Clinical trial NCT03102762
Conditions: Sexual Dysfunction Erectile Dysfunction
Keywords: Erectile dysfunction Botulinum toxin A Botox
Sponsor: Cairo University
Start date: 2017-01-03; Completion date: 2019-01-10
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety and efficacy of intra-cavernosal Botulinum toxin injection as an alternative line of treatment in patients with erectile dysfunction - not responding to oral PDE5i - through cavernosal smooth muscle relaxation.

Detailed description:
The initial Phase 1 study demonstrated safety and efficacy of Botulinum toxin type A in the treatment of Erectile dysfunction in a small randomized controlled trial of 24 men.

The investigators conduct a phase 2 trial to confirm the initial results in a larger group of men.70 males will be included in the study. The participants will be subjected for full history taking, general and genital examination. Penile duplex will be performed to assess a vascular etiology before the treatment and 2 weeks later. The patients will be randomized into a treatment group (35 patients) and a control group (35 patients).

All patients will sign an informed consent. The treatment group will be injected IC with a trimix solution (20 ug alprostadil + 1 mg phentolamine + 30 mg papaverine) for color Doppler assessment, followed, next day by 50 units of BTX-A. The control group will be injected with the trimix solution during penile color Doppler assessment followed next day with a normal saline injection. The erection hardness score (EHS) will be assessed during the Doppler exam.

Procedure: At least 1 day after the penile color Doppler test, the patient is placed in the supine position flaccid and stretched penile length and girth would be measured from tip of the penis to the pubic bone will be done. A rubber band will be applied to the base of the penis. The skin will be prepped with alcohol swabs followed by the IC injection of 100 units of BTX-A. Direct pressure will be applied for 2 minutes. The rubber band will be removed after 15 minutes.

Patients and controls will fill the Sexual Health Inventory for men (SHIM) questionnaire and answer the the Sexual Encounter Profile questions 1 and 2 (SEP 2 \& SEP 3), and the global assessment question (GAQ) before and 4 weeks after treatment.

Arms: arm 1: Experimental: BTX-A Group The treatment group, 35 patients, will be injected with 100 units BTX-A one day following penile colour Doppler assessment. arm 2: Saline Group:

The control group, 35 patients, will be injected with 1 ml normal saline one day following penile colour Doppler assessment.
Interventions: intervention 1: Botulinum Toxin Type A intervention 2: Normal saline
Intervention descriptions: intervention 1: Drug: Botulinum Toxin Type A The treatment group will be injected with 100 units BTX-A one day following penile colour doppler assessment. intervention 2: The treatment group will be injected with 1 ml normal saline one day following penile colour doppler assessment.

Protocol documents:
Prot_SAP_000.pdf: 
 
Research Template 
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 Faculty of Medicine, Cairo University Postgraduate 
 
 
1.  Proposed Study Title 
Safety and efficacy of intra-cavernosal Botulinum toxin injection as an 
alternative line of treatment in patients with erectile dysfunction. 
Degree:  M.D 
 
2.Candidate Name 
                                Abd el rahman Ahmed Ali Hassan Abu rahma  
 
Date of Registration       03 – Jan – 2017 
 
a. Occupation     Master degree of Andrology, sexology and STI's at Cairo university Hospitals 
 
b. Full mailing address  11 A, Mecca st. Zahraa al maadi, Al Maadi, Cairo, Egypt.  
 
 
 
c. 
Phone number 
01120099700  / 01222523122 
 
f. 
E-mail addresses 
dr.abdelrahman.a.a@gmail.com 
 


 
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1. Investigators Contact Information  
 
a.   Principal Investigator 
 
Prof. Dr. Hussein Mohamed Hafez Ghanem, 
Head of Andrology, Sexology and STI’s department, 
Faculty of medicine, 
Cairo university. 
c.  Department name 
Andrology, Sexology and STI's 
 
d. Full mailing address 
P0BOX 11562 
 
e. 
Phone number 
0223649281 
 
b. Other Investigators 
Ass. Prof.  Yasser ibrahem el Khiat, 
Ass. Prof. At Andrology, Sexology and STI’s, 
Faculty of medicine, 
Cairo university. 
Ass. Prof.  Amr Mohamed Abdel Raheem,  
Ass. Prof.  of Andrology 
Faculty of medicine, 
Cairo University 
Dr.  Islam Fathy  Soliman Abdelrahman, 
Lecturer of Andrology 
Faculty of medicine, 
Cairo University 
 
 
 


 
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2. Background and Rationale 
 
For over 4 decades BTX has been used to treat multiple neurologic disorders, such as blepharospasm, 
strabismus, focal dystonias, muscle spasms and spasticity, axillary hyperhidrosis, migraines and 
achalasia. It has been also used off-label to treat overactive bladder and urinary incontinence. BTX is 
a popular treatment for facial wrinkles in both FDA-approved (Glabella) and off-label (crow’s feet, 
transverse forehead lines, lower face, and neck) indications (1,2).   
It has also been used recently to relieve a retracted penis (3).   
Botulinum toxin (BTX) is produced by the gram-positive anaerobic bacterium Clostridium botulinum 
and is considered among the most potent biologic neurotoxins. Its main mechanism of action is the 
strong inhibition of acetylcholine (Ach) release at the pre-synaptic cholinergic junction (2). BTX can 
also affect the autonomic nervous system through its high selectivity for cholinergic synapses which 
results in targeted blockade of cholinergic transmission, inducing strong relaxation (or may be even 
paralysis)of striated muscles (4). It has been also reported that BTX may also affect afferent nervous 
transmission via the inhibition of acetylcholine, adenosine tri-phosphate (ATP),glutamate, nerve 
growth factor and substance P, and a reduction in the axonal expression of nerve capsaicin and 
purinergic (P2X) receptors (5). 
Medical treatment of erectile dysfunction (ED), at its very core, attempts to induce erections by relaxing 
the smooth muscles of the corpora cavernosa and the lining small blood vessels. 
 
The study hypothesis: Evidence has been arising that Botulinum toxin injections can relax smooth 
muscles fibers in the treatment of obesity and hyperactive bladder.  Would a similar effect on cavernsal 
smooth muscles help in the treatment of erectile dysfunction thus avoiding risks of repeated intra-
cavernosal injections with vaso-active substances ( e.g. Priapism and penile fibrosis) and  surgical 
treatment options. 
 
 
3. Objectives                                                                                                             
              To evaluate the safety and efficacy of intra-cavernosal Botulinum toxin injection as an 
alternative line of treatment in patients with erectile dysfunction - not responding to oral PDE5i - 
through cavernosal smooth muscle relaxation. 
 
4. Study Design   
 
Prospective, randomized double blind placebo control ( RDBPC) study. 
5. Ethical committee approval   


 
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Yes 
6. Study Methods 
Population of study & disease condition 
- 
Married male patients with erectile dysfunction 
Inclusion criteria: 
- 
Male patients will be included in the study recruited from Andrology, Sexology & 
STI's outpatient clinic, Kasr El Aini Hospitals, Cairo University,  
complaining of ED - not responding to oral PDE5i. 
- 
Unable to develop erections sufficient for intercourse. 
- 
A “No” response on Sexual encounter profile questions (SEP 2 & 3). 
 
Exclusion criteria: 
- 
Single patients. 
- 
Any medical condition in which sexual activity is not advised. 
- 
Any preexisting motor neuron disease (e.g myasthenia gravis). 
- 
 Neuropathies. 
- 
 Psychological disorders. 
- 
 History of reaction to toxin or albumin. 
- 
 Infection at the site of injection.  
- 
Patients on aminoglycosides (may increase effect of botulinum toxin), penicillamine, 
quinine, chloroquine and hydroxychloroquine (may reduce its effect), calcium channel 
blockers, and blood thining agents e.g. warfarin or aspirin (may result in bruising) 
Methodology in details 
Male patients complaining of ED - not responding to oral PDE5i - will be included 
in the study. All will be subjected for full history taking including assessment of  
intra-vaginal latency time, general and genital examination including measuring of the visible 
penile length at its flaccid state from the skin of the suprapubic area to the tip of penis, then 
stretched flaccid penile length and erected penile length from the pubic bone to the tip of the 
glans penis, at last penile girth at the mid shaft of the penis will be measured.  Penile duplex 
with a trimix solution (20 ugalprostadil + 1 mg phentolamine + 30 mg papaverine)  will be 
performed to assess erectile function. The patients will be randomized into a treatment group 
(35 patients) and a control group (35 patients). 
All patients will sign an informed consent. A rubber band will be applied to the base of the 
penis. The skin will be prepped with alcohol swabs followed by intra cavernous injection of 
the treatment group by 100 units of BTX-A and intra-cavernous injection only with 1 ml saline 


 
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in the control group. Direct pressure will be applied for 2 minutes. The rubber band will be 
removed after 15 minutes.  
 
 
Patients will be asked to resume their sexual activity using PDE5i on demand 2 weeks after 
intra-cavernous injection with BTX-A in the treatment group and saline in the control group.  
Assessment and follow up will be performed 2, 6 and 12 weeks after intra-cavernous injection 
with BTX-A in the treatment group and saline in the control group including measuring of the 
visible penile length at its flaccid state from the skin of the suprapubic area to the tip of penis, 
then stretched flaccid penile length and  erected penile length from the pubic bone to the tip 
of the glans penis, penile girth at the mid shaft of the penis, assesment of erectile function 
using SEP2 & SEP3 questions, the global assessment question and SHIM questionnaire.  
Penile duplex with a trimix solution (20 ug alprostadil + 1 mg phentolamine + 30 mg 
papaverine) will be performed to assess erectile function 2 weeks after intra-cavernous 
injection with BTX-A in the treatment group and saline in the control group. Intra-vaginal 
latency time ( IVLT ) will be assessed in each patient 2, 6 and 12 weeks after intra-cavernous 
injection with BTX-A in the treatment group and saline in the control group. The rational for 
selecting the minimum 2-weeks waiting period is to give a chance for the BTX-A to reach its 
maximum effect. 
Possible Risks 
- 
Redness, pain and prolonged erections. 
- 
Priapism. 
- 
Possible injection site reactions ( e.g. infection, fibrosis, bleeding, bruising or 
hematoma formation). 
- 
Possible uncommon side effects of BTX-A ( e.g. allergic reactions, rash, itching, 
headache, nausea, diarrhoea, stomach pain, loss of appetite, generalised weakness, 
muscle weakness, fever, cough, runny nose, flu symptoms, dizziness, drowsiness, 
anxiety, urinary tract infections, burning/painful urination, or difficulty urinating). 
 
Primary outcomes 
1. Comparison of Penile hemodynamics and response to ICI before and 2 weeks after 
BTX-A injection in the treatment group and saline injection in the control group. 
2. Comparison of the SHIM score, SEP2 & SEP 3 questions, and the global assessment 
question before, 2, 6 and 12 weeks after BTX-A injection in the treatment group and 
saline injection in the control group. 


 
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Secondary outcomes 
1. Comparison of penile size before, 2, 6 and 12 weeks after BTX-A injection in the 
treatment group and saline injection in the control group. 
2. Comparison of intra-vaginal latency time ( IVLT ) before, 2, 6 and 12 weeks after 
BTX-A injection in the treatment group and saline injection in the control group. 
 
Sample size (number of participants included) 
- 
70 male patients will be included in the study recruited from Andrology, sexology 
& STI's outpatient clinic, Faculty of medicine, Kasr al ainy hospitals, Cairo 
University. 
 
Source of funding   
- 
Sponsorships via investigators. 
 
 
 
 
 


 
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7. List of correlatives studies 
 
1. Smaldone MC, Ristau BT, Leng WW. Botulinum toxin therapy for neurogenic detrusor 
overactivity. UrolClin North Am. 2010 Nov;37(4):567-80. doi: 10.1016/j.ucl.2010.06.001. 
2. Carruthers JD, Carruthers A. The use of botulinum toxin type A in the upper face. 
Facial PlastSurgClin North Am. 2006;14(3):253-260. 
3. Shaeer O, Shaeer K, Shaeer A.  Botulinum toxin a (Botox) for relieving penile 
retraction. J Sex Med. 2009 Oct;6(10):2788-94. 
4. Cavallini M, Cirillo P, Fundarò SP, et al. Safety of botulinum toxin A in aesthetic 
treatments: a systematic review of clinical studies. Dermatol Surg. 2014;40 (5):525-536. 
5. Blasi J, Chapman ER, Link E, et al. Botulinum neurotoxin A selectively cleaves the 
synaptic protein SNAP-25. Nature. 1993;365(6442):160-163 
6. Sunil SM, Babu BG, Deepthi S, Veerabhadrappa AC, Vadavadagi SV, Punde P 
Botulinum toxin for the treatment of hyperfunctional lines of the forehea.JIntSocPrev 
Community Dent. 2015 Jul-Aug;5(4):276-82 
7. Shamloul R, Ghanem H. Erectile dysfunction. Lancet. 2013 Jan12;381(9861):153-65 
8. Dean RC, Lue TF. Physiology of penile erection and pathophysiology of erectile 
dysfunction. UrolClin North Am. 2005 Nov;32(4):379-95 
9. Small R. Botulinum toxin injection for facial wrinkles. Am Fam Physician. 2014Aug 
1;90(3):168-75 
 
 
8. Time plan (when to start/ when expected to finish/ when to publish) 
- To start:  Feb 2017 
- To finish: Feb 2018