Intra-operative Assessment of Cavernosal Nerve Stimulus Threshold
Phase: NA
Conditions: Prostatectomy
Sponsor: Case Comprehensive Cancer Center

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STUDY NUMBER:  CASE 1816 
 
Protocol Date: 03/29/2016  
 
STUDY TITLE:  Intra-operative Assessment of Cavernosal Nerve Stimulus Threshold 
 
 
 
 
PRINCIPAL INVESTIGATOR: Eric Klein, MD 
 
PRINCIPAL INVESTIGATOR: Eric Klein, MD  
 
 
 
 
Department of Urology  
 
 
 
 
Glickman Urological and Kidney Institute  
 
 
 
 
Cleveland Clinic 
 
 
 
 
Q10-1 | 9500 Euclid Ave | Cleveland, OH 44195 
 
 
 
 
216.444.5591 | KleinE@ccf.org  
 
CO-PI: 
 
 
 
Bradley Gill, MD, MS   
 
 
 
 
Department of Urology  
 
 
 
 
Glickman Urological and Kidney Institute  
 
 
 
 
Cleveland Clinic 
 
 
 
 
Q10-1 | 9500 Euclid Ave | Cleveland,OH 44195 
 
 
 
 
216.636.9670 | GillB@ccf.org  
 
 
 
 
 
 
 
 
 
Yaw Nyame, MD, MBA   
 
 
 
 
Department of Urology  
 
 
 
 
Glickman Urological and Kidney Institute  
 
 
 
 
Cleveland Clinic 
 
 
 
 
Q10-1 | 9500 Euclid Ave | Cleveland, OH 44195 
 
 
 
 
216.636.9672| NyameY@ccf.org   
 
STATISTICIAN:  
 
Not Applicable (Co-Investigator Managed)   
 
 
 
STUDY COORDINATOR: 
Not Applicable (Co-Investigator Managed)  
 
 
SPONSOR:  
 
 
Department of Urology 
 
 
 
 
Glickman Urological and Kidney Institute 

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Cleveland Clinic   
 
 
 
 
 
 
 
SUPPORT/FUNDING: 
 
Department of Urology 
 
 
 
 
Glickman Urological and Kidney Institute 
 
 
 
 
Cleveland Clinic   
 
SUPPLIED AGENT(S):  
None   
 
IND #:  
 
 
 
None   
 
 
OTHER AGENT(S): 
 
None  
 

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SUMMARY OF CHANGES 
 
 
Protocol 
Date 
Section 
Change 
03-29-16 
 
Initial CASE CCC PRMC Submission per CCF IRB Requirement  
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SCHEMA 
 
Patients will be randomly assigned to a cavernosal nerve electrical stimulation testing 
algorithm of 4 different stimulus patterns in sequence (Table 1) while intercavernosal 
pressure is recorded to detect penile erection. Specifically, a fixed frequency and pulse 
width will be set with amplitude started at 1 mA and increased by 5 mA increments, to a 
maximum of 30 mA or until intracavernosal pressure is observed to persistently rise. 
Upon pressure rise, amplitude will be decreased by 5 mA and then increased by 1 mA 
increments to identify the threshold level. If no pressure changes are appreciated, the 
contralateral neurovascular bundle will be assessed, and if no pressure changes are 
observed here, the procedure will be aborted.  
 
Table 1: Stimulus Parameter Testing Algorithm  
 
Stimulus 
Pattern 
Frequency 
Pulse Width 
Amplitude 
(Variable) 
1 
10 Hz 
100 µs 
1 mA to 30mA 
2 
10 Hz 
200 µs 
1 mA to 30mA 
3 
7 Hz 
100 µs 
1 mA to 30mA 
4 
7 Hz 
200 µs 
1 mA to 30mA 
 
 

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PROTOCOL SUMMARY 
 
Protocol Number/Title 
CASE 1816 
Study Phase 
Pilot   
Brief Background/Rationale
 
 
 
Erectile dysfunction persists in approximately 80% of men 
1 year after prostatectomy. Various erectile rehabilitation 
strategies have not provided benefit. Electrical stimulation 
has been demonstrated to benefit neuroregeneration and the 
functional recovery of neuromuscular systems. Therefore, 
electrical stimulation of the cavernosal nerves during 
radical prostatectomy is being investigated for its potential 
development into a treatment aimed at improving recovery 
of erectile function after prostatectomy. This pilot study is 
intended to determine the threshold of electrical stimulation 
that results in penile erection, as defined by persistent 
intracavernosal pressure increase, such that future studies of 
sub-threshold stimulation may be pursued.  
Primary Objective  
Endpoint for this study is the accrual of 7 patients and 
collection of cavernosal nerve stimulation thresholds for 
induction of penile erection in each.  
Secondary Objective(s) 
None  
Exploratory Objective(s) 
None  
Correlative Objective(s) 
None  
Sample Size 
7 men age 18 years or older  
Disease sites/Conditions 
Prostate cancer being treated with radical prostatectomy. 
Interventions 
Unilateral cavernosal nerve electrical stimulation, possible 
contralateral cavernosal nerve electrical stimulation, and 
intracavernosal pressure recording.  
 
 
 
 
 
 
 
 
 
 

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ABBREVIATIONS  
 
 
 
CCCC Case Comprehensive Cancer Center 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
PRMC
Protocol Review and Monitoring Committee
SOC 
Standard of Care 
CCF 
Cleveland Clinic Foundation 

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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Erectile Dysfunction after Prostatectomy   
1.2  
Cavernosal Nerve Electrical Stimulation and Nerve Regeneration  
1.3  
Study Rationale  
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2 
Secondary Objectives 
 
3.0 
STUDY DESIGN 
3.1 
Prospective Pilot Study  
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
3.4 
Expected Duration of Treatment and Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Treatment Regimen Overview  
6.2 
Dose Escalation  
6.3  
Definition of Dose Limiting Toxicity 
6.4 
General Concomitant Medications and Supportive Care Guidelines 
6.5 
Criteria for Removal from Study 
6.6 
Duration of Follow-Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
Adverse Events  
8.2 
Definitions 
8.3 
Serious Adverse Event Report Form 
8.4 
Reporting Procedures for Serious Adverse Event  
8.5 
Serious Adverse Events and OnCoreTM    
8.6 
Data Safety Toxicity Committee 
8.7 
Data and Safety Monitoring Plan 
 
9.0 
TREATMENT INFORMATION  
9.1 
Investigational Agent(s) 
 
 

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10.0 
EXPLORATORY/CORRELATIVE (NOT APPLICABLE)   
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study Parameters 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT  
12.1 
Intracavernosal Pressure Measurement  
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
REFERENCES 
 
  
 
 

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1.0 
Introduction  
 
1.1 
Erectile Dysfunction after Prostatectomy   
 
Erectile dysfunction persists up to 1 year after radical prostatectomy in approximately 
70% to 80% of cases, whether performed with open or robotic surgical approaches 
(O’Neil 2016). Approximately 30 years ago, it was identified that intraoperative 
preservation of the prostatic neurovascular bundles containing the cavernous nerves 
enabled some men to recover and maintain erectile function after surgery (Lepor 1985). 
Prior to this discovery, the surgery essentially had a 100% rate of erectile dysfunction.  
 
Since that time, technologic advances in pelvic surgery, such as robotic surgery, have 
demonstrated a minimal advantage over open surgery in terms of postoperative erectile 
dysfunction rates. Furthermore, there is limited data to suggest current postoperative 
penile rehabilitation therapies provide a marked improvement in erectile function 
recovery after pelvic surgery. One temporal analysis found stable rates of erectile 
dysfunction, at 70% to 90%, from the mid-1990s through the current era (Schauer 2015). 
A contemporary analysis of patient-reported outcomes confirms that 78% to 88% of men 
demonstrate some degree of erectile dysfunction after prostatectomy (O’Neil 2016).  
 
1.2  
Cavernosal (Cavernous) Nerve Electrical Stimulation   
 
1.2.1  Preclinical Data: Electrical Stimulation and Nerve Regeneration  
 
Electrical stimulation elsewhere in urology, specifically the sacral and pudendal nerves, 
has been applied with permanently implanted devices, and used successfully to treat 
voiding dysfunction. Laboratory studies have shown that temporary pudendal nerve 
stimulation in animal models of incontinence can improve neuroregeneration by 
increasing neurotrophin levels within the nerve, a phenomenon observed in other 
peripheral nerves (Jiang 2013). This beneficial effect of temporary nerve stimulation, and 
the practice of urologic patients treated with nerve stimulators undergoing temporary 
percutaneous test stimulation before implantation, led to our overall hypothesis for a 
long-term series of clinical studies: temporary percutaneous stimulation of the cavernous 
nerves after prostatectomy will improve neuroregeneration, and the subsequent 
postoperative recovery of postoperative erectile function, as defined by a reduced erectile 
dysfunction rate, better quality of erections, shorter time to functional recovery, and 
improved patient satisfaction.  
 
The stimulation assessed in the animal models of pudendal nerve recovery was performed 
with sub-threshold (20 Hz frequency, 0.3 mA amplitude, 100µs pulse width) parameters, 
which did not result in end-organ activation (anal sphincter contraction). The ideal 
application of electrical stimulation to facilitate recovery of erectile function will 
similarly utilize sub-threshold (i.e. stimulation parameters will not result in an erection) 
parameters. Previous work during intraoperative cavernous nerve mapping studies 
confirmed the ability of intraoperative stimulation (20 Hz frequency, 1-10 mA amplitude, 
220µs pulse width) to produce erections (Rehman 1999). However, the stimulus 

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thresholds at which sub-threshold stimulation became supra-threshold stimulation are 
unknown. 
 
1.2.2 Clinical Data: Cavernosal Nerve Stimulation for Anatomic Localization  
 
The use of electrical stimulation has been applied to prostatectomy for the purpose of 
cavernous nerve localization to facilitate their anatomic preservation. Commercially 
available devices for this purpose have been developed; however, current surgical 
approaches and improved understanding of pelvic anatomy have resulted in 
intraoperative electrical stimulation providing no advantage in preserving the prostatic 
neurovascular bundles and cavernous nerves. The implantation of permanent electrodes 
for stimulating (20 Hz frequency, 5mA - 60 mA amplitude, 260 &#120757;s pulse width) 
the cavernous nerves to produce erections has been investigated, but this has never gone 
beyond initial clinical trials (Burnett 2008).  
 
1.3 
Study Rationale  
 
Various laboratory studies have investigated using biologically active molecules to 
facilitate neuroregeneration of the cavernous nerves. These include various growth 
factors, such as neurotrophins, as well as the use of stem cells. While animal models have 
shown some promise with these, the clinical investigation of such treatments has been 
limited by their unknown systemic effects and other potential adverse risks they pose. 
These challenges highlight the potential for application of non-biologic therapies, such as 
electrical stimulation, to augment neuroregeneration. Electrical stimulation, which has 
been demonstrated safe and well tolerated in many other human appilcations, has been 
shown to enhance neuroregeneration. As cavernosal nerve electrical stimulation can 
result in penile erection, determining sub-threshold stimulation parameters is necessary 
such that men can undergo stimulation after surgery and not develop penile erection with 
an indwelling foley catheter. This will facilitate both their comfort and social acceptance 
of the treatment.  
 
2.0  
Objectives 
 
2.1  
Primary Objective  
 
To determine the cavernosal nerve electrical stimulation amplitude thresholds at which an 
erection, as indicated by persistent increases in intracavernosal pressure, occurs for 
various stimuli of fixed frequency and fixed pulse-width.  
 
2.2  
Secondary Objective  
 
There are no secondary objectives of this study.  
 
3.0 
Study Design 
 
3.1  
Prospective Pilot Study   

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This is a prospective pilot study used to determine a threshold range of cavernosal nerve 
electrical stimulation parameters that result in penile erection. Assignment to the order of 
stimulation paradigms will be randomized. No placebos are used. No blinding is used.  
 
3.2 
Number of Subjects 
 
This study will enroll a total of 7 men, over age 18, who are undergoing prostatectomy 
for prostate cancer.  
 
3.3 
Replacement of Subjects  
 
If men do not respond to intraoperative electrical stimulation, as evidenced by 
intracavernosal pressure increase, they will not be replaced. These men will be deemed 
non-responders. If men opt out of stimulation preoperatively, they will be replaced. If the 
cavernous nerves are sacrificed intraoperatively, these men will be replaced. In total, only 
7 men will undergo stimulation testing.  
 
3.4  
Expected Duration of Treatment and Subject Participation 
 
Treatment will be performed intraoperatively and take approximately 20 to 30 minutes. 
Thereafter, patients will be monitored as part of standard care, for approximately 24 
hours postoperatively. Following this, they will be reassessed at the standard 
postoperative outpatient follow-up visit approximately 7 to 21 days after prostatectomy.  
 
4.0 
Subject Selection 
 
Each of the criteria in the sections that follow must be met in order for a subject to be 
considered eligible for this study. Use the eligibility criteria to confirm a subject’s 
eligibility.  
 
4.1 
Inclusion Criteria 
 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment:  
 
Below are common examples: Edit per protocol or see further examples hyperlinked 
above.  
 
 
 
4.1.1 Subjects must have prostate cancer being treated via radical prostatectomy 
by a single surgeon (primary investigator) with planned intraoperative nerve 
sparing.  
 
 
 
4.1.2 Subjects must have intact preoperative erectile function, sufficient for 
penetrative intercourse without medication nor assistive device, as defined by a 
SHIM / IIEF-2 score 22 or higher, which is collected as part of routine care.  
 
 
 
4.1.3 Age > 18 years, as prostate cancer is not routinely treated in children.  

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4.1.7 Subjects must have the ability to understand and the willingness to sign a 
written informed consent document. 
 
4.2 
Exclusion Criteria 
 
The presence of any of the following will exclude a subject from study enrollment. 
 
 
 
4.2.1 Baseline erectile dysfunction, as defined by the use of medications or 
devices to assist erection, lack of baseline erections, or a SHIM / IIEF-2 21 or 
lower, which is collected as part of routine care.  
 
 
 
4.2.2 Lack of successful intraoperative nerve sparing.   
 
 
 
4.2.3 Neurologic, metabolic, or vascular diseases that may negatively impact 
erectile function, such as: diabetes mellitus, peripheral vascular disease, coronary 
artery disease, stroke, multiple sclerosis, parkinson’s disease, multiple systems 
atrophy, epilepsy, or spinal cord injury. 
 
_
 
4.2.4 Inability to provide a fully informed consent.  
  
4.3 
Inclusion of Women and Minorities  
 
Men of all races and ethnic groups are eligible for this trial. Women are not eligible due 
to the lack of a prostate and penis.  
 
5.0 
Registration 
 
All subjects who have been consented are to be registered in the OnCore™ Database. For 
those subjects who are consented, but not enrolled, the reason for exclusion must be 
recorded. 
 
All subjects will be registered through Cleveland Clinic and will be provided a study 
number by contacting the study coordinator listed on the cover page.  
 
Subjects will be randomized to the order of the four stimulus paradigms being studied.  
 
6.0  
Treatment Plan 
 
6.1 
Treatment Regimen Overview 
 
All cavernous nerve electrical stimulation patterns (labeled 1 – 4 in Table 1) will be 
tested in each patient in a randomized order.  
 
Table 1: Stimulus Parameter Testing Algorithm  
 

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Stimulus 
Pattern 
Frequency 
Pulse Width 
Amplitude 
(Variable) 
1 
10 Hz 
100 µs 
1 mA to 30mA 
2 
10 Hz 
200 µs 
1 mA to 30mA 
3 
7 Hz 
100 µs 
1 mA to 30mA 
4 
7 Hz 
200 µs 
1 mA to 30mA 
 
Treatment will only be administered intraoperatively.  
 
Appropriate dose modifications for the Electrical Stimulation are described in Section 
7.0.  
 
Reported adverse events and potential risks of Electrical Stimulation are described in 
Section 8.0.  
 
There are no restrictions on other investigational or commercial agents or therapies that 
may be administered with the intent to treat the subject.  
 
6.1.1 Electrical Stimulation  
 
In addition to a dosing schema, please add a narrative description of the investigational 
agent administration.  
 
Investigational Agent Administration  
 
Subjects will receive stimulation patterns 1 – 4 in a randomized order. Specifically, a 
fixed frequency and pulse width will be set with amplitude started at 1 mA and increased 
by 5 mA increments, to a maximum of 30 mA or until intercavernosal pressure is 
observed to persistently rise. Upon pressure rise, amplitude will be decreased by 5 mA 
and then increased by 1 mA increments to identify the threshold level. 
 
If no response is observed on the cavernosal nerve assessed, the contralateral cavernosal 
nerve will be tested with the same stimulus pattern. If no response is seen on the 
contralateral nerve, the procedure will be aborted.  
 
6.2 
Electrical Stimulation Dose Escalation  
 
Dose escalation will proceed within each stimulus pattern according to the following 
scheme. The pulse width and frequency will be fixed. Amplitude started at 1 mA and 
increased by 5 mA increments, to a maximum of 30 mA or until intercavernosal pressure 
is observed to persistently rise. Upon pressure rise, amplitude will be decreased by 5 mA 
and then increased by 1 mA increments to identify the threshold level.  
 
If no response is observed on the cavernosal nerve assessed, the contralateral cavernosal 
nerve will be tested with the same stimulus pattern. If no response is seen on the 
contralateral nerve, the procedure will be aborted.  

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6.3 Definition of Dose-Limiting Toxicity (Applicable for dose escalation studies only) 
 
No dose-limiting toxicities are anticipated in this study. The ranges of electrical 
stimulation that will be tested have been proven safe and effective in prior work on 
intraoperative cavernosal nerve stimulation for anatomic mapping.  
 
Management and dose modifications are outlined in Section 7. 
 
6.4 
General Concomitant Medications and Supportive Care Guidelines 
 
Subjects should receive full supportive care, including transfusions of blood and blood 
products, cytokines, antibiotics, antiemetics, etc. when appropriate. All routine care for 
prostatectomy patients will be provided. There is no contraindication to routine care due 
to participation in this study.  
 
6.5 
Criteria for Removal from Study 
 
• Intercurrent illness that prevents further administration of intraoperative treatment.  
 
• The investigator considers it, for safety reasons, to be in the best interest of the subject.  
 
• Unacceptable intraoperative adverse events related to the surgical course.  
 
• Subject decision to withdraw from the study (full consent).  
 
• Death during surgery.  
 
• Sponsor reserves the right to temporarily suspend or prematurely discontinue this study. 
 
The date and reason for discontinuation must be documented.  
 
Every effort should be made to complete the appropriate assessments.  
 
6.6 
Duration of Follow Up 
 
Subjects will be followed for toxicity and adverse events as part of routine post-
prostatectomy care (approximately 24 hours) during the immediate postoperative 
hospitalization. Subsequently, they will undergo a full postoperative assessment 
(approximately 7 – 21 days) at their initial postoperative visit for foley catheter removal. 
Subsequent reassessment will occur at the second postoperative visit (approximately 2 to 
4 months) assessing cancer control.  
 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 

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study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 
7.0  
Dose Delays/Dose Modifications 
 
Dose delays and dose modifications will not occur as part of this intraoperative study.  
 
8.0 
Adverse Events and Potential Risks  
 
The risks of this study are low relative to those of prostatectomy. No adverse events 
related to electrical stimulation are anticipated based upon its transient use 
intraoperatively and experience electrical stimulation in other segments of urology, as 
well as the published literature. The potential adverse events and risks intercavernosal 
needle insertion are mild in severity and are familiar to urologists on account of the use of 
intercavernosal injection therapy and intercavernosal aspiration in treating urologic 
conditions. Overall, these adverse events pose a low risk to the patient and are all easily 
treatable with minimal likelihood of requiring a secondary intervention.  
 
8.1  
Adverse Events  
 
8.1.1 Electrical Stimulation   
 
Adverse Event 
Action on Study Drug 
Recommend Management 
Erectile Dysfunction 
N/A 
Expectant management as 
in routine care following 
prostatectomy. 
Pareasthesia or Pain 
N/A 
Standard clinical care. 
 
8.1.2 Intracavernosal Pressure Recording  
 
Adverse Event 
Action on Study Drug 
Recommend Management 
Bleeding  
N/A 
Tamponade 
Hematoma  
N/A 
Observation 
Infection 
N/A 
Oral antibiotic therapy 
directed at skin flora  
Pain 
N/A 
Standard clinical care.  
 
 
8.2 
Definitions  
 
8.2.1 
Adverse Event   
 
An adverse event (AE) is any unfavorable or unintended event, physical or 
psychological, associated with a research study, which causes harm or injury to a 
research participant as a result of the participant’s involvement in a research study. The 
event can include abnormal laboratory findings, symptoms, or disease associated with the 

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research study. The event does not necessarily have to have a causal relationship with the 
research, any risk associated with the research, the research intervention, or the research 
assessments.  
 
Adverse events may be the result of the interventions and interactions used in the 
research; the collection of identifiable private information in the research; an underlying 
disease, disorder, or condition of the subject; and/or other circumstances unrelated to the 
research or any underlying disease, disorder, or condition of the subject.  
 
For the purpose of this study the following events would not be considered adverse 
events and would not be recorded in the database: 
• Expected potential complications and outcomes of prostatectomy  
 
8.2.2   Serious Adverse Events  
 
A serious adverse event (SAE) is any adverse experience occurring at any dose that 
results in any of the following outcomes:  
• Results in death.  
• Is a life-threatening adverse experience.  The term life-threatening in the 
definition of serious refers to an adverse event in which the subject was at risk 
of death at the time of the event.  It does not refer to an adverse event which 
hypothetically might have caused death if it were more severe.  
• Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization.  Any adverse event leading to hospitalization or prolongation 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization 
may fulfill the criteria of “medically important” and as such may be reportable as 
a serious adverse event dependant on clinical judgment.  In addition where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent.  
• Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal 
life’s functions. 
• Is a congenital anomaly/birth defect.  
• Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a 
serious adverse experience when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples 

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of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood disease or disorders, or 
convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
 
For the purpose of this study the following events would not be considered serious 
adverse events and would not be recorded in the database: 
• Expected potential complications and outcomes of prostatectomy  
 
8.2.3 Adverse Event Evaluation  
 
The investigator or designee is responsible for ensuring that all adverse events (both 
serious and non-serious) observed by the clinical team or reported by the subject which 
occur after the subject has signed the informed consent are fully recorded in the subject’s 
medical records. Source documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant and requiring treatment or 
causing apparent clinical manifestations related to the electrical stimulation or 
intracavernosal pressure recording should be reported as an adverse event. Those related 
to expected potential complications and outcomes of prostatectomy will not be.  
 
The investigator or sub-investigator (treating physician if applicable) will provide the 
following for all adverse events (both serious and non-serious): 
• Event term (as per CTCAE) 
• Description of the event 
• Date of onset and resolution 
• Expectedness of the toxicity 
• Grade of toxicity  
• Attribution of relatedness to the investigational agent (as determined by 
consensus of the primary and co-investigators)  
• Action taken as a result of the event 
• Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) will be utilized for AE reporting.  
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject.  
 

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Attribution is the relationship between an adverse event or serious adverse event and the 
study drug.  Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 
• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 
 
Protocol must specify if attribution is required for individual components of the treatment 
regimen or the treatment regimen as a whole. 
 
8.3  
Serious Adverse Event Report Form 
 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported 
as instructed below.  The electronic FDA SAE reporting forms should not be used.   
 
8.4  
Reporting Procedures for Serious Adverse Events 
 
For the purposes of safety reporting, all adverse events will be reported that occur from 
the time of initial stimulation attempt through 30 days after the final dose of study drug. 
Adverse events, both serious and non-serious, and deaths that occur during this period 
will be recorded in the source documents. All SAEs should be monitored until they are 
resolved or are clearly determined to be due to a subject’s stable or chronic condition or 
intercurrent illness(es). Related AEs will be followed until resolution to baseline or grade 
1 or stabilization.  
 
8.4.1 SAE Reporting Requirements 
 
• Participating investigators (all sites) must report all serious adverse events to the 
Lead Site Principal Investigator (e.g. Sponsor-Investigator) within 24 hours of 
discovery or notification of the event. The participating investigator must also 
provide follow-up information on the SAE until final resolution.  
o Eric Klein – kleine@ccf.org  
o Bradley Gill – gillb@ccf.org  
o Yaw Nyame – nyamey@ccf.org   
• The Lead Site Principal Investigator will review the SAE and report the event to 
the FDA, external collaborator(s), and IRB as applicable. 
• It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL 
serious adverse events that occur on the study (e.g. ALL SAEs that occur at each 
enrolling institution) are reported to all participating sites. 
 
Manufacturer Reporting Requirements:  
• None - The device used to provide electrical stimulation (Medtronic NIM 3.0 
Nerve Monitoring System) is commercially available and designed for 
intraoperative nerve stimulation.  

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Institutional Review Board Reporting Requirements: 
• Investigative sites will report adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events.  
 
8.5 
Serious Adverse Events s and OnCoreTM  
 
• All SAEs will be entered into OnCore.   
• A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded 
into Oncore. 
 
8.6  
Data Safety and Toxicity Committee 
 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial 
(internal or external) are reported to the Case Comprehensive Cancer Center’s Data and 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
sponsor and/or other regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as 
per CCCC Data and Safety Monitoring Plan. 
  
8.7 
Data and Safety Monitoring Plan (DSMP) 
 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI guidelines.  
 
9.0 
TREATMENT 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 9.1.  
 
9.1 Investigational Agents 
 
9.1.1  Electrical Stimulation  
 
Product description:  
Current delivery from a stimulus generator through a lead to a monopolar stimulus 
electrode applied to a specific nerve. The delivered stimulus is returned through a 
stimulus return electrode affixed to the lower extremity. A separate grounding electrode 
is also attached to the lower extremity to further ensure safety.  
 
Product preparation:  
The electrodes are sterile and disposable. A new set of electrodes is used for each patient. 
The leads are attached to the stimulus generator and the electrode end is maintained in a 
sterile fashion for application in the operative field. Stimulus settings are configured via 

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touch screen by the appropriately certified operating room personnel or co-investigator 
charged with data recording.  
 
Storage requirements:  
The electrodes are stored with surgical supplies and disposed of upon their expiration 
date if unused.  
 
Stability:  
The electrodes have a finite shelf life and are disposed of when their expiration date is 
reached.  
 
Route of administration:  
Electrical stimulus via electrical current is supplied to the targeted nerve by placing the 
stimulus electrode on the nerve and depressing the stimulation button.  
 
Procurement:  
Electrodes are commercially available from Medtronic and will be purchased for the 
study.  
 
Packaging and labeling:  
The commercially available electrodes are pre-packaged and labeled.  
 
Accountability:  
The investigator or designated study personnel are responsible for maintaining accurate 
dispensing records of the study treatment. All treatments must be accounted for, 
including any accidentally or deliberately destroyed. Under no circumstances will the 
investigator allow the investigational treatment to be used other than as directed by the 
protocol.  
 
Treatment Destruction:  
Only the necessary number of electrodes will be ordered for this study. If a surplus of 
electrodes is noted (for instance due to early study closure) they will be disposed of or 
returned to the manufacturer refund, if possible.  
 
10.0 
EXPLORATORY or CORRELATIVE STUDIES 
 
Not applicable for this study.  
 
11.0  STUDY PARAMETERS AND CALENDAR  
 
11.1 
Study Parameters 
 
Study parameters include persistent intracavernosal pressure rise to indicate penile 
erection in response to stimulus. This will be documented for each stimulus variable 
tested. Pressure will be recorded  
 

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11.1.1 Screening Evaluation  
 
There is no screening evaluation besides information on erectile function gathered from 
the history acquired during standard care that is used to confirm study eligibility.  
 
11.1.2 Treatment Period 
 
Treatment is entirely intraoperative and will be done over a course of 20 to 30 minutes.  
 
11.2 
Calendar  
 
All follow-up as part of this study will be performed as standard post-prostatectomy care, 
as outlined below. Deviations from the following time points are permissible and will not 
require exclusion from the study.  
 
Postoperative Care (0 - 24 hours postoperative): overall assessment, drain removal  
First Postoperative Visit (7 - 21 days postoperative): overall assessment, catheter removal  
Second Postoperative Visit (2 - 4 months postoperative): assessment of cancer control 
 
12.0  MEASUREMENT OF EFFECT  
 
12.1 
Intercavernosal Pressure Measurement  
 
 
Effect in this study will be measured by intracavernosal pressure recording. This is 
perfomed via sterile 20-22 guage needle inserted perpendicularly into the right corpora 
cavernosa at the 9 o’clock position, which is connected to sterile arterial line tubing. 
Pressure will be recorded with a standard blood pressure transducer on the anesthesia 
cart.   
 
13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
8.0 (Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
 
The OnCore™ Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management. 
OnCore™ is a Clinical Trials Management System housed on secure servers maintained 
at Case Western Reserve University. OnCore™. Access to data through OnCore™ is 
restricted by user accounts and assigned roles. Once logged into the OnCore™ system 
with a user ID and password, OnCore™ defines roles for each user which limits access to 
appropriate data. User information and password can be obtained by contacting the 
OnCore™ Administrator at OnCore-registration@case.edu. 
 

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OnCore™ is designed with the capability for study setup, activation, tracking, reporting, 
data monitoring and review, and eligibility verification. This study will utilize electronic 
Case Report Form completion in the OnCore™ database. A calendar of events and 
required forms are available in OnCore™. 
 
13.2 
Regulatory Considerations 
 
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws. 
13.2.1 Written Informed consent 
 
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and be allowed time to consider the 
information provided.  
The original, signed written Informed Consent Form must be kept with the Research 
Chart in conformance with the institution’s standard operating procedures. A copy of the 
signed written Informed Consent Form must be given to the subject. Additionally, 
documentation of the consenting process should be located in the research chart. 
13.2.2 Subject Data Protection 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to 
subject’s medical information that includes all hospital records relevant to the study, 
including subjects’ medical history.  
 
13.2.3  Retention of records 
 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for as long as needed to comply with local, 
national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted.  
 
13.2.4  Audits and inspections  
 
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform 
audits or inspections, including source data verification. The purpose of an audit or 

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inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonization (ICH), and any 
applicable regulatory requirements.  For multi-center studies, participating sites must 
inform the sponsor-investigator of pending audits.  
 
14.0  STATISTICAL CONSIDERATIONS  
 
This is a pilot study aimed at determining the range of sub-threshold cavernosal nerve 
electrical stimulation parameters. No statistical comparisons are being made as part of 
this study. Only descriptive statistics of the stimulus parameters will be calculated.  
 
Sample size was determined based upon other pilot studies of intraoperative cavernosal 
nerve stimulation. In one study by Lue, et al (J Urol. 1995, 154: 1426-1428) two differing 
stimulation types were assessed with groups of 6 and 16 men, respectively. Similarly, 
another study by Rehman, et al. (BJUI. 1999, 84: 305-310) investigated stimulation in 
groups of men with (N=4) and without (N=10) erectile dysfunction. Our study is a pilot 
study for dose-ranging sub-threshold neurostimulation parameters and we anticipate a 
sample size of 7 men will provide a sufficient assessment of the range of parameters that 
is clinically relevant. 
 
Anticipated accrual rate is approximately 2 patients per month.  
 

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REFERENCES 
1. Lepor H, et al. Precise localization of the autonomic nerves from the pelvic plexus 
to the corpora cavernosa: a detailed anatomical study of the adult male pelvis. J 
Urol. 1985; 133(2): 207-212.  
2. O’Neil, et al. The Comparative Harms of Open and Robotic Prostatectomy in 
Population Based Samples. J Urol. 2016; 195: 321-329.  
3. Jiang HH, et al. Effects of acute selective pudendal nerve electrical stimulation 
after simulated childbirth injury. Am J Physiol Renal Physiol. 2013; 304: F239-
F247.  
4. Rehman J, et al. Intraoperative electrical stimulation of cavernosal nerves with 
monitoring of intracorporeal pressure in patients undergoing nerve sparing radical 
prostatectomy. BJUI. 1999; 84: 305-310.  
5. Schauer I, et al. Have rates of erectile dysfunction improved within the past 17 
years after radical rpsotatectomy? A systematic analysis of the control arms of 
prospective randomized trials on penile rehabilitation. Andrology. 2015; 3: 661-
665 
6. Burnett AL, et al. Intraoperative assessment of an implantable electrode array for 
cavernous nerve stimulation. J Sex Med. 2008; 5(8): 1949-1954.