Clinical trial NCT00812838
Conditions: Peyronie's Disease
Sponsor: Mohit Khera
Start date: 2009-08-07; Completion date: 2019-01-15
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Peyronie's disease is a condition in which a plaque, or hard lump, forms on the penis. It causes hardened tissue, pain, and an abnormal bending in the penis. These symptoms are more severe during an erection. Significant bending of the penis can result in pain, poor erections, and an inability to engage in sexual intercourse.

This disease affects about 3% of the male population. The average age of onset of this disease is 57 years old. The cause of the disease is unknown. However, many believe that it may be due to trauma to the penis (such as injury or extremely vigorous sexual activity).

Detailed description:
Treatments for this disease have been limited and often unsuccessful. The goal of treatment is to reduce pain and maintain sexual function. Oral medicines that prevent plaque formation and promote plaque breakdown have not been effective. Many patients with the disease will require injections of medicines directly into the plaque. These injections have been used for over 50 years in the treatment of major Peyronie's disease. The disease often resolves on its own without treatment. Surgery may be performed to remove hardened tissue in the penis. However, surgery is not done during the first 12 months of the disease.

There are 2 phases of the disease: the active phase and the inactive phase. The active phase usually occurs during the first 12 months of the disease. The stabilization of the plaque is known as the inactive phase. We are inviting men with stable disease to take part in this study which will test BOTOX® versus a placebo (a placebo contains no medicine).

This will be a randomized, placebo-controlled, cross-over, single-center trial. The placebo group has the option to cross over to the treatment arm (ARM 1) of the study at the end of their 16 weeks of placebo arm (ARM 2). Study drug is Botulinum toxin type A (BOTOX®). Subjects who meet the inclusion criteria for the study will be randomized to either the treatment or placebo arm.

* Treatment: Injection solution will consist of 100 units of BOTOX® in 10 cc of preservative free normal saline, or
* Placebo: Injection solution will consist of 10 cc preservative free normal saline.

Arms: arm 1: Injection solution will consist of 100 units of BOTOX® in 10 cc of preservative free normal saline arm 2: Injection solution will consist of 10 cc preservative free normal saline

Subjects had the choice of crossing over to ARM 1 at the end of 16 weeks.

Cross-over: For subjects in Arm 2, crossover to BOTOX treatment will begin after the Week 16 Visit by repeating the study schedule as for Week 0 to Week 16.
Interventions: intervention 1: 100 units of Botulinum Toxin Type A intervention 2: Preservative free normal saline intervention 3: 100 units Botulinum Toxin A
Intervention descriptions: intervention 1: Approximately 20 to 30 injections of 100 units of BOTOX® given with a 20 gage needle directly into the penile plaque intervention 2: Approximately 20 to 30 injections of 10cc of preservative free normal saline given with a 20 gage needle directly into the penile plaque intervention 3: Approximately 20 to 30 injections of 100 units of BOTOX® given with a 20 gage needle directly into the penile plaque

Protocol documents:
Prot_SAP_000.pdf: 


TABLE OF CONTENTS 
 
I. 
Background and Rationale ...................................................................................................3 
II. 
Purpose .................................................................................................................................4 
III. 
Drug Information .................................................................................................................4 
IV. 
Eligibility Criteria ................................................................................................................5 
V. 
Design ..................................................................................................................................6 
VI. 
Randomization .....................................................................................................................6 
VII. 
Schedule of Events ...............................................................................................................7 
VIII. Procedures ............................................................................................................................8 
IX. 
Risks .....................................................................................................................................9 
X. 
Criteria for Discontinuing the Study ..................................................................................11 
XI. 
Sample Size ........................................................................................................................11 
XII. 
Data Analysis .....................................................................................................................11 
XIII. Safety Monitoring Plan ......................................................................................................12 
 
XIV. Adverse Event Reporting ...................................................................................................13 
 
XV. 
Data Handling and Record Keeping ..................................................................................13 
XVI. Protocol Changes ...............................................................................................................13 
XVII. Ethics and Good Clinical Practices ....................................................................................14 
 
A. 
IRB and Other Institutional Review Committees ..................................................14 
 
B. 
Informed Consent Process .....................................................................................14 
 
C. 
Declaration of Helsinki ..........................................................................................15 
XVIII. Confidentiality ...................................................................................................................15 
XIX. References ..........................................................................................................................15 
APPENDICES ...............................................................................................................................17 
I. 
IIEF Questionnaire ................................................................................................................18 
II. 
Scott Department of Urology QA/QC Guidelines ................................................................22 
 
 
Khera H-22411 
Page 2 of 35 
1/30/15 


I. 
BACKGROUND AND RATIONALE 
 
Over the past several years botulinum toxin type A (BTX-A, BOTOX®) has been used in many 
applications to prevent scar formation.  Gassner and Sherris previously found that 
chemoimmobilization of facial wounds with BTX-A improved wound healing and cosmetic 
appearance.1  These clinical findings are supported by a randomized, double-blinded, placebo-
controlled study showing a significant improvement in scar appearance in BTX-A treated facial 
wounds compared to saline injected controls.2  In addition, we recently published the first article 
demonstrating that BTX-A is effective in treating urethral strictures, which are caused by scar 
formation.3  Finally, Comperat and colleagues demonstrated that BTX-A injections in the 
bladder leads to less fibrosis.  In the study, bladder wall specimens were obtained from 
cystectomy in 45 patients with neurogenic overactive bladders with and without injection of 
botulinum toxin A into the detrusor.  Bladder wall specimens were evaluated for inflammation, 
edema, and fibrosis.  When comparing specimen from patients who had received botulinum 
toxin injection to those from patients who had not, there was no difference concerning 
inflammation and edema.  However, patients who had received botulinum toxin injection showed 
significantly less fibrosis of the bladder wall than those who had not received the toxin injection 
(p<0.00073).4  
 
A major contributor to fibrosis and scar formation is thought to be tension from the underlying 
muscle contractions acting on the wound edges during healing.2  BTX-A acts at the 
neuromuscular junction by blocking vesicle transport of acetylcholine, in essence producing a 
chemical denervation.5  By decreasing underlying muscle tension/spasm in healing wounds 
BTX-A may be a viable option to prevent fibrosis and scar formation.  
 
Penile curvature secondary to scar or plaque formation along the shaft of the penis is known as 
Peyronie’s disease.  Significant penile curvatures can result in pain, poor erections, and an 
inability to engage in sexual intercourse.  Peyronie’s disease is an acquired disease of the tunica 
albuginea surrounding the corpora cavernosa of the penis and affects approximately 3% of the 
male population.6  The average age of onset of this disease is 57 years old.  The etiology of 
Peyronie’s disease remains unknown.  However, many believe that traumatic inflammatory 
changes to the septal fibers of the erect penis from either blunt penile injury or repeated 
microtrauma associated with sexual activity.  
 
Traditionally, treatments for Peyronie’s disease have been limited and often unsuccessful.  Oral 
medical therapies that prevent the scar formation and promote scar breakdown have been 
ineffective.  Many patients with Peyronie’s disease will require injection therapy of the penis.  
Injections of pharmaceutical agents directly into the Peyronie’s plaque have been used for over 
50 years in the treatment of clinically significant Peyronie’s disease.  The three most common 
agents used for injection therapy are verapamil, interferon, and collagenase.7 Intracellular 
calcium levels play an important role in the metabolism and synthesis of collagen.  Calcium 
channel blockers such as verapamil increase collagenase activity and decrease collagen secretion, 
although quite high tissue doses are needed for this.  Interferons are low molecular weight 
proteins involved in the normal function of the body’s immune system.  They are known to 
inhibit the proliferation of myofibroblasts, decrease collagen production, and increase the 
activity of collagenase.  Finally, collagenase is a purified bacterial enzyme that attacks and 
Khera H-22411 
Page 3 of 35 
1/30/15 


breaks down collagen.  It has been used clinically to treat severe burns and lumbar disk disease.  
All three of the agents have been shown to result in mild to moderate improvement in penile 
curvature when compared to placebo.7 
 
There are two phases of Peyronie’s disease: the active phase and the quiescent phase.  The active 
phase usually occurs during the first 12 months of the disease and is associated with constant 
changing of the plaque and penile pain.  Surgery is contraindicated during the active phase and is 
usually indicated after 18 months from the onset of the disease, when the plaque has stabilized.  
The stabilization of the plaque is known as the quiescent phase.  During the active phase, 
approximately 15-20% of patients can get spontaneous resolution of their disease.  Therefore, 
injections initiated during the active phase are also discouraged by some because this may lead to 
further trauma as opposed to allowing for spontaneous resolution. 
 
Hypothesis: BTX-A penile injections into Peyronie’s plaques can significantly prevent scar 
formation and promote scar breakdown as evidenced by reduced penile curvature. 
 
 
II. 
PURPOSE 
 
The purpose of this study is to establish the efficacy of botulinum toxin in treating Peyronie’s 
disease. 
 
 
III. 
DRUG INFORMATION 
 
BOTOX® is the brand name for Botulinum toxin type A. For this study’s treatment injections, 
we will be using 100 units of BOTOX® in 10 cc of preservative free normal saline, or 10 cc of 
preservative free normal saline for placebo. 
 
BOTOX® and Placebo will be provided by Allergan, Inc.   
 
BOTOX® is a purified neurotoxin complex supplied as a sterile, vacuum dried purified 
botulinum toxin type A, produced from fermentation of Clostridium botulinum type A. 
 
One unit of BOTOX® corresponds to the calculated median intraperitoneal lethal dose (LD 50) in 
mice.  The specific activity of BOTOX® is approximately 20 units/nanogram of neurotoxin 
protein complex.  
 
BOTOX® blocks neuromuscular transmission by binding to acceptor sites on motor or 
sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of 
acetylcholine.  This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to 
the successful docking and release of acetylcholine from vesicles situated within nerve endings. 
When injected intramuscularly at therapeutic doses, BOTOX® produces partial chemical 
denervation of the muscle resulting in a localized reduction in muscle activity.  In addition, the 
muscle may atrophy, axonal sprouting may occur, and extra-junctional acetylcholine receptors 
Khera H-22411 
Page 4 of 35 
1/30/15 


may develop.  There is evidence that reinnervation of the muscle may occur, thus slowly 
reversing muscle denervation produced by BOTOX®.  
 
BOTOX® is not expected to be present in the peripheral blood at measurable levels following IM 
or intradermal injection at the recommended doses.  The recommended doses of neurotoxin 
administered at each treatment session are not expected to result in systemic, overt distant 
clinical effects, i.e., muscle weakness, in patients without other neuromuscular dysfunction.  
However, some clinical systemic effects have been shown by a single fiber electromyography 
after IM doses of botulinum toxins appropriate to produce clinically observable local muscle 
weakness. 
 
BOTOX® is contraindicated in the presence of infection at the proposed injection site(s), and in 
individuals with known hypersensitivity to any ingredient in the formulation. 
 
BOTOX® is supplied in a single-use vial.  Each vial contains 100 units of vacuum-dried 
Clostridium botulinum type A neurotoxin components. 
 
Unopened vials of BOTOX® should be stored in a refrigerator (2° to 8° C) for up to 24 months 
(or the expiration date on the product label).  Administer BOTOX® within four hours of 
reconstitution and within 30 minutes of drawing into syringe; during this period the reconstituted 
BOTOX® should be stored in a refrigerator (2° to 8° C).   
 
Additional BOTOX® information is available in the BOTOX® Prescribing Information package 
insert. 
 
 
IV. 
ELIGIBILITY CRITERIA   
 
 
A. Inclusion:  
1. Subjects with stable Peyronie’s plaques. 
2. Males at least 18 years of age  
3. Prior history of failed penile injection therapies is allowed. 
4. Must give informed consent. 
 
 
B. Exclusion:   
1. Subjects in the active phase of Peyronie’s disease. 
2. Subjects with less than 1 year history of Peyronie’s disease. 
3. Subjects taking oral medications for Peyronie’s disease which include Trentol, 
Viagra, vitamin E, colchicines, L-arginine, and tamoxifen. There will be a 2 week 
wash-out period if patients are on these medications.  
4. Subjects with more than 1 penile plaque will be excluded from the study.  
5. Subjects with calcified plaques demonstrated by ultrasound will be excluded from 
the study. 
6. Known allergy or sensitivity to any components of the study medication 
(botulinum toxin A), anesthetics, or any other product associated with the 
treatment and general study procedures.  
Khera H-22411 
Page 5 of 35 
1/30/15 


7. Any medical condition or neuromuscular disorder that may put the patient at 
increased risk with exposure to botulinum toxin A (BTX-A), including 
myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis.  
8. Patient taking aminoglycosides or any drug known to interfere with 
neuromuscular transmission.  
9. Patient has hemophilia or other clotting factor deficiencies or disorders that cause 
bleeding diathesis.  
10. Patient must not be taking aspirin, non-steroidal anti-inflammatory drugs, or 
Coumadin for 7 or more days prior to Botox injection.  
11. Episode of unstable angina pectoris, myocardial infarction, transient ischemic 
attack, or cerebrovascular accident within the past 6 months. 
 
 
V. 
DESIGN 
 
This is a randomized, placebo-controlled, cross-over, single-center trial.  Study drug is 
Botulinum toxin type A (BOTOX®).  Subjects who meet the inclusion criteria for the study will 
be randomized to either the treatment or placebo arm. 
 
ARM 1 - Treatment:   Injection solution will consist of 100 units of BOTOX® in 10 cc of 
preservative free normal saline, or  
ARM 2 - Placebo:  Injection solution will consist of 10 cc preservative free normal saline. 
 
The Week 16 Visit will be the end of the study participation for those subjects in Arm 1 and who 
did not develop ED (as defined as a drop in IIEF scores of more than 4 points from Baseline IIEF 
score). The Week 16 Visit will be the end of study participation for subjects in Arm 2 and who 
developed ED. For subjects in Arm 2, crossover to BOTOX treatment will begin after the Week 
16 Visit by repeating the study schedule as for Week 0 to Week 16. Continuation visits at 
Months 6, 9, and 12 will occur for subjects in Arm 1 and who developed ED. 
 
 
VI. 
RANDOMIZATION PROCEDURES:  
 
The subjects will be randomized to the arms as they are enrolled and meet eligibility criteria.  
The odd number (1, 3, 5…) of subjects will be in ARM 1 and even numbers (2, 4, 6…) of 
subjects will be in the ARM 2. The randomization scheme will not result in selection bias.   
Khera H-22411 
Page 6 of 35 
1/30/15 


 
VII. 
SCHEDULE OF EVENTS 
 
  PROCEDURE 
Baseline 
(Pre-
treatmen
t) 
Week 
0 
Clinic 
Visit 
Week 
2 
Phone 
Visit 
Week 
4 
Clinic 
Visit 
Week 
6 
Phone 
Visit 
Week 8 
Clinic 
Visit 
Week 
10 
Phone 
Visit 
Week 
12 
Clinic 
Visit 
Week 
14 
Phone 
Visit 
1Week 16  
Clinic Visit 
(2End of Study) 
(3Placebo 
Crossover) 
4Month 
6  
Clinic 
Visit 
 
4Month 
9 
 Clinic 
Visit 
4Month 12 
Clinic Visit 
(End of 
Study) 
Signed, written 
informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Blood pressure, 
pulse, O2 saturation 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Penile injection: 
Caverject 20mcg/cc 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Penile curvature 
assessment & 
photos 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Penile ultrasound 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
IIEF questionnaire 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Penile injection: 
BTX-A or 3Placebo 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Collect AE 
information 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
1End of study for subjects receiving BOTOX and did not develop ED (as defined as a drop in IIEF scores of more than 4 points from Baseline IIEF score). 
2End of study participation for subjects receiving placebo and develop ED. 
3For subjects receiving placebo, crossover to BOTOX treatment will begin by repeating the study schedule as for Week 0 to Week 16. 
4Continuation visits for subjects receiving BOTOX and developed ED. 
 
 
Khera H-22411 
Page 7 of 35 
3/29/09 


 
VIII. PROCEDURES 
 
Subjects who meet the inclusion criteria for the study will be randomized to either the treatment 
or placebo arm. Prior to treatment, all subjects will have a penile injection with Caverject 
20mcg/cc to induce a penile erection. During the erect state, penile curvature will be assessed, 
pictures will be taken for later measurement of penile curvature, and ultrasound will be used to 
assess penile blood flow and plaque size. A penile duplex with intercavernosal injections of a 
vasoactive substance is part of our standard care for Peyronies disease diagnosis. Subjects will 
also be asked to complete the International Index of Erectile Function (IIEF) questionnaire.  
 
Injections will be performed using our standard protocol currently used for verapamil injections, 
but instead we will be using 100 units of BTX-A in 10cc of preservative free normal saline, or 
10cc of preservative free normal saline for placebo and plaque breakdown injections. The 
standard injection procedure consists of the following:  
 
1. Subjects will be explained the risks and benefits of the procedure and will give 
informed consent.  
2. Blood pressure, pulse, and oxygen saturation will be monitored throughout the 
procedure.  
3. A penile block with 10cc of lidocaine without epinephrine will be given, followed by 
an observation period of 10 minutes to assure no immediate adverse reaction to 
lidocaine.  
4. Approximately 20 to 30 injections with a 20 gage needle will be given directly into 
the penile plaque. The skin will not be punctured with each injection, but the needle 
will move within the plaque. Injection solution will consist of 100 units of BTX-A in 
10 cc of preservative free normal saline, or 10 cc of preservative free normal saline.  
5. Subjects in the placebo arm will only receive 10 cc of preservative free normal saline.  
6. Subjects will be monitored for 1 hour after the procedure to ensure that their vital 
signs are stable and that there are no signs of penile hematoma. 
7. Safety will be assessed by following the subject closely for one hour after the 
procedure.  
8. Subjects will be given strict instructions to call and return to the clinic or the ER for 
any adverse side effects.  
 
Subjects randomized to ARM 1will receive one injection of 10 cc preservative normal saline at 
study start (week 0), followed by 100 U Botox in 10cc saline at visit two (week 4), then saline 
injections at weeks 8 and 12, thus a total of 4 injections (1 saline, 1 Botox, 2 saline).  
 
Subjects randomized to ARM 2 will receive one injection of 10cc preservative normal saline at 
Weeks 0, 4, 8 and 12. 
 
All subjects will be telephoned two weeks after each injection to inquire on the occurrence of 
any adverse events. Subjects will be asked a general, non-direct question such as, “How have 
you been feeling since the last visit?” Direct questioning will then be done as appropriate. 
 
Khera H-22411 
Page 8 of 35 
3/29/09 


At the completion of 16 weeks (4 weeks after last treatment), subjects will have a repeat penile 
injection of Caverject, penile pictures will be taken, and penile ultrasonography will be 
performed. Subjects will also be asked to complete the IIEF again.  
 
The Week 16 Visit will be the end of the study participation for those subjects in Arm 1 and who 
did not develop ED (as defined as a drop in IIEF scores of more than 4 points from Baseline IIEF 
score). Subjects developing ED, will have continuation visits at Months 6, 9, and 12.  At these 
visits, a complete physical will be done.  Information about any adverse events and changes in 
concomitant medications will be collected.  The subjects will complete the IIEF questionnaire. 
 
If at the end of 16 weeks there is a significant improvement in the subjects treated with BTX-A 
as compared to the placebo arm, the men in the placebo arm will be given the option to cross 
over into the treatment arm and complete a 12 week course of BTX-A injections (1 saline 
injection, 1 Botox injection, 2 saline injections).  For those in Arm 2 who develop ED, 
participation will end after the Week 16 visit. 
 
 
IX. 
RISKS 
 
BOTOX®:  It is expected that some participants may have some or all of the following side 
effects when given BOTOX®. Other side effects may occur which were not seen before. Side 
effects are usually temporary and manageable. However, it is possible they could cause serious 
disease or death. The study may include risks that are unknown at this time. 
 
There have been rare reports of serious and/or immediate or even deadly abnormally sensitive 
reactions after treatment with BOTOX. These reactions include allergic reaction, skin rash, 
itching, swelling, and difficulty in breathing. 
 
There have been rare reports of sudden death, sometimes associated with difficulty in 
swallowing or pneumonia. There have also been rare reports of heart problems (including 
irregular heart beats and heart attack, some resulting in death). Some of these patients were 
already at risk for heart disease. It is not known if BOTOX actually caused these problems. 
 
It should not be used when infection is present at the injection site or in people known to be 
abnormally sensitive to BOTOX. 
 
The following events have been observed since it has been marketed: skin rash, itching, and 
allergic reaction. In general, these side effects occur within the first week following injection 
and, while usually temporary, they may last several months. Pain, tenderness, or bruising around 
the injection site may also occur. Local weakness of the injected muscle(s) is expected. 
Weakness of nearby muscles may also occur due to spread of BOTOX. 
 
BOTOX contains albumin, which comes from human blood. Although the blood is rigorously 
tested, there is an extremely remote risk for the transmission of viruses and similar infectious 
agents. 
 
Khera H-22411 
Page 9 of 35 
1/30/15 


CAVERJECT®:  Possible side effects of therapy with Caverject are penile pain after injection, 
usually mild to moderate in severity.  A potentially serious reaction is priapism; therefore, 
patients should be instructed to seek medical attention if an erection last for more than 4 hours. 
 
The injection can induce a small amount of bleeding at the site and a hematoma may form.  
There may be an occurrence of nodules or hard tissue in the penis, redness, and swelling. 
 
Hypertension was reported in about 2% of patients.  Headaches and dizziness were reported in 
2% or less of patients.  About 1% of the patients complained of backache.  Upper respiratory 
infections were reported in 4% and flu-like symptoms in 2%.  Sinusitis was reported in 2% and 
nasal congestion and coughs in 1%.  Prostatic disorders were reported in 2%.  Localized pain at 
injection site was reported in about 2% and trauma, such as, injuries, fractures, abrasions, 
lacerations, and dislocations were reported in 2%. 
 
Less than 1% of patients in clinical studies reported the following events that were judged as 
possibly related to the use of Caverject:  testicular pain and disorder, scrotal disorder, scrotal 
edema, hematuria, impaired urination, urinary frequency, urinary urgency, pelvic pain, 
hypotension, vasodilation, peripheral vascular disorder, supraventricular extrasystoles, vasovagal 
reaction, hypesthesia, non-generalized weakness, diaphoresis, rash, non-application site pruritus, 
skin neoplasm, nausea, dry mouth, increased serum creatinine, leg cramps, and mydriasis. 
 
LIDOCAINE®:  Adverse experiences with Lidocaine are, in general, dose-related and may 
result form high plasma levels caused by excessive dosage, rapid absorption or inadvertent 
intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished 
tolerance on the part of the patient.   
 
Central nervous system symptoms that may be experienced are lightheadedness, nervernousness, 
apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, 
vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, 
unconsciousness, respiratory depression and arrest.   
 
Cardiovascular manifestations are usually depressant and are characterized by bradycardia, 
hypotension, and cardiovascular collapse, which may lead to cardiac arrest. 
 
Allergic reactions are characterized by cutaneous lesions, urticaria, edema, or anaphylactoid 
reactions.  These reactions to Lidocaine are extremely rare. 
 
The effect of the study treatments on the ability to have erections and to have intercourse is 
unknown.  It is not known whether the treatments the subject receives in this study will worsen 
or will improve his ability to have intercourse 
 
Additional risks that may be experience by subjects participating in this study are: 
 
The risk of developing erectile dysfunction after these injections is unknown. 
 
Khera H-22411 
Page 10 of 35 
1/30/15 


Inserting needles into the penis may be uncomfortable. Pain, tenderness, or bruising around the 
injection site may occur. 
 
The ultrasound rarely results in physical discomfort but some anxiety before and during the 
procedure may be experienced. 
 
Completing the questionnaire may cause some anxiety or embarrassment to the subject due to the 
personal nature of the questions. 
 
The loss of confidentiality regarding research information is a possibility; although, the risk is 
very small. 
 
 
X. 
CRITERIA FOR DISCONTINUING THE STUDY 
 
 
A. Subjects unable to tolerate BTX-A due to side effects. 
 
B. Subjects can request removal from the study for any reason at any time. 
 
C. Subjects may be withdrawn at any time at the discretion of the investigator for safety, 
compliance, or other reasons. 
 
A discontinuation occurs when an enrolled subject ceases participation in the study, regardless of 
the circumstances, prior to completing the protocol.  
 
The reasons for a subject discontinuing from the study will be recorded in the Case Report Form. 
 
 
XI. 
SAMPLE SIZE 
 
This will be a pilot study and therefore 10 subjects in each arm, for a total of 20 subjects, will 
allow us to determine if the therapy is effective.  To allow for screen failures, 45 subjects are 
planned for screening. 
 
 
XII. 
DATA ANALYSIS 
 
 
A. The primary outcome measure will be:  
 
1. change in penile curvature, as measured by a protractor from pictures taken at 
baseline versus the end of treatment at 16 weeks  
 
 
B. Secondary outcomes will be measured objectively and subjectively.  
 
 
C. Objective measures will be:  
1. improvements in penile blood flow  
2. reduction in penile plaque size as seen on ultrasound  
 
 
D. Subjective measures will be:  
Khera H-22411 
Page 11 of 35 
1/30/15 


 
1. changes in IIEF scores  
 
As mentioned above, these objective and subjective measurements will be performed before and 
after the 16 week treatment.   
 
Data will be analyzed using a t-test to compare differences between the two groups. 
 
 
XIII. SAFETY MONITORING PLAN: 
 
This safety monitoring plan applies to the investigator-initiated clinical trials conducted at the 
Scott Department of Urology at Baylor College of Medicine. The safety monitoring plan sets 
forth mechanisms for reviewing and evaluating toxicity and any other study-relevant safety-
related data for the investigator-initiated clinical trials.  Such review and evaluation will ensure 
the safety of all study participants and the integrity of study data collected.  The confidentiality 
of study data will be maintained at all times. 
 
A. Purpose: 
 
The Safety Monitoring Plan is meant to assure that this clinical investigation has a 
system for appropriate oversight and monitoring of the conduct of the clinical 
investigation.  This oversight ensures the safety of the study subjects and the validity 
and integrity of the data. 
 
B. Protocol Monitoring:  
 
The PI will be responsible of monitoring the safety and efficacy of the trial, executing 
the Safety Monitoring Plan, and complying with the reporting requirements. 
Monitoring will be performed on a regular basis. All clinical and safety data including 
AE’s, toxicities, and responses will be reviewed by the PI, investigators and research 
staff at regularly scheduled research meetings. The PI will provide a summary of the 
Safety Monitoring Plan findings to the appropriate regulatory authorities on an annual 
basis as part of the progress report. The progress report will include participant 
demographics, expected versus actual recruitment rates, summary of AEs and SAEs, 
any QA or regulatory issues that occurred during the past year, and any actions or 
changes with respect to the protocol.  
 
C. Data Collection:   
 
Data will be collected using the protocol’s case report forms. Participants will be 
identified on the forms by their study ID number. The clinical study coordinator of 
the trial will maintain the codes that link the name of the participant to their study ID 
number. The study coordinator will maintain the code in a secured cabinet and the 
code will be kept confidential. Only the clinical study coordinator and PI can access 
and view the codes. Data quality will be monitored by random inspection of the 
completed forms by a member of the Scott Department of Urology’s Research 
Khera H-22411 
Page 12 of 35 
1/30/15 


Administration QA unit. Any problems detected by QA personnel will be discussed 
with the PI. 
 
D. Safety Monitoring: 
 
During the treatment phase of the study, participants will be asked about AEs at each 
visit. The investigators and/or the study coordinator will document all AEs. All AEs 
occurring during the course of the study will be collected, documented, and reported 
to the PI. AEs will be followed to the point of a satisfactory resolution. Study 
participants may have their study drug discontinued or they may be withdrawn from 
the study if the PI determines it is the best decision in order to protect the safety of the 
participant. Additional AE information is contained in Appendix II - Adverse Event 
Reporting. 
 
 
XIV. ADVERSE EVENT REPORTING 
 
 
Adverse Events will be reported in accordance to all applicable FDA, ICH, and IRB 
rules, regulations, and guidelines.  
 
 
XV. 
Data Handling and Record Keeping 
 
A. Case Report Forms 
 
Protocol-specific data will be collected on Case Report Forms (CRFs). The completed 
dataset should not be made available in any form to third parties, except for 
authorized representatives of appropriate Health/Regulatory Authorities, without 
written permission from BCM. 
 
B. Record Retention 
 
To enable evaluations and/or audits from Health Authorities/BCM, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records; e.g., hospital records), all original signed informed 
consent forms, copies of all CRF’s, and detailed records of drug disposition.  To 
comply with international regulations, the records should be retained by the 
investigator in compliance with regulations. 
 
 
XVI. Protocol Changes  
 
If it is necessary for the study protocol to be amended, the amendment will be submitted 
to the BCM IRB for approval.  Amended procedures will not be in effect until after IRB 
approval has been given.  The principal investigator is responsible for the distribution of 
Khera H-22411 
Page 13 of 35 
1/30/15 


the approved documents to the staff.  The FDA guidelines for submission of an amended 
protocol will be used for notification purposes.  
 
Revisions to questionnaires or CRFs will not require IRB or FDA approval; therefore, 
these revisions will not be reported. 
 
 
XVII. Ethics and Good Clinical Practice 
 
This study must be carried out in compliance with the protocol and the principles of 
Good Clinical Practice, as described in Novartis standard operating procedures and: 
 
• ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
• US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
• Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
 
A. Institutional Review Board (IRB) and Other Institutional Review Committees 
 
Before implementing this study, the protocol, the proposed informed consent form 
and other information to subjects, must be reviewed by a properly constituted and 
other institutional review committees, as required. A signed and dated statement that 
the protocol and informed consent document(s) have been approved by the IRB and 
committees will be provided to the FDA in a general correspondence submission. 
 
B. Informed Consent Process 
 
The investigator or his designated personnel must explain to each subject (or legally 
authorized representative) the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved and any 
discomfort it may entail. Each subject must be informed that participation in the study 
is voluntary and that he/she may withdraw from the study at any time and that 
withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. Informed consent will be obtained in every 
patient prior to performing a biopsy or any protocol-related procedures or tests.  
 
This informed consent should be given by means of a standard written statement, 
written in non-technical language. The subject should read and consider the statement 
before signing and dating it, and should be given a copy of the signed document. If 
the subject cannot read or sign the documents, oral presentation may be made or 
Khera H-22411 
Page 14 of 35 
1/30/15 


signature given by the subject’s legally appointed representative, if witnessed by a 
person not involved in the study, mentioning that the patient could not read or sign 
the documents. No patient can enter the study before his informed consent has been 
obtained. The original signed informed consent form will be kept with the research 
study documents, a copy will be given to the subject, and a copy will be placed in the 
subject’s medical chart. 
 
C. Declaration of Helsinki 
 
The investigator must conduct the trial in accordance with the principles of the 
Declaration of Helsinki. Copies of the Declaration of Helsinki and amendments will 
be provided upon request or can be accessed via the website of the World Medical 
Association at http://www.wma.net/e/policy/17-c_e.html. 
 
 
XVIII. CONFIDENTIALITY 
 
Each subject will be assigned a unique, consecutive three-digit identification number 
(i.e., 001, 002, …). The study number will be utilized for identification of the subject 
throughout the study. The clinical study coordinator of the trial will maintain the code 
that links the name of the participant to their study ID number. The study coordinator will 
maintain the code in a secured cabinet and the code will be kept confidential. Only the 
clinical study coordinator and PI can access and view the codes. 
 
The research records will be maintained in the Scott Department of Urology. The 
computers used for this study are password protected. The data will be kept by the 
clinical coordinator in a secure locked area. Areas are protected after hours by an 
electronic door locking systems. The Scott Department of Urology adheres to the HIPAA 
guidelines. 
 
 
XIX. REFERENCES 
 
1. 
Gassner, H.G. and Sherris, D.A.: Chemoimmobilization: improving predictability in the 
treatment of facial scars. Plast Reconstr Surg, 112: 1464, 2003. 
 
2. 
Gassner, H.G., Sherris, D.A, and Otley, C.C.: Treatment of facial wounds with botulinum 
toxin A improves cosmetic outcome in primates. Plast Reconstr Surg, 105: 1948, 2000. 
 
3. 
Khera, M., Boone, T.B., and Smith, C.P.: Botulinum toxin type A: a novel approach to the 
treatment of recurrent urethral strictures. J Urol, 172: 574, 2004. 
 
4. 
Comperat, E., Reitz, A., Delcourt, A., Capron, F., Denys, P., and Chartier-Kastler, E: 
Histologic features in the urinary bladder wall affected from neurogenic overactivity—a 
comparison of inflammation, oedema and fibrosis with and without injection of botulinum 
toxin type A. Eur Urol, 50: 1058, 2006. 
Khera H-22411 
Page 15 of 35 
1/30/15 


 
5. 
Smith, C.P. and Chancellor, M.B.: Emerging role of botulinum toxin in the management of 
voiding dysfunction. J Urol, 171: 2128, 2004. 
 
6. 
Sommer, F., Schwarzer, U., Wassmer, G., Bloch, W., Braun, M., Klotz, T. et al.: 
Epidemiology of Peyronie’s disease. Int J Impot Res, 14: 379, 2002. 
 
7. 
Russell, S., Steers, W., and McVary, K.T.: Systemic evidence-based analysis of plaque 
injection therapy for Peyronie’s disease. Eur Urol, 51: 640, 2007. 
 
8. 
Doig GS and Simpson F. Randomization and allocation concealment: A practical guide for 
researchers. J Crit Care 2005;20:187-193. 
 
Khera H-22411 
Page 16 of 35 
1/30/15 


 
 
APPENDICES 
Khera H-22411 
Page 17 of 35 
1/30/15 


APPENDIX I 
 
 
 
IIEF QUESTIONNAIRE 
 
 
 
Khera H-22411 
Page 18 of 35 
1/30/15 


International Index of Erectile Function (IIEF) Questionnaire* 
 
Study ID: H-22411: BOTOX in Peyronie's Disease    Date: 
 
 
  Visit #:  
 
 
 
Please circle your answer 
 
1. Over the past 4 weeks, how often were you able to get an erection during sexual activity? 
No sexual activity ............................................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) .................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
2. Over the past 4 weeks when you had erections with sexual stimulation, how often were your erections hard enough for 
penetration? 
No sexual activity ............................................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) .................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
3. Over the past 4 weeks when you attempted sexual intercourse, how often were you able to penetrate (enter) your partner? 
Did not attempt intercourse .............................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) .................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
4. Over the past 4 weeks during intercourse, how often were you able to maintain your erection after you had penetrated 
(entered) your partner? 
Did not attempt intercourse .............................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) .................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
5. Over the past four weeks, during sexual intercourse, how difficult was it to maintain your erection to completion of 
intercourse? 
Did not attempt intercourse .............................................   0 
Extremely difficult ............................................................   1 
Very difficult ....................................................................   2 
Difficult ............................................................................   3 
Slightly difficult ................................................................   4 
Not difficult ......................................................................   5 
 
6. Over the past four weeks, how many times have you attempted sexual intercourse? 
No attempts .....................................................................   0 
One to two attempts ........................................................   1 
Three to four attempts .....................................................   2 
Five to six attempts .........................................................   3 
Seven to ten attempts .....................................................   4 
Eleven or more attempts .................................................   5 
 
7. Over the past four weeks when you attempted sexual intercourse, how often was it satisfactory for you? 
Did not attempt intercourse .............................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) .................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
Page 1 of 2 


International Index of Erectile Function (IIEF) Questionnaire* 
 
8. Over the past four weeks, how much have you enjoyed sexual intercourse? 
No intercourse .................................................................   0 
No enjoyment ..................................................................   1 
Not very enjoyable ..........................................................   2 
Fairly enjoyable ...............................................................   3 
Highly enjoyable ..............................................................   4 
Very highly enjoyable ......................................................   5 
 
9. Over the past four weeks, when you had sexual stimulation or intercourse, how often did you ejaculate? 
No sexual stimulation/intercourse ...................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) .................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
10. Over the past four weeks when you had sexual stimulation or intercourse, how often did you have the feeling of orgasm 
or climax? 
No sexual stimulation/intercourse ...................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) .................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
11. Over the past four weeks, how often have you felt sexual desire? 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) .................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
12. Over the past four weeks, how would you rate your level of sexual desire? 
Very low/none at all .........................................................   1 
Low .................................................................................   2 
Moderate .........................................................................   3 
High.................................................................................   4 
Very high .........................................................................   5 
 
13. Over the past four weeks, how satisfied have you been with your overall sex life? 
Very dissatisfied ..............................................................   1 
Moderately dissatisfied....................................................   2 
About equally satisfied and dissatisfied...........................   3 
Moderately satisfied ........................................................   4 
Very satisfied ..................................................................   5 
 
14. Over the past four weeks, how satisfied have you been with your sexual relationship with your partner? 
Very dissatisfied ..............................................................   1 
Moderately dissatisfied....................................................   2 
About equally satisfied and dissatisfied...........................   3 
Moderately satisfied ........................................................   4 
Very satisfied ..................................................................   5 
 
15. Over the past four weeks, how do you rate your confidence that you could get and keep an erection? 
Very low ..........................................................................   1 
Low .................................................................................   2 
Moderate .........................................................................   3 
High.................................................................................   4 
Very high .........................................................................   5 
 
*RC Rosen, A Riley, G Wagner et al. The international index of erectile dysfunction (IIEF): a multidimensional scale for assessment of 
erectile dysfunction. Urology 1997 49: 822-30. 
Page 2 of 2 


International Index of Erectile Function (IIEF) Questionnaire* 
 
 
Study ID: 
 
 
 
 
 
 Date:  
 
  Visit #:  
 
 
 
 
Please circle your answer 
 
1. Over the past 4 weeks, how often were you able to get an erection during sexual activity? 
No sexual activity ............................................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) ..................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
2. Over the past 4 weeks when you had erections with sexual stimulation, how often were your erections hard enough 
for penetration? 
No sexual activity ............................................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) ..................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
3. Over the past 4 weeks when you attempted sexual intercourse, how often were you able to penetrate (enter) your 
partner? 
Did not attempt intercourse .............................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) ..................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
4. Over the past 4 weeks during intercourse, how often were you able to maintain your erection after you had 
penetrated (entered) your partner? 
Did not attempt intercourse .............................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) ..................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
5. Over the past four weeks, during sexual intercourse, how difficult was it to maintain your erection to completion of 
intercourse? 
Did not attempt intercourse .............................................   0 
Extremely difficult ............................................................   1 
Very difficult .....................................................................   2 
Difficult ............................................................................   3 
Slightly difficult.................................................................   4 
Not difficult ......................................................................   5 
 
6. Over the past four weeks, how many times have you attempted sexual intercourse? 
No attempts .....................................................................   0 
One to two attempts ........................................................   1 
Three to four attempts .....................................................   2 
Five to six attempts .........................................................   3 
Seven to ten attempts .....................................................   4 
Eleven or more attempts .................................................   5 
 
 
Khera H-22411 
Page 19 of 35 
1/30/15 


7. Over the past four weeks when you attempted sexual intercourse, how often was it satisfactory for you? 
Did not attempt intercourse .............................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) ..................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
8. Over the past four weeks, how much have you enjoyed sexual intercourse? 
No intercourse .................................................................   0 
No enjoyment ..................................................................   1 
Not very enjoyable ...........................................................   2 
Fairly enjoyable ...............................................................   3 
Highly enjoyable ..............................................................   4 
Very highly enjoyable ......................................................   5 
 
9. Over the past four weeks, when you had sexual stimulation or intercourse, how often did you ejaculate? 
No sexual stimulation/intercourse....................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) ..................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
10. Over the past four weeks when you had sexual stimulation or intercourse, how often did you have the feeling of 
orgasm or climax? 
No sexual stimulation/intercourse....................................   0 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) ..................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
11. Over the past four weeks, how often have you felt sexual desire? 
Almost never/never .........................................................   1 
A few times (much less than half of the time) ..................   2 
Sometimes (about half of the time) ..................................   3 
Most times (much more than half of the time) .................   4 
Almost always/always .....................................................   5 
 
12. Over the past four weeks, how would you rate your level of sexual desire? 
Very low/none at all .........................................................   1 
Low ..................................................................................   2 
Moderate .........................................................................   3 
High .................................................................................   4 
Very high .........................................................................   5 
 
13. Over the past four weeks, how satisfied have you been with your overall sex life? 
Very dissatisfied ..............................................................   1 
Moderately dissatisfied ....................................................   2 
About equally satisfied and dissatisfied ...........................   3 
Moderately satisfied ........................................................   4 
Very satisfied ...................................................................   5 
 
14. Over the past four weeks, how satisfied have you been with your sexual relationship with your partner? 
Very dissatisfied ..............................................................   1 
Moderately dissatisfied ....................................................   2 
About equally satisfied and dissatisfied ...........................   3 
Moderately satisfied ........................................................   4 
Very satisfied ...................................................................   5 
 
Khera H-22411 
Page 20 of 35 
1/30/15 


15. Over the past four weeks, how do you rate your confidence that you could get and keep an erection? 
Very low ..........................................................................   1 
Low ..................................................................................   2 
Moderate .........................................................................   3 
High .................................................................................   4 
Very high .........................................................................   5 
 
*RC Rosen, A Riley, G Wagner et al. The international index of erectile dysfunction (IIEF): a multidimensional scale for assessment 
of erectile dysfunction. Urology 1997 49: 822-30. 
 
Khera H-22411 
Page 21 of 35 
1/30/15 


 
APPENDIX II 
 
 
 
 
SCOTT DEPARTMENT OF UROLOGY 
BAYLOR COLLEGE OF MEDICINE 
 
 
QUALITY ASSURANCE PROGRAM GUIDELINES 
 
 
 
Page 22 
1/30/15 


 
 
 
 
 
SCOTT DEPARTMENT OF UROLOGY 
 
BAYLOR COLLEGE OF MEDICINE 
 
 
QUALITY ASSURANCE PROGRAM GUIDELINES 
 
 
 
 
 
 
 
 
 
Carol Daniels 
Research Administrator 
 
Linda Higgins, CCRP 
Manager, Regulatory Affairs  
 
 
 
 
 
 
 
 
 
 
 
Research Administration 
713-798-9199 
 
 
 
 
 
 
 
 
March 24, 2004 
Khera H-22411 
Page 23 of 35 
1/30/15 


 
TABLE OF CONTENTS 
 
 
1.0 
PURPOSE 
 
2.0 
QUALITY ASSURANCE AUDITS 
2.1  
Yearly Audit 
2.1.1 
Sponsor/Monitor Audit 
2.1.2 
Investigator File Audit 
 
2.1.3 
Informed Consent Document Audit 
2.1.4 
Date Collection 
2.2 
Quality Assurance Checklist 
2.3 
Quality Assurance Review Form 
 
 
 
 
 
 
3.0 
CONDUCT OF A QUALITY ASSURANCE AUDIT 
3.1  
Patient Case Review Form 
3.1.1 
Eligibility 
3.1.2 
Treatment 
3.1.3 
Disease Outcome/Response Determination 
3.1.4 
Toxicity 
3.1.5 
Data Quality 
3.2  
Regulatory Requirements 
3.2.1 
Consent Form 
3.2.2 
IRB Approvals 
3.3 
Investigational Drug Accountability 
3.3.1 
Drug Logs 
3.3.2 
On-Site Audit   
 
4.0 
DEFINITIONS AND EXAMPLES OF DEVIATIONS FOR PATIENT CASE REVIEW 
4.1 
Major Deviation 
4.1.1 
Eligibility 
4.1.2 
Treatment 
4.1.3 
Disease Outcome/Response Assessment 
4.1.4 
Toxicity 
4.1.5 
General Data Quality 
4.1.6 
Informed Consent 
4.2 
Minor 
 
5.0 
QUALITY ASSURANCE CASE REVIEW FORM 
 
6.0 
IRB REVIEW FORM 
 
7.0 
INVESTIGATIONAL DRUG ACCOUNTABILITY FORM 
 
8.0 
QUALITY ASSURANCE AUDIT CHECKLIST  
 
9.0 
PREPARING FOR A QUALITY ASSURANCE AUDIT 
 
10.0 
HELPFUL HINTS 
Khera H-22411 
Page 24 of 35 
1/30/15 


 
 
SCOTT DEPARTMENT OF UROLOGY 
 
BAYLOR COLLEGE OF MEDICINE 
 
QUALITY ASSURANCE PROGRAM GUIDELINES 
 
 
Quality Assurance: All actions taken to ensure that standards and procedures are adhered to and that 
services meet performance requirements. The planned systematic activities necessary to ensure that a 
system conforms to established requirements.  The policy, procedures and systematic actions 
established in an enterprise for the purpose of providing and maintaining a specified degree of 
confidence in data integrity and accuracy throughout the lifecycle of the data which includes input, 
update, manipulation, and output. 
 
1.0  
PURPOSE 
 
The purpose of the quality assurance/audit program is to: 1.) Enhance the delivery of accurate and reliable 
clinical trials data and results; 2.) Verify the accuracy of data; 3.) Verify that the ‘in house clinical trials’ 
program of the Scott Department of Urology is in compliance with protocol and regulatory requirements; and 4.) 
Provide educational support to the clinical research staff regarding issues related to data quality, data 
management and other aspects of quality assurance.  
 
 
2.0  
QUALITY ASSURANCE AUDITS 
 
2.1 
Yearly Audit 
 
Each “in house clinical trial” will be audited yearly.  Each clinical trial will remain at risk for random 
audit.  The yearly audit will consist of:  
 
2.1.1 
Sponsor/Monitor Audit 
 
2.1.2 
Investigator File Audit 
 
2.1.3 
Informed Consent Audit 
 
2.1.4 
Data Collection 
 
The research coordinator is required to produce the following data relevant to each 
patient's research binder: 
 
2.1.4.1 
Clinical trial-specific case report forms 
2.1.4.2 
Hospital charts, or legible copies. 
2.1.4.3 
Clinic (outpatient) charts. 
2.1.4.4 
Operative, pathology and radiotherapy reports. 
2.1.4.5 
Documentation that the Institutional Review Board (IRB) has initially and annually 
reviewed and approved each protocol on the list including any protocol 
modifications. 
Khera H-22411 
Page 25 of 35 
1/30/15 


2.1.4.6 
Source documents for all data entered on the case report forms. 
2.1.4.7 
Copies of the signed and dated consent forms for each patient. 
2.1.4.8 
Physicians order for vector administration or drug administration as applicable. 
2.1.4.9 
Copies of the protocols including model consent forms. 
2.1.4.10 Copies of all adverse events submitted to the IRB 
2.1.4.11 Copies of all amendments to the original protocol 
 
2.2 
Quality Assurance Audit Checklist  
 
A Quality Assurance Audit Checklist has been developed to assist research coordinators to maintain 
accurate research binders. 
 
2.3. 
Quality Assurance Review Form  
 
A Quality Assurance Review Form has been developed for use when auditing a research binder.  It is 
used as an all-inclusive review of each research binder. 
 
 
3.0  
CONDUCT OF A QUALITY ASSURANCE AUDIT 
 
The purpose of the audit is to assure the accuracy of the data and to verify compliance with protocol and 
regulatory requirements.  The audit is conducted in three parts: 
 
3.1  
Patient Case Review 
 
The major objective of the audit program is to verify study data that could affect the interpretation of 
primary study endpoints.  This is done by comparing the data records with the patient’s primary record 
to evaluate compliance to protocol requirements and accuracy in data reporting. This review will entail 
examination of the following criteria for each participant: 
 
3.1.1 
Eligibility 
 
Verify all eligibility criteria, stratification factors and required prestudy parameters to confirm 
patient met all eligibility criteria as specified by the protocol. 
 
3.1.2. Treatment Compliance with Protocol  
 
Establish in the primary record the patient's actual height and weight and body surface area. 
Verify doses, dates of treatment, and administration were according to protocol specifications.  
 
3.1.3 
Disease Outcome/Response Determination 
 
Verify that disease outcome was evaluated according to protocol.  Responses (PR, CR) should be 
verified through review of x-rays, scans, pathology reports, and records of physical examinations. 
 
3.1.4 
Toxicity Assessment 
 
Verify that toxicities were assessed according to protocol by use of required baseline and follow-up 
studies.  Verify that toxicities were properly graded and accurately reported and any Adverse Events 
Khera H-22411 
Page 26 of 35 
1/30/15 


were filed. All drug-related toxicities must be coded and recorded according to the Group's toxicity 
criteria. 
 
3.1.5 
Data Quality 
 
The primary record will be compared to the flow sheets to determine accuracy in the reporting of 
eligibility, treatment administration, reporting and coding of toxicities, and response assessment.  All 
laboratory results required by protocol must be reported on the flow sheets, or reported as not having 
been done.  Initial form sets, pathology material, flowsheets, etc. must be included in the research 
binder. 
 
3.2   
Regulatory Requirements  
 
3.2.1 
Consent Form 
 
Consent forms must be the protocol specific consent form approved by the Institutional Review 
Board (IRB), be dated and signed prior to registration, and contain applicable elements outlines 
in Title 45, Code of Federal Regulations, Part 46, Protection of Human Subjects.  Any 
significant new findings that may relate to the subject's willingness to continue participation 
should be provided to the subject in accordance with Section 46.116(b)(5). 
 
3.2.2 
IRB Approvals 
 
Minutes of the IRB meetings or detailed letters from the IRB will be accepted as documentation of IRB 
review.  Documentation will be reviewed to ensure full initial IRB approval of the protocol prior to 
patient registration, annual re-approval of the protocol, and full board IRB approval of designated 
protocol modifications. There must not be more than 365 days between annual approvals and protocols 
must receive annual approval as long as data is being gathered on patients.  
 
3.3 
Investigational Drug Accountability 
 
Drug Accountability Record Maintenance 
 
As of February 15, 1983, the NCI has required that drug accountability record forms be maintained by 
all institutions conducting clinical trials with NCI supplied investigational drugs.  Institutions must use 
NCI forms to account for all drugs that are supplied by the NCI (including commercial drugs).   
Auditors are required to inspect the drug logs and tour the area where the investigational drugs are 
stored. 
 
3.3.1 
Drug Logs 
 
This review verifies that the drug logs are maintained according to the NCI instructions.   The 
shipping receipts indicating the protocol numbers, the quantity of drug shipped and the drug lot 
numbers are compared to the drug log for accuracy. Drug handling procedures are reviewed to 
assure the return of expired drugs to the NCI drug repository with the appropriately completed 
form, disposal of any unused portions of drugs, and transfer or return of drugs from closed 
protocols.  If any drugs have been dispensed to a satellite, these records will also be audited.  
The dates and dosages recorded on the flowsheets will then be compared to the drug logs for the 
patients selected for the drug audit. 
 
Khera H-22411 
Page 27 of 35 
1/30/15 


3.3.2 
On-Site Audit 
 
During the on-site audit, a tour of the storage facilities will be conducted. The area in which the 
drugs are stored should be a separate, secure, limited-access area; and the drugs must be stored 
at the correct temperature and must be identified by protocol number.  A physical inventory will 
be done to verify the quantity, and lot numbers will be compared with the drug logs for 
accuracy. 
 
 
4.0 
DEFINITIONS AND EXAMPLES OF DEVIATIONS FOR PATIENT CASE REVIEW 
 
4.1 
Major Deviation 
Variance from protocol-specified procedures that makes the resulting data questionable.   
 
4.1.1 
Eligibility 
 
 
4.1.1.1 
Patient did not meet eligibility criteria as specified by protocol. 
4.1.1.2 
Unable to confirm eligibility due to missing documentation. 
 
             4.1.2 
Treatment 
 
4.1.2.1 Incorrect agent/treatment used. 
4.1.2.2 Additional agent/treatment used which is not permitted by protocol. 
4.1.2.3 Incorrect dose deviations (greater than +/- 10%). 
4.1.2.4 Unjustified dose modifications or failure to modify doses according to 
protocol. 
4.1.2.5 Treatment doses incorrectly administered, calculated, or documented. 
4.1.2.6 Unjustified delays in treatment. 
 
4.1.3     Disease Outcome/Response Assessment 
 
4.1.3.1 
Failure to assess disease status according to the required protocol guidelines. 
4.1.3.2 
Repetitive or substantial inaccuracy in the assessment of tumor response. 
4.1.3.3 
Substantial inaccuracy in the detection of cancer (as in prevention study) or 
determination of cancer progression. 
4.1.3.4 
Response (PR, CR) cannot be verified. 
4.1.3.5 
Failure to detect cancer (as in a prevention study) or failure to identify cancer 
progression 
 
4.1.4 
Toxicity 
 
4.1.4.1 Failure to obtain the required protocol baseline and follow-up studies required   
to effectively assess toxicity. 
4.1.4.2 Unreported major toxicity (Grade 4 or 5). 
4.1.4.3 Repetitive failure to report Grade 2 - 3 toxicities. 
4.1.4.4 Serious or repetitive failure to properly characterize toxicity or grade. 
4.1.4.5 Failure to file required NCI Adverse Event Reports according to the protocol 
and NCI Guidelines if applicable. 
 
Khera H-22411 
Page 28 of 35 
1/30/15 


4.1.5 
General Data Quality 
 
4.1.5.1 Unacceptable level of missing documentation (for example, missing charts, repetitive 
failure to obtain protocol specified laboratory tests or diagnostic studies). 
4.1.5.2 Frequent inaccuracies or errors in submitted data. 
4.1.5.3 Use of white out in the primary record. 
4.1.5.4 Delinquent data  
4.1.5.4.1.1 
greater than 3 months for initial form sets and pathology materials 
4.1.5.4.1.2 
greater than 6 months for follow-up data while patient on  treatment 
4.1.5.4.1.3 
greater than one year for follow-up data for first two years patient is off 
treatment. 
4.1.6     Informed Consent 
 
4.1.6.1 
Consent form missing. 
4.1.6.2 
Consent form not signed and dated by patient. 
4.1.6.3 
Consent form signed after patient started treatment. 
4.1.6.4 
Consent form not the current IRB-approved version at the time of registration. 
4.1.6.5 
Consent form does not include updates or information distributed as an amendment to 
the protocol. 
4.1.6.6 
Consent form does not include required elements. 
 
4.2 
Minor Deviations 
 
Deviations that do not affect the outcome or interpretation of the study and are not described above as 
major deviations. An unacceptable frequency of minor deviations will be treated as a major deviation. 
 
5.0  
QUALITY ASSURANCE CASE REVIEW FORM  
 
 
 
 
Khera H-22411 
Page 29 of 35 
1/30/15 


SCOTT DEPARTMENT OF UROLOGY 
 
QUALITY ASSURANCE CASE REVIEW FORM 
 
Patient # 
 
 
 
Protocol # 
 
 
 
Disease 
 
 
 
Investigator          
 
 
 
 
 
ELIGIBILITY 
No 
Major 
Minor 
NA 
 
 
 
 
 
Patient did not meet all eligibility criteria as specified by protocol. 
 
 
 
 
Documentation missing; unable to confirm eligibility. 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
Incorrect agent/treatment used. 
 
 
 
 
Additional agent/treatment used which is not permitted by protocol. 
 
 
 
 
Incorrect dose deviations (greater than +/- 10%). 
 
 
 
 
Unjustified dose modifications. 
 
 
 
 
Treatment doses incorrectly administered, calculated, or documented.  
 
 
 
 
Unjustified delays in treatment. 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
DISEASE OUTCOME/RESPONSE DETERMINATION 
 
 
 
 
 
 
 
 
 
Inaccurate documentation of initial sites of involvement. 
 
 
 
 
Tumor measurements/eval of status of disease not performed according to protocol. 
 
 
 
 
Protocol-directed response criteria not followed. 
 
 
 
 
Claimed response (CR, PR) cannot be verified. 
 
 
 
 
Failure to detect cancer (prevention study) or failure to identify cancer progression. 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
TOXICITY 
 
 
 
 
 
 
 
 
 
Grades/types or dates/duration of serious toxicities inaccurately recorded. 
 
 
 
 
Toxicities cannot be substantiated. 
 
 
 
 
Follow-up studies necessary to assess toxicities not performed. 
 
 
 
 
Failure to report an Adverse Event. 
 
 
 
 
Recurrent under or over-reporting of toxicities. 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
DATA QUALITY 
 
 
 
 
Date of Last Contact:  
 
 
Recurrent missing documentation. 
 
 
 
 
Protocol-specified laboratory tests not documented. 
 
 
 
 
Protocol-specified diagnostic studies not documented. 
 
 
 
 
Frequent data inaccuracies. 
 
 
 
 
Delinquent data submission. 
 
 
 
 
Khera H-22411 
Page 30 of 35 
1/30/15 


CONSENT FORM                                                
 
 
 
 
 
Date Signed:  
 
 
 
 
 
 
 
Consent form missing. 
 
 
 
 
Consent form not signed and dated by patient. 
 
 
 
 
Consent form signed after patient started on treatment. 
 
 
 
 
Consent form does not contain all required signatures. 
 
 
 
 
Consent form used was not current IRB-approved version at the time of patient 
registration. 
 
 
 
 
Consent form not protocol specific. 
 
 
 
 
Consent form does not include updates or information required by IRB 
 
 
 
 
Other (specify) 
 
 
 
 
NOTE:  “No” = OK.  “Yes” = Major or Minor.  All responses checked other than "No" must be 
explained. 
 
 
 
 
 
 
Auditor’s Printed Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Auditor’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Printed Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
Khera H-22411 
Page 31 of 35 
1/30/15 


 
6.0 
IRB REVIEW FORM  
 
Protocol # 
 
 
 
 
 
 
 
 
No. of Patients 
 
 
 
 
 
 
 
 
Initial IRB Approval                                                          Date: 
 
 
 
 
 
Continuing review                                                              Date: 
 
 
 
 
 
 
 
 
 
Amendment approvals 
Amendment Version 
 
Date of Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAJOR IRB Deficiency  
 
 
 
 
 
 
 
 
 
Protocol never approved by IRB 
 
 
 
 
Initial IRB approval documentation missing 
 
 
 
 
Initial IRB approval by expedited review 
 
 
 
 
Expedited approval for other than approved exceptions 
 
 
 
 
Registration and/or treatment prior to IRB approval 
 
 
 
 
Re-approval delayed > 30 days but < 1 year 
 
 
 
 
Registration of pt during a period of delayed re-approval 
 
 
 
 
Missing re-approval 
 
 
 
 
Expired re-approval 
 
 
 
 
Reportable adverse events not reported to IRB 
 
 
 
 
Lack of full board IRB approval of designated protocol 
modifications within 4 months 
 
 
 
 
 
 
 
 
 
LESSER IRB Deficiency  
 
 
 
 
 
 
 
 
 
Re-approval delayed < 30 days 
 
 
 
 
Delayed re-approvals for closed protocols with all patients on 
follow-up 
 
 
 
 
This list does not represent an all inclusive list of major and lesser deficiencies. 
 
Comments: 
 
 
 
 
IRB Assessment: 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
Page 32 
1/30/15 


 
7.0 
INVESTIGATIONAL DRUG ACCOUNTABILITY FORM 
 
 
 
 
1 = Yes  
2 = No  
3 = Not Applicable 
 
 
Case#  
 
 
 
Protocol # 
 
 
 
1.     NCI Drug Accountability Record Form (DARF) in use? 
 
 
 
A. Completely and correctly filled out? 
 
 
 
B. Protocol and drug specific? 
 
 
 
C. Satellite records accounted for? 
 
 
 
D. NCI logs kept as primary transaction record? 
 
 
 
E.  Physician order for gene vector 
 
 
 
F.  Release of GMP vector 
 
 
 
G. Balance on log matches physical inventory? 
 
 
 
H. Random patients cross-checked with log? 
 
 
 
2.      Storage 
 
 
 
A. Identified by protocol number? 
 
 
 
B. Stored in limited-access, secured area?  
 
 
 
3.     Drug order receipts kept? 
 
 
 
4.     Drugs returned to the NCI and/or other transferred correctly? 
 
 
 
 
 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
Khera H-22411 
Page 33 of 35 
1/30/15 


 
8.0  
QUALITY ASSURANCE AUDIT CHECKLIST  
 
 
PATIENT'S NAME 
 
 
PATIENT'S   # 
 
 
 
 
 
 
 
PROTOCOL # 
 
 
 
 
 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL: 
 
_______ 
Documentation of IRB approval prior to the registration and treatment of the patient. 
 
_______ 
Annual IRB approvals. 
 
_______ 
Protocol modification approvals. 
 
 
CONSENT FORM: 
A copy of the consent dated and signed by the patient.  
 
 
PRIMARY SOURCE DOCUMENTATION: 
 
The primary record must verify the data reported regarding study parameters.  
 
_______ 
Hospital chart, or legible copies. ______             Operative reports 
  
 
 
 
 
 
 
 
             
_______ 
Clinic chart, or legible copies.  
_______            Pathology reports. 
 
_______ 
X-rays, scans and reports. 
 
_______            Radiotherapy records. 
 
_______ 
Other special studies. 
 
 
_______ 
Chemotherapy records. 
 
 
RESEARCH RECORDS: 
 
_______ 
Eligibility checklist (If applicable). 
_______ 
Special Forms. 
 
_______ 
Prestudy form.  
 
 
_______ 
Off-study form. 
 
_______ 
Study specific flow sheets. 
 
_______ 
Copy of the protocol  
 
 
 
 
 
 
 
 
including model consent. 
 
 
INVESTIGATIONAL DRUG ACCOUNTABILITY RECORD FORMS:  
 
_______ 
Control and Satellite DARFs 
 
_______ 
Copies of Return form 
_______ 
Copies of Transfer forms 
 
_______ 
Copies of Shipping receipts  
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
Khera H-22411 
Page 34 of 35 
1/30/15 


 
9.0  
PREPARING FOR A QUALITY ASSURANCE AUDIT 
 
The best time to begin preparing for an audit is just prior to registering a patient to a study. 
 
9.1 
IRB Approval 
 
Confirming that the IRB has approved the protocol prior to registration. 
 
9.2 
Consent Form 
 
Confirming that the patient has signed the most current IRB approved consent form.  
Keep a copy of the signed and dated consent form in the research record. 
 
9.3 
Eligibility Criteria 
 
Verifying in the medical record all the prestudy required data as specified by the 
eligibility criteria and the study calendar. 
 
10. 
HELPFUL HINTS 
 
10.1 
Copy the source documentation for the data reported as you abstract the data from the 
patient's primary record.  This could possibly prevent a discrepancy for not being able to 
document the data reported when reviewed by auditors. 
 
10.2 
Approximately four weeks prior to the audit, you will receive the list of cases to be 
audited.  
 
10.3 
Thoroughly review the protocol for the eligibility criteria, study parameters, treatment 
requirements and response definitions.  
 
10.4 
For investigational drug accountability audit, notify the pharmacist, or the person 
responsible for the drug logs.  Be sure the shipping receipts, return forms, transfer forms 
and drug logs will be available for the audit.  Prepare for a tour of the area where the 
drugs are stored. 
 
10.5 
Notify the IRB Chairperson that you need documentation of initial and annual approval 
along with protocol modification approvals for each protocol on the list of cases.  This 
documentation may be in the form of IRB letters of approval from the IRB Chairperson 
and/or minutes of the IRB meetings. 
 
10.6 
Once the source documentation is available, compare the data sheets with the medical 
records for accuracy, paying close attention to dates. 
 
10.7 
Clearly identify the data in the medical records to facilitate quick retrieval during the 
audit. It is suggested using colored tabs indicating treatment cycles, dates or week 
numbers.  Be creative - the important point is for you to quickly find the documentation 
as requested by the auditors. 
 
10.8 
Be available all day to assist the auditors. 
 
10.9 
If the original medical records are not available, legible copies may be used.  
Khera H-22411 
Page 35 of 35 
1/30/15