue Core
An Institutional Review Board (IRB) must also approve any future research study using your tissue 
sample. In order to participate in this study, you must be willing to provide this sample for future 
research. 
Your blood and tissue (prostate) sample will be stored de-identified, which means that no 
identifying information will be stored with it. Researchers will not know the name, date of birth, 
medical record number, social security number, etc., of the person who donated the sample.
The research that may be performed with your blood/prostate sample is not designed to help you 
specifically. There is no personal benefit to you from taking part in this aspect of the research 
study. It might help people who have diseases at some point in the future, but it is not known if 
this will happen. The results of the research performed with your blood /prostate sample will not 
be given to you or your doctor. The results will not be put in your medical record. The research 
using your blood/prostate sample will not affect your care.
Your blood/prostate sample will be used only for research and will not be sold. The findings 
from this research may result in the future development of products that are of commercial value. 
There are no plans to share any of the profits with you which may occur as a result of the 
research.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00043227
Meeting Date Approved 4/19/2021          
Version Valid Until: 4/18/2022


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HOW LONG WILL I BE IN THE STUDY?
This study is only 1 day, which is the day of your prostate biopsy or prostatectomy.  
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. Risks and side effects related to the propranolol we are studying include:
Risks associated with the stress surveys:
As part of this study, you will be asked questions about how you are feeling emotionally. Filling 
out this form may increase those feelings you are being questioned about.   
Risks of Propranolol
Below are side effects and how common they are that have been observed in people while taking 
propranolol.   You will only receive 1 dose of this medication.  
Common side effects of propranolol:

Feeling Weak

Low Energy
Infrequent side effects of propranolol:

Bronchospasm

Dizziness

Diarrhea

Throwing up or feeling like throwing up

Stomach Cramps
Rare side effects of propranolol:

A Spasm of the Larynx

Abnormal Heart Rhythm

Abnormally Low Blood Pressure

Acute Respiratory Distress Syndrome

Blood Pressure Drop Upon Standing

Complete Stoppage of the Heart

Confusion

Constriction of Blood Vessels of the Extremities

Hallucination

Hives or rash

Insufficient Blood Supply to the Colon

Large Purple or Brown Skin Blotches

Life Threatening Allergic Reaction

Slow Heartbeat

Throat Irritation

Fever
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00043227
Meeting Date Approved 4/19/2021          
Version Valid Until: 4/18/2022


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In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other side effects that we cannot predict. You 
should tell the research staff about all the medications, vitamins and supplements you take and 
any medical conditions you have. This may help avoid side effects, interactions and other risks.
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
Risks of Blood Draws
You may experience discomfort, bruising and/or bleeding where the needle is inserted. 
Occasionally some people become dizzy lightheaded or feel faint. Infection may occur on rare 
occasions.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
You are not expected to receive any direct benefit from taking part in this research study. We 
hope the information learned from this study will benefit other people in the future.
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all 
the choices you have. Instead of being in this study, you have these options:
This is not a treatment study. Your alternative is to not participate in this study.
WHAT ARE THE COSTS?
All study costs, including any study medications and procedures related directly to the study, will 
be paid for by the study. Costs for your regular medical care, which are not related to this study, 
will be your own responsibility.
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
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Institutional Review Board 
IRB Number:IRB00043227
Meeting Date Approved 4/19/2021          
Version Valid Until: 4/18/2022


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court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research subjects. The Certificate 
cannot be used to refuse a request for information from personnel of the United States federal or 
state government agency sponsoring the project that is needed for auditing or program evaluation 
by Wake Forest Baptist Health Comprehensive Cancer Center which is funding this project or 
for information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA). You should understand that a Certificate of Confidentiality does not 
prevent you from voluntarily releasing information about yourself or your involvement in this 
research. If you want your research information released to an insurer, medical care provider, or 
any other person not connected with the research, you must provide consent to allow the 
researchers to release it. The Certificate of Confidentiality will not be used to prevent disclosure 
as required by federal, state, or local law. The Certificate of Confidentiality will not be used to 
prevent disclosure for any purpose you have consented to in this informed consent document.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a research study.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
WILL YOU BE PAID FOR PARTICIPATING?
You will receive a $50 gift card as payment for taking part in this study and parking will be 
validated for research related visits.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by The Comprehensive Cancer Center of Wake Forest Baptist 
Hospital. The sponsor is providing money or other support to help conduct this study. 
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
WFU School of Medicine 
Institutional Review Board 
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Meeting Date Approved 4/19/2021          
Version Valid Until: 4/18/2022


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the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Ashok Hemal, M.D. or George Kulik, D.V.M, 
Ph.D.at 
 or 
, respectively.
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes: your health 
history, how you respond to study procedures, laboratory and other test results, and physical 
examinations.
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. Only the following people or organizations will be granted access to your 
Protected Health Information:
1) The study investigator and his/her staff, or others at Wake Forest University Health 
Sciences who oversee research
2) Other people or laboratories providing services for this research project on behalf of 
Wake Forest University Health Sciences and Wake Forest University Baptist Medical 
Center 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
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Institutional Review Board 
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Version Valid Until: 4/18/2022


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centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA), the Department of Health and Human Services 
(DHHS) and similar agencies in other countries.
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
1) Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, 
without violating confidentiality of the participant and to the extent permitted by other 
applicable laws.
2) Representatives from government agencies such as the US Food and Drug 
Administration (FDA).
3) The study investigator and his/her staff, or others at Wake Forest University Health 
Sciences who oversee research
4) Other people or laboratories providing services for this research project on behalf of 
Wake Forest University Health Sciences and Wake Forest University Baptist Medical 
Center 
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for at least six years after the study is finished. At that time any 
research information not already in your medical record will either be destroyed or it will be de-
identified. You will not be able to obtain a copy of your Protected Health Information in the 
research records until all activities in the study are completely finished
You can tell Ashok Hemal, M.D. or George Kulik, D.V.M, Ph.D. that you want to take away 
your permission to use and share your Protected Health Information at any time by sending a 
letter to this address:
Ashok Hemal, M.D. or George Kulik, D.V.M, Ph.D.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00043227
Meeting Date Approved 4/19/2021          
Version Valid Until: 4/18/2022


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However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this Web site at any time.
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be at the Principal Investigator’s discretion and may include any medical 
reason the Investigator may find it inappropriate for your care to be in the study. 
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Ashok Hemal, M.D. or George Kulik, D.V.M, Ph.D.at 
 or 
, respectively.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
.
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Institutional Review Board 
IRB Number:IRB00043227
Meeting Date Approved 4/19/2021          
Version Valid Until: 4/18/2022


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You will be given a copy of this signed consent form. 
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00043227
Meeting Date Approved 4/19/2021          
Version Valid Until: 4/18/2022