Clinical trial NCT00737893
Conditions: Prostate Cancer Erectile Dysfunction
Keywords: Erythropoietin Radical Prostatectomy Erectile Dysfunction Prostate Cancer
Sponsor: Johns Hopkins University
Start date: 2017-07-01; Completion date: 2019-12-31
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study aims to explore the effectiveness of human erythropoietin versus placebo in promoting the recovery of erectile function in patients undergoing bilateral nerve-sparing radical retropubic prostatectomy for clinically localized prostate cancer.

Pre-clinical studies have shown erythropoietin potently promoted recovery of erectile function in rats and humans have similar receptors on penile tissues and the periprostatic neurovascular bundles. A clinical non-randomized study conducted in men undergoing radical prostatectomy demonstrated a benefit to recovery of erectile function.

Therefore, the hypothesis is that erythropoietin offers nerve protection in men undergoing nerve-sparing radical prostatectomy and results in a reduced degree of erectile dysfunction and also an improved rate of erection recovery following surgery.

Detailed description:
This study will evaluate the effectiveness of erythropoietin versus placebo in the recovery of erectile function in patients undergoing bilateral nerve-sparing radical prostatectomy for prostate cancer.

Recent laboratory findings in rat models and on human urogenital tissues suggest that erythropoietin may play a role in protection of the cavernous nerves during surgery. Some degree of nerve trauma occurs during bilateral nerve-sparing radical prostatectomy, but for most it is temporary. Erythropoietin will be studied as an investigational drug for enhancement of erectile function postoperatively in a prospective, randomized study. Erythropoietin has been used in many men undergoing open radical prostatectomy in the past according to FDA indications for preparation for noncardiac, nonvascular surgery with a high risk of blood loss. Evidence also suggests it is safe with no demonstration of increased risk of venous thromboembolism (blood clots) or cardiac events for men with prostate cancer undergoing radical prostatectomy.

The length of the study is 12 months and involves receiving a dose of study drug or placebo on the day before surgery, the day of surgery, and the day following surgery. The dose is given by subcutaneous injection. The study will also require the completion of questionnaires which will be completed online every three months until study completion (at 3, 6, 9, and 12 months) to assess outcomes.

Arms: arm 1: 20,000 units of EPO given on the day before surgery, the day of surgery, and the day after surgery. arm 2: Placebo doses given the day before surgery, the day of surgery, and the day after surgery.
Interventions: intervention 1: Placebo intervention 2: Erythropoietin (EPO)
Intervention descriptions: intervention 1: Saline injection (solution prepared by research pharmacy) subcutaneously given the day before surgery, day of surgery, and the day after surgery. intervention 2: Erythropoietin (EPO)-induced Protein 29, Human; 20,000 units subcutaneously given the day before surgery, day of surgery, and the day after surgery.

Protocol documents:
Prot_SAP_000.pdf: 
Date: ____________________    
Principal Investigator: _________________ 
Application Number: ___________ 
 
JHMIRB eFormA  01 
Version 3 Dated:   8/15/05 
Page 0 of 9 
Date of This Version: 3/16/17 
 
ERYTHROPOIETIN TO ENHANCE RECOVERY OF 
ERECTILE FUNCTION IN MEN FOLLOWING 
RADICAL PROSTATECTOMY  
 
NCT00737893 
 


Date: March 16, 2017 
Principal Investigator: Mohamad E. Allaf, M.D. 
Application Number: IRB00048594 
 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   8/15/05 
Page 1 of 9 
 
Johns Hopkins Medicine - eIRB Protocol (eForm A)  
 
 
 
 Use the section headings to write the eForm A, inserting the appropriate material in each. If a 
section is not applicable, leave heading in and insert N/A. 
 When submitting eForm A (new or revised), enter the date submitted to the field at the top of 
eForm A. 
 
*************************************************************************************************** 
 
1. Abstract 
This research proposal aims to explore the efficacy of recombinant human erythropoietin versus 
placebo in promoting the recovery of erectile function in patients undergoing bilateral nerve-sparing  
radical prostatectomy for clinically localized prostate cancer. The proposal represents a translational 
objective deriving from findings from the Burnett urological laboratory that have defined 
neuroprotective and neurotrophic roles of erythropoietin involving the penile autonomic innervation 
following cavernous nerve injury. We have completed preclinical studies in a rat model of cavernous 
nerve injury that mimics the cavernous nerve trauma of radical prostatectomy in which we showed 
erythropoietin potently promotes the recovery of erectile function. We have also shown that the 
erythropoietin receptor is expressed in rat major pelvic ganglia and cavernous nerves and preliminarily 
confirmed similar findings in innervation of the human penis. This work suggests the potential benefit 
of using erythropoietin to promote erectile function recovery rates in men undergoing radical 
prostatectomy and other pelvic surgeries. A retrospective comparison of 36 patients at Johns Hopkins 
suggested a benefit in erectile function for patients receiving erythropoietin. Our hypothesis is that 
erythropoietin offers neuroprotection for the penile autonomic innervation in men undergoing nerve-
sparing radical prostatectomy, and we plan to conduct a randomized controlled trial to demonstrate 
enhanced recovery of erectile function postoperatively. 
 
Specific Aim: To evaluate the effect of short-term perioperative recombinant human 
erythropoietin administration on erectile function recovery in men undergoing bilateral nerve-
sparing radical prostatectomy. The research proposal will test the hypothesis that erythropoietin 
exerts neuromodulatory effects that will result in a reduced time interval of erectile dysfunction and an 
improved rate of erection recovery after this surgery. The aim relates to the knowledge that nerve 
trauma occurs even during cavernous nerve-sparing radical prostatectomy and this neuropathic event 
affecting the penis largely accounts for the temporary or permanent erectile dysfunction observed in 
many men undergoing the surgery. The investigation will apply a single center, randomized, double-
blind, placebo-controlled 12 month study design and employ validated instruments to assess erectile 
function, urinary continence, and health related quality of life status.    
 
 
 
2. Study Procedures 
The study design will be a single center, randomized, double-blind, placebo-controlled, 2-arm study, 
comparing the effects of recombinant human erythropoietin vs. saline placebo on erectile function 
recovery in men after bilateral nerve-sparing radical prostatectomy. The dosing regimen: a three (3) day 


Date: March 16, 2017 
Principal Investigator: Mohamad E. Allaf, M.D. 
Application Number: IRB00048594 
 
 
 
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intensive treatment of 300 units/kg subcutaneously and then 33,000 units intravenously was used in a 
previously reported clinical trial of erythropoietin for acute stroke. Similarly, the dosing regimen for 
this clinical trial will be ~300 units/kg subcutaneously for a 3-day treatment plan – the exact dose will 
be 20,000 units given as a subcutaneous treatment on the day prior to surgery and 20,000 units given 
subcutaneously on the day of and day after surgery.  
 
The sample size will be 25 patients randomized to each study arm (50 patients total). Study procedures 
will involve screening and informed consent after initial consultation, baseline evaluation including 
medical clearance and completion of validated questionnaires, randomization, therapy (preoperative 
day dosing, dosing 0-2 hours prior to surgery, postoperative day 1 dosing), follow-up with blood draw 
for hematocrit and hemoglobin levels at 2 weeks post-op and then follow-up (completion of efficacy 
questionnaires at 3, 6, 9 and 12 months postoperatively). Assessment tools will consist of the following 
questionnaires which will be administered online using a REDCap site hosted by the Data Informatics 
Services Core within the Johns Hopkins Biostatistics Center or via mail per patient preference: IIEF 
questionnaire, the Quality of Erection Questionnaire (QEQ), and the version of the Expanded Prostate 
Cancer Index Composite (EPIC) that combines the Short Form Health Survey (SF-12) and AUA 
Symptom Index (AUA-SI). Standard practice associated with surgery, blood transfusion and 
postoperative laboratory testing will be performed.  Patients will be prescribed a phosphodiesterase type 
5 inhibitor (sildenafil, tadalafil or vardenafil) at 1 month following surgery to be used as conventional 
“on-demand” therapy.  Adverse event monitoring will be performed. PSA monitoring is recommended 
at 3 and 12 months with the definition for biochemical recurrence set a PSA of 0.2ng/mL (rising from 
an undetectable level after surgery). 
 
EPO Erection Recovery following RRP Protocol 
 
 
Consult 
Baseline 
Eval 
Pre-
Op 
Day 
Surgical 
Day 
Post-
Op 
Day 1 
Post-
Op 
Day 2 
Two 
Weeks 
Post-
Op
One 
Month 
Post-
Op
Three 
Months 
Post-
Op
Six 
Months 
Post-
Op
Nine 
Months 
Post-
Op
Twelve 
Months 
Post-
Op
Informed Consent
√
Medical Clearance
√
IIEF1
√
√
√
√
√
QEQ
√
√
√
√
√
EPIC, SF12, AUASI1
√
√
√
√
√
Randomization
√
Blood work (HCT)
√
√
√
√
√
EPO Administration
√
√
√
RX – 
(Phosphodiesterease 
type 5 inhibitor)
 
 
 
 
 
 
 
√ 
 
 
 
 
AE monitoring2
√
√
√
√
√
√
√
√
√
PSA monitoring
√
√
1Questionaires will be administered online using REDCap or via mail per patient preference 
2Postoperative AE monitoring will be performed by an RN or MD via telephone 
 
An IND# application has been filed and approved by the FDA for this protocol, IND 100,709. 
 


Date: March 16, 2017 
Principal Investigator: Mohamad E. Allaf, M.D. 
Application Number: IRB00048594 
 
 
 
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3. Inclusion/Exclusion Criteria 
 
Inclusion Criteria:    
1. Male sex 40 to 65 years of age with localized prostate cancer (clinical stage < T2a, Gleason 
grade < 3+4=7 (Gleason 8 or 4+3=7 will be excluded), PSA < 10 ng/mL) 
2. Scheduled to undergo curative radical prostatectomy applying bilateral nerve-sparing procedure 
3. Intact pre-surgical erectile function (International Index of Erectile Function [IIEF]-5 / Sexual 
Health Inventory for Men (SHIM) score > 22)   
4. Willingness to attempt intercourse at least 5 times per month following surgery.   
5. Has a sexual partner of at least 6 months with current sexual activity (within the past 4 weeks) 
6. Pre-surgical hematocrit ≤ 48.     
 
Exclusion criteria:   
1. Known penile deformity or a history of Peyronie’s disease 
2. Pre or post operative androgen therapy  
3. Pre or post operative radiation therapy 
4. Taking anticoagulation therapy 
5. History of sickle cell anemia 
6. History of high or low blood pressure that is not controlled 
7. Taking nitrates medications   
8. History of heart problems such as angina, heart failure, irregular heartbeats, or myocardial 
infarction 
9. History of drug or alcohol abuse 
10. Current smoker has a 20 pack/year history of cigarette smoking 
11. History of acute or chronic depression  
12. History of liver problems or kidney problems  
13. History of retinitis pigmentosa or severe vision loss, including a condition called NAION 
14. History of spinal trauma or surgery to the brain or spinal cord  
15. Other contraindications to the use of PDE 5 inhibitors 
16. Patient is currently participating in another clinical investigation that would serve as a 
contraindication to administering erythropoietin. 
 
 
4. Drugs/ Substances/ Devices 
Erythropoietin (EPO) is a cytokine-hormone that stimulates erythropoiesis under hypoxic conditions. 
Recently, EPO protein and its receptor have been found to be abundantly expressed within the central 
and peripheral nervous systems.6, 7 Exogenous administration of EPO in animal models focusing on 
brain, spinal cord, and sciatic nerve injury has resulted in attenuated neuronal damage and hastened 
recovery.8-10 In humans, a recent clinical trial confirmed the therapeutic efficacy and safety of 
recombinant human EPO (rhEPO) administration in patients suffering from acute ischemic stroke.11 
The recently established role of EPO as a neurotrophic factor makes it an attractive drug to evaluate in 
the context of neurogenic erectile dysfunction. 
 


Date: March 16, 2017 
Principal Investigator: Mohamad E. Allaf, M.D. 
Application Number: IRB00048594 
 
 
 
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This body of work stimulated a study in our laboratory to investigate the effects of EPO administration 
on a validated cavernous nerve injury rat model of erectile dysfunction.12 Male Sprague-Dawley rats 
underwent unilateral CN transection with excision of a 5mm segment of the contralateral CN, as 
described previusly.13 A group of animals received daily EPO treatment, and a group received EPO 
pretreatment (24 hours and 1 hour prior to injury). The appropriate control groups consisting of saline 
treatment and pretreatment as well as a sham group (nerve dissection but no injury) were also included 
in this study. On day 14 following the injury, the rats underwent electrical stimulation of the transected 
nerve with simultaneous intracavernous pressure (ICP) and systemic arterial pressure monitoring. This 
model of nerve injury endures a reproducibly exact peripheral nerve injury while preserving the 
alignment of the CN permitting nerve recovery and simultaneously serving to connect the measured 
erectile response exclusively to the recovery of the injured nerve supply.   
 
Exogenous treatment with daily doses of rhEPO starting 24 hours prior to CN injury preserved erectile 
function to a greater extent than saline treatment at 14 days following injury (Figure 1). Erection 
recovery, calculated as stimulated ICP area above the baseline pressure indexed to systemic pressure, 
was significantly greater for rats treated with daily rhEPO than for controls treated with saline 
(20.32.9 versus 8.63.2, p<0.05). Daily treatment for 14 days resulted in a significant increase in the 
hematocrit values of treated animals (51.4 vs. 65.8, p<0.01). Because of the clinical ramifications of 
this effect and in light of data supporting the efficacy of pretreatment regimens in the context of nerve 
injury, a group of rats underwent a pretreatment protocol. Pretreatment with rhEPO (24 hours and 1 
hour prior to CN injury) resulted in erection recovery comparable to that of daily treatment (20.34.0 
versus 20.32.9, p=0.99) without significant changes in hematocrit values (48.9 vs. 48.2, p=0.56). 
Treated animals achieved recovery of erections to approximately 60% of those achieved by sham 
treated rats. Treatment of sham animals with daily rhEPO had no effect on erectile responses after 14 
days. 
A. 
Representative tracing showing ICP responses to CN electrical stimulation.  In the rhEPO treated animal, stimulation of the transected CN produced 
substantial erection recovery in contrast to the saline treated animal. 
B. 
Mean ICP area normalized to the systemic pressure  SEM when stimulating transected right CN after treatment with saline, rhEPO daily, and rhEPO 
pretreatment versus sham treatment.  (I+Saline=CN injury treated with saline, I+EPO=CN injury treated with daily rhEPO, I+PreEPO=CN injury 
pretreated with rhEPO, Sham=Sham animals treated with saline, Sham+EPO=Sham animals treated with daily rhEPO). a, p<0.02 vs. I+Saline; b, 
p<0.01 vs. Sham; c, p<0.04 vs. I+Saline; d, p<0.02 vs. Sham; e, p=0.94 vs. Sham+EPO; f, p<0.001 vs. I+Saline. 
 
To identify the presence of EPO receptors in major pelvic ganglia (MPG) and penile tissues, we 
performed immunohistochemistry on rat tissue sections. EPO receptor was localized to the neuronal 


Date: March 16, 2017 
Principal Investigator: Mohamad E. Allaf, M.D. 
Application Number: IRB00048594 
 
 
 
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bodies within the MPG. RT-PCR confirmed the presence of EPO receptor mRNA in MPG tissue. EPO 
receptor mRNA levels were unchanged one day after injury and saline treatment but were increased by 
approximately 7 fold with injury and EPO treatment at the same time point. EPO receptor 
immunoreactivity in the penis was observed in the penile dorsal nerves, sinusoidal endothelium of the 
corpus cavernosum, and endothelial cells lining the dorsal vein and arteries. In addition, preliminary 
immunolocalization studies of human tissues reveal positive staining for the EPO receptor in the axons 
of widely excised neurovascular bundles. All slides processed without primary antibody or with 
blocking peptide showed no staining.   
 
Electron microscopy was used to examine the CN distal to the site of injury and to assess axonal 
regeneration. The number of axons per Remak bundle in addition to the morphology of these axons was 
used to determine regeneration within the CN. Sham (intact) animals had a mean of 4.90.2 axons per 
Remak bundle while injured animals treated with saline had a mean of 1.00.1 (p<0.001). Daily rhEPO 
treatment resulted in a greater recovery of axons per Remak bundle when compared to saline treated 
animals (2.70.2 versus 1.00.1,  p<0.001). Sprouting of unmyelinated fibers typically passes through a 
phase in which Remak bundles contain very small unmyelinated axons or axons in polyaxonal 
pockets.14 Such profiles were evident in all rhEPO treated animals, suggesting neuronal regeneration. 
 
Thus, we have shown that EPO promotes the recovery of erectile function in a rat model of nerve injury 
and that the EPO receptor is expressed in penile nerves and endothelium of penile blood vessels.   
 
 
5. Study Statistics 
The primary outcome variable is the patient’s score on the IIEF questionnaire (erectile function 
domain) at 3, 6, 9, and 12 months post-surgery. 
 
The secondary outcome variables will be the patient’s scores on the QEQ, combined EPIC/SF-
12/AUASI questionnaires, other domains of the IIEF questionnaire, and change in hemoglobin. 
 
For statistical analysis based on ANOVA, the sample size is powered for a power of 80% with one-
sided alpha of 0.05 showing a sample size of 23 patients in each arm is necessary to detect an expected 
difference of 5 points in IIEF scores (i.e. 20 vs. 15) at 6 months post-surgery. Therefore, the study is 
planned to enroll 25 patients in each arm. 
 
 
6. Risks 
Completion of the questionnaires and administration of EPO are the only 2 procedures from this 
protocol that are outside of the realm of standard of care for the radical prostatectomy patient. All of the 
questionnaires will be completed by the participants pre-operatively allowing them time to assess if this 
activity is something they are willing to complete 4 times post-operatively. If the questionnaires cause 
any type of discomfort or uneasiness at that time or any time during the study, the participant can 
decide to end their involvement with the protocol.  
 


Date: March 16, 2017 
Principal Investigator: Mohamad E. Allaf, M.D. 
Application Number: IRB00048594 
 
 
 
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Possible adverse effects of EPO include pain, redness or swelling at the injection site, headache, joint or 
muscle pain, nausea, vomiting, indigestion, stomach pain, diarrhea, constipation, runny nose, sneezing, 
difficulty falling or staying asleep, excessive sweating, or rash.  
 
Serious adverse effects associated with EPO (extremely rare) include anaphylaxis, cerebrovascular 
accident, deep venous thrombosis, hypertension, acute left ventricular failure, myocardial infarction, 
pulmonary embolism, seizure, thrombotic disorder, hemoptysis, chronic cough, production of 
antibodies causing severe anemia, transient ischemic attack, aphasia, confusion and death.   
 
The occurrence of any serious adverse effects will end the patient’s participation in the study and halt 
enrollment in the study to determine the safety of continuing the study. Each and every possible adverse 
effect of EPO will be investigated and treated individually to minimize the participant’s discomfort. 
The safety of having the individual complete the study will also be assessed on an individual basis. At 
any time the participant can decide to terminate his participation in the study and no penalty or loss of 
benefits to which they are entitled. 
 
 
7. Confidentiality 
Paper consent forms, enrollment check sheets, and other source or study documentation will be kept in 
a study binder. This binder will be stored in a locked office available only to the study team. Electronic 
data will be housed in a secure password protected REDCap database maintained by the Data 
Informatics Services Core within the Johns Hopkins Biostatistics Center. Only the study team will have 
access to this secure database. Of note, to maintain the protected healthy information of patients 
enrolled in this study, only the study Principal Investigator and primary coordinators will have the 
ability to export data containing identifying information from this master database. For the purposes of 
analysis, only de-identified data will be exported. 
 
 
8. Benefits 
The patients’ conditions may improve as a result of participation in this study, specifically as related to 
erectile function. However, there is no guarantee of this. The information from this research study may 
lead to a better treatment in the future for people with prostate cancer. The patients may not benefit 
from participation in this study.  Their conditions may not get better or may become worse while they 
are in this study. 
 
 
9. Payment and Remuneration 
There will be no payment or remuneration for the participants in this study.  
 
 
10. Costs 
The cost of the EPO will be covered by the study. There are no other anticipated costs outside of usual 
care. The participant’s insurance, as part of routine care after radical prostatectomy, will be charged for 


Date: March 16, 2017 
Principal Investigator: Mohamad E. Allaf, M.D. 
Application Number: IRB00048594 
 
 
 
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the PDE5 inhibitor drugs such as Viagra, Cialis or Levitra. If the PDE5 inhibitor (Viagra, Cialis or 
Levitra) is not covered by the participants insurance, they will be responsible for the bill.  
 


Date: March 16, 2017 
Principal Investigator: Mohamad E. Allaf, M.D. 
Application Number: IRB00048594 
 
 
 
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References 
 
1. Catalona, W. J., Carvalhal, G. F., Mager, D. E. et al.: Potency, continence and complication  rates in 
1,870 consecutive radical retropubic prostatectomies. J Urol, 162: 433, 1999. 
 
2. Walsh, P. C., Marschke, P., Ricker, D. et al.: Patient-reported urinary continence and sexual function 
after anatomic radical prostatectomy. Urology, 55: 58, 2000. 
 
3. Fraiman, M. C., Lepor, H., McCullough, A. R.: Changes in Penile Morphometrics in Men with Erectile 
Dysfunction after Nerve-Sparing Radical Retropubic Prostatectomy. Mol Urol, 3: 109, 1999. 
 
4. Nehra, A., Goldstein, I., Pabby, A. et al.: Mechanisms of venous leakage: a prospective 
clinicopathological correlation of corporeal function and structure. J Urol, 156: 1320, 1996. 
 
5. Podlasek, C. A., Gonzalez, C. M., Zelner, D. J. et al.: Analysis of NOS isoform changes in a post 
radical prostatectomy model of erectile dysfunction. Int J Impot Res, 13 Suppl 5: S1, 2001. 
 
6. Marti, H. H., Wenger, R. H., Rivas, L. A. et al.: Erythropoietin gene expression in human, monkey and 
murine brain. Eur J Neurosci, 8: 666, 1996. 
 
7. Campana, W. M., Myers, R. R.: Erythropoietin and erythropoietin receptors in the peripheral nervous 
system: changes after nerve injury. FASEB J., 15: 1804, 2001. 
 
8. Celik, M., Gokmen, N., Erbayraktar, S. et al.: Erythropoietin prevents motor neuron apoptosis and 
neurologic disability in experimental spinal cord ischemic injury. PNAS, 99: 2258, 2002. 
 
9. Erbayraktar, S., Grasso, G., Sfacteria, A. et al.: Asialoerythropoietin is a nonerythropoietic cytokine 
with broad neuroprotective activity in vivo. PNAS, 100: 6741, 2003. 
 
10. Brines, M. L., Ghezzi, P., Keenan, S. et al.: From the Cover: Erythropoietin crosses the blood-brain 
barrier to protect against experimental brain injury. PNAS, 97: 10526, 2000. 
 
11. Ehrenreich, H., Hasselblatt, M., Dembowski, C. et al.: Erythropoietin therapy for acute stroke is both 
safe and beneficial. Mol Med, 8: 495, 2002. 
 
12. Allaf, M.E., Hoke, A., Burnett, A.L.: Erythropoietin promotes the recovery of erectile function 
following cavernous nerve injury. J Urol, 174: 2060, 2005. 
 
13. Burnett, A.L., Becker, R.E:  Immunophillin ligands promote penile neurogenesis and erection recovery 
following cavernous nerve injury. J Urol, 171(1): 495-500, 2004. 
 
14.  Friede, R. L., Bischhausen, R.: The fine structure of stumps of transected nerve fibers in subserial 
sections. J Neurol Sci, 44: 181, 1980.