Conditions: Premature Ejaculation
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 59
Healthy volunteers: no

Brief summary:
This is a safety and efficacy study of OnabotulinumtoxinA for the treatment of premature ejaculation (PE) in male participants.

Detailed description:
This is a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-escalation study to assess a range of doses of OnabotulinumtoxinA for the treatment of male participants with PE. Participants will attend a minimum of 6 or 7 clinic visits and also have 1 or 2 telephone visits. Partners will need to attend a clinic visit during the screening period to provide informed consent and to receive training on measurement and recording of the intravaginal ejaculatory latency time (IELT). Participants will be enrolled in cohorts. Within the first 5 cohorts, 8 participants are to receive OnabotulinumtoxinA and 2 participants to receive placebo. For cohort 6, 12 participants will receive OnabotulinumtoxinA and 12 participants will receive placebo. Participants will receive a single treatment of study medication delivered bilaterally to the bulbospongiosus muscle. The initial OnabotulinumtoxinA total dose in this dose escalation study will be 5 U and the maximum OnabotulinumtoxinA total dose will be 100 U. Upon request and if eligible, participants in cohort 6, will have the option to receive a second injection of OnabotulinumtoxinA (Open-label).

Arms:
arm 1: OnabotulinumtoxinA Dose 1 injected into specified muscle per protocol on Day 1. arm 2: OnabotulinumtoxinA Dose 2 injected into specified muscle per protocol on Day 1. Participants were eligible for another treatment after 12 weeks. arm 3: OnabotulinumtoxinA Dose 3 injected into specified muscle per protocol on Day 1. arm 4: OnabotulinumtoxinA Dose 4 injected into specified muscle per protocol on Day 1. arm 5: OnabotulinumtoxinA Dose 5 injected into specified muscle per protocol on Day 1. arm 6: OnabotulinumtoxinA Dose 6 injected into specified muscle per protocol on Day 1. arm 7: Placebo (normal saline) injected into specified muscle per protocol on Day 1.

Interventions: intervention 1: OnabotulinumtoxinA intervention 2: Normal Saline
Intervention descriptions: intervention 1: OnabotulinumtoxinA injected into specified muscle per protocol on Day 1. intervention 2: Placebo (normal saline) injected into specified muscle per protocol on Day 1.

Protocol document:
Prot_000.pdf: 
NCT01917006 
 
Study ID: 191622‐133 
 
Title: An Exploratory Study of the Safety and Efficacy of BOTOX® for the Treatment of Premature 
Ejaculation 
 
Protocol Amendment 2 Date: 15 Jul 2016 


 
 
Approval Date: 
 
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Allergan Confidential 
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Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
 
which is the property of Allergan 
 
An Exploratory Study of the Safety and Efficacy of BOTOX® for the Treatment of Premature 
Ejaculation 
 
Protocol Number:   
191622-133 Amendment 2 
EudraCT Number (if applicable): 
Phase: 
2013-001650-94 
2a 
Name of Investigational Product: 
BOTOX® 
Sponsor: 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California USA 
92612 
+1-714-246-4500 
+1-800-347-4500 
Allergan Ltd. 
1st Floor, Marlow 
International, 
The Parkway, Marlow 
Buckinghamshire 
SL7 1YL United Kingdom 
Tel: +44 (0) 1628 494444 
Fax: +44 (0) 1628 494449 
Emergency Telephone Numbers 
Refer to the Study Contact 
Page 
 
SAE Reporting Fax Number: 
Back Up Fax Number: 
 
 
Allergan Medical Safety Physician 
Contact Information: 
 
 
 


 
 
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Allergan Signatory: 
 
 
 
 
Refer to the final page of this protocol for electronic signature 
and date of approval. 
 
The following information can be found on FDA Form 1572 and/or study contacts page 
and/or trial master file:  Name and contact information of Allergan study personnel; name, 
address, and statement of qualifications of each investigator; name of each subinvestigator 
working under the supervision of the investigator; name and address of the research facilities 
to be used; name and address of each reviewing IRB; 21 CFR 312.23 section 6(iii)b. 
 


 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
• Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 


 
 
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Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 8 
List of Figures ........................................................................................................................... 9 
Protocol Summary .................................................................................................................. 10 
1. 
Background and Clinical Rationale ................................................................................. 20 
1.1 
Epidemiology, Definition, and Assessment ........................................................... 20 
1.2 
Etiology of Premature Ejaculation ......................................................................... 21 
1.3 
Physiology of Ejaculation ...................................................................................... 21 
1.4 
Treatment of Premature Ejaculation ...................................................................... 21 
1.5 
Rationale for BOTOX ............................................................................................ 23 
1.6 
Nonclinical Toxicology .......................................................................................... 24 
2. 
Study Objectives and Clinical Hypotheses ...................................................................... 26 
2.1 
Study Objectives .................................................................................................... 26 
2.2 
Clinical Hypotheses ............................................................................................... 26 
3. 
Study Design .................................................................................................................... 27 
3.1 
Sentinel Dosing (Cohorts 1-5 only) ....................................................................... 28 
3.2 
Data Review Committee (Cohorts 1-5 only) ......................................................... 29 
3.3 
Open Label Period (Cohort 6) ................................................................................ 29 
3.3.1  Qualification for Open-Label Period ......................................................... 30 
3.3.2  Day 1 of Open-Label Period Injection ....................................................... 30 
4. 
Study Population and Entry Criteria ................................................................................ 30 
4.1 
Number of Patients ................................................................................................. 30 
4.2 
Study Population Characteristics ........................................................................... 31 
4.3 
Inclusion Criteria .................................................................................................... 31 
4.4 
Exclusion Criteria................................................................................................... 32 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 35 
4.5.1  Permissible Medications/Treatments ......................................................... 35 
4.5.1.1 
Acceptable Contraceptive Methods ........................................... 36 
4.5.2  Prohibited Medications/Treatments/Techniques ........................................ 36 
4.5.3  Anticoagulant and Antiplatelet Medications .............................................. 37 
4.6 
Sexual Activity and Practices ................................................................................. 38 


 
 
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5. 
Study Treatments ............................................................................................................. 39 
5.1 
Study Treatments and Formulations ....................................................................... 39 
5.2 
Control Treatment .................................................................................................. 39 
5.3 
Methods for Blinding ............................................................................................. 39 
5.4 
Treatment Allocation Ratio and Stratification........................................................ 39 
5.5 
Method for Assignment to Treatment Groups/Randomization .............................. 40 
5.6 
Treatment Regimen and Dosing ............................................................................. 40 
5.6.1  Treatment Regimen/Dosage Adjustments (Cohorts 1-5 only) ................... 41 
5.7 
Storage of Study Medications/Treatments ............................................................. 41 
5.8 
Preparation of Study Medications/Treatments ....................................................... 41 
5.9 
Treatment Administration ...................................................................................... 42 
5.9.1  Anesthesia and Sedation ............................................................................ 42 
5.9.2  Bulbospongiosus Injection Technique ....................................................... 43 
5.9.3  Posttreatment Observation Period .............................................................. 43 
5.9.4  Posttreatment Instructions for Patients....................................................... 44 
6. 
Response Measures and Summary of Data Collection Methods ..................................... 45 
6.1 
Efficacy Measures .................................................................................................. 45 
6.1.1  Primary Efficacy Measure .......................................................................... 45 
 
 
 
 
6.2 
Safety Measures ..................................................................................................... 46 
6.3 
Examination Procedures, Tests, Equipment, and Techniques ................................ 46 
6.3.1  Medical History, Physical Examination, and Vital Signs........................... 46 
6.3.1.1 
Medical History ......................................................................... 46 
6.3.1.2 
Physical Examination................................................................. 47 
6.3.1.3 
Vital Signs .................................................................................. 47 
6.3.2  Blood Specimen Procedures ...................................................................... 47 
6.3.2.1 
Hematology ................................................................................ 48 
6.3.2.2 
Serum Chemistry ....................................................................... 48 
6.3.3  Urine Specimen Procedures ....................................................................... 48 
6.3.3.1 
Central Laboratory Urine Analysis ............................................ 49 
6.3.3.2 
Urine Culture and Sensitivity ..................................................... 49 
6.3.4  Intravaginal Ejaculatory Latency Time ...................................................... 49 
6.3.4.1 
Definition of Evaluable Intravaginal Ejaculatory Latency Time 
Events ......................................................................................... 51 
6.3.4.2 
Screening Intravaginal Ejaculatory Latency Time Collection ... 51 


 
 
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6.3.4.3 
Posttreatment Intravaginal Ejaculatory Latency Time Collection
.................................................................................................... 52 
6.3.5  Masturbatory Events .................................................................................. 52 
 
 
6.3.5.2 
Ejaculation Adverse Events ....................................................... 54 
 
 
 
 
 
 
 
 
 
 
 
6.4 
Other Study Supplies .............................................................................................. 56 
6.5 
Summary of Methods of Data Collection .............................................................. 57 
7. 
Statistical Procedures ....................................................................................................... 58 
7.1 
Analysis Populations .............................................................................................. 58 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 58 
7.2.1  Primary Efficacy Variable .......................................................................... 58 
7.2.2  Secondary Efficacy Variables ..................................................................... 58 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 59 
7.3.1  Primary Efficacy Analyses ......................................................................... 59 
7.3.2  Secondary Efficacy Analyses ..................................................................... 59 
 
 
 
 
 
 
 
 
 
 
7.4 
Subgroup Analyses ................................................................................................. 62 
7.5 
Sample Size Calculation ........................................................................................ 62 
7.6 
Interim Analyses..................................................................................................... 64 
8. 
Study Visit Schedule and Procedures .............................................................................. 64 
8.1 
Patient Entry Procedures ........................................................................................ 64 
8.1.1  Overview of Entry Procedures ................................................................... 64 
8.1.2  Informed Consent and Patient Privacy ....................................................... 64 
8.2 
Washout of Prohibited Medications ....................................................................... 64 
8.3 
Procedures for Final Study Entry ........................................................................... 65 
8.3.1  Extended Screening Period ........................................................................ 65 


 
 
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8.4 
Visits and Associated Procedures ........................................................................... 66 
8.5 
Instructions for the Patients .................................................................................... 66 
8.6 
Unscheduled Visits ................................................................................................. 67 
8.7 
Compliance with Protocol ...................................................................................... 67 
8.8 
Early Discontinuation of Patients .......................................................................... 67 
8.9 
Withdrawal Criteria ................................................................................................ 67 
8.10  Study Termination .................................................................................................. 68 
8.11  Definition of Study End ......................................................................................... 68 
9. 
Adverse Events ................................................................................................................ 68 
9.1 
Definitions .............................................................................................................. 68 
9.1.1  Adverse Event ............................................................................................ 68 
9.1.2  Definition of Ejaculation Adverse Events .................................................. 69 
9.1.3  Serious Adverse Event ............................................................................... 69 
9.1.4  Severity ...................................................................................................... 70 
9.1.5  Relationship to Study Medication or Study Procedure .............................. 70 
9.2 
Procedures for Reporting Adverse Events ............................................................. 70 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 70 
9.4 
Procedures for Unblinding of Study Medication ................................................... 71 
10.  Administrative Items ....................................................................................................... 72 
10.1  Protection of Human Patients ................................................................................ 72 
10.1.1  Compliance with Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ................................................................... 72 
10.1.2  Compliance With IRB or IEC Regulations ................................................ 72 
10.1.3  Compliance With Good Clinical Practice .................................................. 72 
10.1.4  Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) .................................................................................. 72 
10.2  Changes to the Protocol ......................................................................................... 72 
10.3  Patient Confidentiality ........................................................................................... 73 
10.3.1  Patient Privacy ........................................................................................... 73 
10.4  Documentation ....................................................................................................... 73 
10.4.1  Source Documents ..................................................................................... 73 
10.4.2  Case Report Form Completion................................................................... 75 
10.4.3  Study Summary .......................................................................................... 76 
10.4.4  Retention of Documentation ...................................................................... 76 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments .. 76 


 
 
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10.5.1  Labeling/Packaging .................................................................................... 76 
10.5.2  Clinical Supply Inventory .......................................................................... 77 
10.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies ..... 77 
10.6  Monitoring by the Sponsor .................................................................................... 77 
10.7  Handling of Biological Specimens......................................................................... 77 
10.8  Publications ............................................................................................................ 78 
10.9  Coordinating Investigator ...................................................................................... 78 
11.  References ........................................................................................................................ 79 
12.  Attachments ..................................................................................................................... 82 
 
 
 
 
 
12.2  Sexual Intercourse Diary ........................................................................................ 89 
 
12.4  The Bulbospongiosus Muscle ................................................................................ 93 
12.5  Package Insert ........................................................................................................ 94 
12.6  Glossary of Abbreviations ...................................................................................... 95 
12.7  Protocol Amendment 1 Summary .......................................................................... 97 
12.8  Protocol Amendment 2 Summary .......................................................................... 99 
 
List of Tables 
Table 1 
Schedule of Visits and Procedures for Cohorts 1 to 5..................................... 15 
Table 2 
Schedule of Visits and Procedures for Cohort 6 ............................................. 17 
Table 3–1 
Planned Dose Escalation Scheme ................................................................... 28 
Table 7–1 
Power Calculation with Different Expected Fold-change Comparison Ratio 
and Coefficient of Variations .......................................................................... 63 
Table 7–2 
Coefficient of Variation at Week 12 in Priligy Pivotal Studies ....................... 63 
 


 
 
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List of Figures 
Figure 12–1 
Male Anatomy Showing Superficial Location of the Bulbospongiosus Muscle 
for Study Medication Injection ....................................................................... 93 
 
 


 
 
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Protocol Summary 
 
Study Compound(s):  BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex (United States 
Adopted Name is OnabotulinumtoxinA) 
Phase:  2a   
Study Objective(s):  To explore the safety and efficacy of a range of doses of BOTOX for the treatment of 
premature ejaculation (PE) in male patients 
Clinical Hypotheses:  BOTOX injected bilaterally into the bulbospongiosus muscle has an acceptable safety 
profile and shows an efficacy signal in comparison to placebo, as demonstrated by an increased intravaginal 
ejaculatory latency time (IELT). 
Study Design 
Structure:  Multicenter, randomized, double-blind, placebo-controlled pilot study, followed by an open-label 
observation period   
Duration:  Up to 24 weeks following randomization  
Study Treatment Groups:  BOTOX 
Controls:  Placebo (saline) 
Dosage/Dose Regimen:  Patients will receive a single treatment of either BOTOX or placebo delivered 
bilaterally to the bulbospongiosus muscle.  The initial BOTOX total dose will be 
 and the maximum 
BOTOX total dose will be 
  
For Cohort 6, patients may participate in two periods:  randomization and open-label.  During the randomization 
period, patients will receive a single treatment of either BOTOX 
 or placebo delivered bilaterally to the 
bulbospongiosus muscle.  All patients continuing into the open-label period will receive an additional treatment 
of BOTOX 
 delivered bilaterally to the bulbospongiosus muscle. 
The table below shows the planned dose escalation scheme.   
Cohort 
Total Dose 
Sample Size 
Total Patients in Cohort 
1 
N = 8 
10 
Placebo 
N = 2 
2 
N = 8 
10 
Placebo 
N = 2 
3 
N = 8 
10 
Placebo 
N = 2 
4 
N = 8 
10 
Placebo 
N = 2 
5 
N = 8 
10 
Placebo 
N = 2 
6 
N = 12 
24 
Placebo 
N = 12 
* Based on DRC recommendations Cohort 6 is to be performed with 
 of BOTOX and a randomization ratio 
of 1:1  for the first 12 weeks with 24 patients 
Randomization/Stratification:   For Cohorts 1-5, patients will be enrolled in cohorts consisting of 10 patients.  
Within each cohort, 8 patients will receive BOTOX and 2 patients will receive placebo (see table above).  
Sentinel dosing of the first 2 patients (1 BOTOX, 1 placebo) will occur at the commencement of Cohort 1 and 
also for any subsequent cohort that escalates the dose.  Following a 1-week observation period providing there 
are no safety concerns with the sentinel patients, the remainder of the cohort will be enrolled. 


 
 
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Dose escalation will be based on the independent Data Review Committee (DRC) recommendation, following 
review of 4 weeks of safety and efficacy data from the preceding cohort.  The DRC may also recommend to 
repeat cohorts, de-escalate the dose, assess alternative doses, or stop the study.   
Based on the DRC recommendation for Cohort 6, patients will be enrolled in a 1:1 ratio of BOTOX 
 to 
placebo in the randomized period of the study and may elect to continue into the open-label period as described 
below.  No stratification will be implemented.  
Visit Schedule: 
Cohorts 1 to 5:  
• 
Screening period (washout if required will occur during the screening period) 
• 
Day 1:  Treatment visit 
• 
Day 2:  Follow-up telephone visit  
• 
Week 1:  Follow-up visit (telephone visit for nonsentinel patients, clinic visit for sentinel patients) 
• 
Weeks 2, 4, and 8:  Follow-up clinic visits 
• 
Week 12:  Clinic visit/study exit visit 
 
Cohort 6 (Randomized Period): 
• 
Screening period (washout if required will occur during the screening period) 
• 
Day 1:  Treatment visit 
• 
Day 2:  Follow-up telephone visit  
• 
Week 1:  Follow-up telephone visit 
• 
Weeks 2, 4, and 8:  Follow-up clinic visits 
• 
Week 12:  Clinic visit/study exit visit  
 
Cohort 6 (Open-Label Period): 
• 
Day 1:  Treatment visit (may occur on the same day as the week 12 visit of the randomization period) 
• 
Day 2:  Follow-up telephone visit  
• 
Week 2 and 8:  Telephone follow-up visit  
• 
Weeks 4 and 12:  Follow-up clinic visit/study exit visit 
 
Study Population Characteristics 
Number of Patients:  Based on the proposed doses it is anticipated that approximately 74 patients will be 
enrolled in the 6 planned cohorts.  The actual number of patients entering the study will be determined by the 
number of cohorts (eg, escalations, repeat doses, de-escalations, or when the study is stopped).  No more than 
80 patients will be enrolled in the study. 
Condition/Disease:  premature ejaculation (PE) 
Key Inclusion Criteria:   
• 
written informed consent has been obtained from both the patient and his female partner 
• 
male aged 18 to 60 years 
• 
in a stable monogamous sexual relationship with a female partner for at least 6 months (with the 
intention to continue with the same partner for the duration of the study) 
• 
diagnosed with lifelong PE (defined as symptoms starting at the time the patient became sexually 
active) 


 
 
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• 
 
 
 
 
 
 
 
 
• 
 
 
 
 
  
 
 
 
 
 
• 
 
 
• 
 
 
 
 
 
 
 
Key Exclusion Criteria:   
• 
any medical or surgical condition that could be associated with secondary (acquired) PE or patient has 
PE which is situational or attributable to relationship issues 
• 
 
• 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
• 
 
 
 
• 
patient has had prior genital, prostatic or lower urinary tract surgery (other than vasectomy or 
circumcision) 
• 
 
 


 
 
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• 
 
 
• 
 
• 
history of any neurologic condition that may affect sexual function or findings at study entry which 
may be consistent with a neurological condition that may affect sexual function 
• 
 
• 
 
• 
botulinum toxin therapy of any serotype for any non-urological condition or usage (eg, cosmetic or 
chronic migraine) during the 12 weeks prior to screening, or planned usage during the course of this 
study 
 
Response Measures  
Efficacy:  
• 
IELT (measured by stopwatch and captured on the SID) 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
General Statistical Methods and Types of Analyses:   
The final analysis will be performed when all patients have completed or exited the study.  The modified 
intent-to-treat (mITT) population, defined as all randomized patients that have received study medication and 
have postbaseline IELT data available, will be used to analyze all efficacy variables.  Analyses on the mITT 
population will be based on the dose actually received by the patient.  The per protocol (PP) population, defined 
as patients in the mITT population without significant protocol deviations, will also be used for efficacy 
analysis.  The primary efficacy variable (change from baseline in logarithm value of the patient’s geometric 
mean IELT) in relation to dose levels will be analyzed by using an analysis of covariance (ANCOVA) model 
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across the BOTOX dose levels.  Geometric mean IELT data up to week 12 will be log-transformed prior to 
analysis.  Analysis of the primary efficacy variable using the PP population will also be performed.   
A pairwise comparison of each BOTOX dose group versus placebo will be made for percent responders for the 
patient-reported outcomes of 
  
All safety analyses will be performed on the safety population (ie, all patients who receive study medication).  
The incidence of adverse events will be presented.  Mean change from baseline will be compared for each 
BOTOX dose group versus placebo for the 
 questionnaires. 
Data will be summarized with descriptive statistics, frequency tables, and data listings.  Categorical variables 
will be analyzed using Fisher’s exact test, Pearson’s chi-square test, or Cochran-Mantel-Haenszel methods, as 
appropriate.  Continuous variables will be analyzed using either ANCOVA or corresponding nonparametric 
methods. 
Sample Size Calculation:  For this exploratory study, an empirical sample size is used.  For Cohorts 1-5, 
8 patients will be randomized to receive BOTOX and 2 patients to placebo.  In Cohort 6, 24 patients will be 
randomized in a 1:1 ratio of BOTOX to placebo.   


 
 
 
 
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1. 
Background and Clinical Rationale  
1.1 
Epidemiology, Definition, and Assessment  
Premature ejaculation (PE) is one of the most common forms of male sexual dysfunction, 
affecting approximately 13% to 30% of adult men (depending on the definition used) 
(Laumann et al, 2005; Patrick et al, 2005), although this is likely an underestimate due to a 
reluctance to report the condition (Symonds et al, 2003).  Unlike erectile dysfunction (ED), 
PE does not appear to be associated with increasing age (Althof, 2006; Porst et al, 2007). 
Studies of men with PE have consistently shown high levels of personal distress and 
reductions in levels of sexual functioning, self-esteem, satisfaction, overall quality of life, as 
well as interpersonal difficulty (Rowland et al, 2007; Rosen and Althof, 2008).  The 
condition for many men serves as a barrier to seeking and becoming involved in relationships 
(Symonds et al, 2003).  Studies in the female partner also consistently show greater sexual 
problems, reduced satisfaction, distress, interpersonal difficulty, and decreased sexual 
pleasure (Rowland et al, 2007; Althof, 2006).  PE thereby causes emotional and physical 
dissatisfaction for both the man and also for the couple as a whole 
(Graziottin and Althof, 2011).   
PE has been defined by the International Society of Sexual Medicine (ISSM) as “a male 
sexual dysfunction characterized by ejaculation which always or nearly always occurs prior 
to or within about 1 minute of vaginal penetration, and the inability to delay ejaculation on 
all or nearly all vaginal penetrations, and negative personal consequences, such as distress, 
bother, frustration, and/or the avoidance of sexual intimacy” (McMahon et al, 2008).   
PE can be classified into 2 main subtypes (Godpodinoff, 1989; Waldinger, 2008): 
• life-long (primary), which is present from the time a male begins puberty and continues 
throughout life  
• acquired (secondary), which develops later in life and may be due to other causes  
Stopwatch assessment of the intravaginal ejaculatory latency time (IELT) is widely used in 
clinical trials as an objective assessment of the condition.  Multinational normative data from 
an unselected population of approximately 500 men demonstrated a median IELT of 
5.4 minutes (range 0.55 to 44.1 minutes) (Waldinger, 2005a).  Using 0.5 and 2.5 percentiles 
as disease cutoffs, this equated to IELTs of 0.9 and 1.3 minutes, respectively.  Therefore, an 


 
 
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IELT of < 1 minute is regarded as an acceptable limit for disease definition 
(Waldinger et al, 2005b).  
1.2 
Etiology of Premature Ejaculation 
Previously PE was assumed to be due to psychological or interpersonal issues.  However, 
recent animal and human sexual psychopharmacological studies have attributed a 
neurobiological basis, and possible genetic etiology to primary PE (Waldinger, 2002). 
Neurobiological factors include glans penis hypersensitivity, hypersensitive ejaculatory 
reflex, increased cortical representation of the pudendal nerve, and disturbances in central 
serotonergic neurotransmission (McMahon et al, 2008).  Genetic factors include a possible 
association between a 5-HT transporter (5-HTT) promoter gene polymorphism and short 
IELTs in men with lifelong PE (Janssen et al, 2009).  
1.3 
Physiology of Ejaculation 
Ejaculation is the culmination of male sexual behavior and is intimately associated with 
orgasm.  It is composed of 2 distinct phases: 
• Emission is the ejection of semen into the posterior urethra via epithelial secretion and 
smooth muscle contraction within the accessory sex glands.   
• Expulsion is the intense rhythmic contractions of the pelvic floor muscles that propels the 
semen distally through the bulbar and penile urethra and empties the semen out of the 
urethral meatus.  The bulbospongiosus muscle (BSM) is the principal muscle involved in 
expulsion although other muscles such as the ischiocavernosus muscles are also involved 
to a much lesser extent.  
The process is triggered by a complex spinal reflex which originates within the spinal 
generator for ejaculation (SGE) in the thoracolumbar region of the spinal cord.  Ejaculation is 
an autonomic mediated event and tight coordination of the sympathetic, parasympathetic, and 
somatic divisions of the nervous system are necessary for normal ejaculation to occur 
(Giuliano and Clèment, 2012). 
1.4 
Treatment of Premature Ejaculation 
There are a limited number of treatment options currently available for the treatment of PE.  
Treatments currently being used for PE include behavioral techniques, topical therapies, and 
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First-line therapy for PE tends to include behavioral techniques such as the 'stop-start' and 
'squeeze' techniques (Semans, 1956; Masters and Johnson, 1970), and precoitus masturbation 
(Sadeghi-Nejad and Watson, 2008).  These techniques are only moderately successful and 
can be intrusive during sexual intercourse for the patient and female partner, and 
time-consuming to learn.  Although short-term benefits have been reported, long-term 
response rates fall to 25% at 3 years for behavioral therapy (Hawton et al, 1986).   
Topical therapies tend to be local anesthetics or herbal-based creams, gels, ointments, or 
spray formulations and are applied shortly prior to intercourse (Morales, 2012), eg, 
Promescent® (United States [US]) and STUD 100/Premjact desensitizing spray (United 
Kingdom [UK]) which have local anesthetics (such as lidocaine) as the active ingredient.  
These topical therapies have limited clinical evidence to support their effective use in patients 
with PE.  In addition, topical therapies are only moderately effective and have been 
associated with penile hypoanesthesia and vaginal numbness, which in some cases results in 
female anorgasmia (McMahon et al, 2008).  Topical therapies also affect spontaneity of 
sexual intercourse as patients need to allow sufficient time for the treatment to take effect. 
Several oral pharmacological agents have been used for the treatment of PE including 
centrally acting agents such as selective serotonin reuptake inhibitors (SSRIs), tricyclic 
antidepressants, and tramadol; however, these classes of medications may require daily 
dosing and are associated with neurocognitive and systemic adverse effects.  Many men are 
reluctant to use these medications because of these adverse effects.  Locally acting 
medications such as phosphodiesterase type-5 inhibitors (PDE5i) and alpha antagonists have 
also been used; however, there is limited robust evidence to support their usage in the 
treatment of PE.  In addition, the majority of these pharmacological treatments require 
on-demand dosing which hinders the spontaneity of intercourse (McMahon et al, 2008).   
No oral treatment has been specifically approved for the treatment of PE by the US Food and 
Drug Administration (US FDA), and the only oral medication specifically approved by 
European regulators for this indication is the short-acting SSRI, dapoxetine; which can be 
used as an “on demand” therapy.  Dapoxetine is associated with vasovagal-mediated syncope 
and there is little data on the long-term adverse effects of its usage (Hutchinson et al, 2012). 
Therefore, there is a significant unmet need for an effective and safe long-acting PE 
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1.5 
Rationale for BOTOX  
BOTOX® is licensed globally in over 80 countries for a wide range of indications 
characterized by muscle hyperactivity.  Approved therapeutic indications targeting skeletal 
muscle include blepharospasm, hemifacial spasm, strabismus, cervical dystonia, and focal 
spasticity.  BOTOX is also approved in over 30 countries for cosmetic indications targeting 
skeletal muscle, including upper facial rhytides (forehead, lateral canthus, and glabellar 
lines). 
In addition, urological indications targeting the smooth muscle have recently received 
regulatory approval in the US, many of the European Union countries, Australia, New 
Zealand, and Canada for the use of BOTOX in the treatment of neurogenic detrusor 
overactivity, as well as for the treatment of overactive bladder. 
It is proposed that a pharmacologic decrease in muscle contractility, as might be achieved 
with targeted BOTOX injections, could be an effective treatment for PE.  BOTOX has a 
well-described mode of action, with presynaptic blockade of acetylcholine release at the 
neuromuscular junction leading to a decrease in neuromuscular transmission and long-term 
relaxation of an injected muscle.  If injected into the skeletal muscles of the pelvic floor, such 
as the bulbospongiosus, which are involved in the rhythmic contractions during ejaculation, it 
can be hypothesized that a delay in the initiation of rhythmic pelvic floor contractions and a 
resultant delay in ejaculation will occur. 
A nonclinical study in 33 male Long-Evans rats demonstrated that bilateral injections of 
BOTOX of either 0.5 U or 1 U in the bulbospongiosus muscle resulted in a significant 
increase in ejaculatory latency when compared to pretreatment levels.  Rats injected with 
saline did not show a significant increase in ejaculatory latency.  There were no safety issues 
identified and BOTOX treatment did not impact the ability to achieve mount or intromission 
(Serefoglu et al, 2012).  
Based on previous experience with BOTOX in a wide variety of neuromuscular conditions 
(both skeletal and smooth muscle), it would be expected that a single treatment 
administration will provide a sustained effect lasting several months. 
The purpose of this study is to explore several doses of BOTOX to assess if BOTOX may 
have utility in the treatment of PE.   
The safety of BOTOX has been widely studied and found to be safe across a wide range of 
indications.  In 3 completed phase 2 studies, the safety of BOTOX has also been evaluated 
after a single injection into the male reproductive system (ie, the prostate) in 468 men with 


 
 
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benign prostatic hyperplasia (Studies 191622-091, -100, and -517).  The 191622-091 
spermatogenesis and semen quality study demonstrated that following injections of 
200 U BOTOX directly into the prostate, there was no impact on any semen parameters 
compared to placebo (including sperm count, semen volume, sperm concentration, sperm 
motility, and sperm morphology).  Also, in Studies 191622-100 and 191622-517, where 
BOTOX doses up to 300 U were injected into the prostate gland, there was no effect on 
erectile function.  Therefore, it is expected that injection into muscles that are involved in 
sexual function (ie, bulbospongiosus muscle) at the proposed doses will be safe and will have 
no impact on semen parameters or erectile function. 
The safety of bulbospongiosus injections with BOTOX is further supported by a randomized, 
placebo-controlled, pilot study (Gottsch et al, 2011).  In the study, 100 U BOTOX was 
injected into the bulbospongiosus muscle of 23 male patients with chronic pelvic pain 
syndrome to assess relief of pain symptoms.  There were no complications in any patient 
related to the injection procedure, and no analgesics were required during or following the 
injections.  Over the 3 months of follow up, no adverse events or systemic side effects were 
reported. 
The data from this study will be used to assist in the design of future clinical trials for PE, 
and the study data may also help develop a better understanding of diseases capable of being 
treated with BOTOX.  
1.6 
Nonclinical Toxicology 
BOTOX has been studied in rodents and primates in over 300 nonclinical studies since 1991.  
Single- and repeat-dose nonclinical safety studies, including reproductive toxicity, and 
genotoxicity of BOTOX in various animal species have shown no noteworthy adverse local 
or systemic effects following intramuscular administration at clinically relevant dose levels.   
Rats had no noteworthy adverse local or systemic effects following single dose injections in 
skeletal muscle up to 10 U/kg and in monthly doses (7 repeated injections) up to 16 U/kg.  
The lowest observable adverse effect level (LOAEL) for systemic toxicity occurred 
following single doses at 50 U/kg and at 24 U/kg with repeated administration.  When 
BOTOX was given intravenously (IV) to rats, no adverse effects were observed up to 
10 U/kg, while doses of ≥ 25 U/kg were associated with similar decreases in body weight as 
those observed following intramuscular (IM) administration.  Deaths were observed 
occasionally at 50 U/kg and frequently at ≥ 100 U/kg.  The IV single dose LOAEL for 
systemic toxicity was approximately 50 U/kg.  In monkeys, single IM administrations of 
≤ 16 U/kg did not produce evidence of systemic toxicity while doses of 24 U/kg or greater 


 
 
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produced multiple clinical signs and occasional mortality.  In repeat dose studies, increased 
tolerance was associated with the dispersion of the total BOTOX dose over multiple injection 
sites.  Bimonthly or trimonthly injections of 16 U/kg divided into 2 injection sites produced 
clinical signs of systemic toxicity and mortality; however, when divided over 6 sites, no 
systemic toxicity was observed.  The no observed adverse effect level (NOAEL) in monkeys 
was 8, 12, or 16 U/kg for 2, 4, or 6 injection sites, respectively. 
Reproductive toxicity studies were conducted in mice, rats, and rabbits.  BOTOX was not 
found to be selectively toxic to reproduction in rats.  Adverse effects on male fertility and 
female estrous cycling and fertility occurred only at dosages that induced exaggerated 
pharmacological effects.  Embryo-fetal toxic and teratogenic effect evaluations did not show 
any selective fetal toxicity and maternal effects were due to the anticipated pharmacological 
actions of BOTOX.  Maternal and developmental NOAEL values determined for rats in 
peri- and postnatal studies were the same as those established in other reproductive studies 
and no effects of BOTOX were observed on the behavior or reproductive performance of 
filial 1 animals. 
The mutagenic potential for BOTOX has been determined in a battery of evaluations 
including the Ames assay, AS52/XPRT mammalian cell forward gene study, in vitro 
chromosomal aberration in Chinese Hamster Ovary cells, and an in vivo mouse micronucleus 
assay.  No mutagenic or genotoxic potential of BOTOX was demonstrated. 
BOTOX is not structurally related to any known carcinogens and has been shown to be 
nongenotoxic and nonmutagenic.  There is no evidence of any cumulative effects due to 
toxin.  Thus, long-term studies to evaluate the carcinogenic potential of BOTOX in animals 
are not deemed necessary and have not been performed.  This is consistent with the 
International Council on Harmonisation (ICH) Guideline on the Need for Carcinogenicity 
Studies of Pharmaceuticals (ICH Topic S1A, CPMP/ICH/140/95). 
The antigenic potential of BOTOX was evaluated in a comprehensive battery of tests that 
included studies for indirect hemagglutinin reactions, passive cutaneous anaphylaxis in rats 
and guinea pigs, and antigenicity in guinea pigs.  Results of these studies indicate that 
BOTOX, which contains human serum albumin (HSA), and its placebo, are antigenic in 
animal models.  This is an expected response to the administration of a foreign protein, HSA, 
in a nonhomologous test system.  HSA is found in the BOTOX formulation far in excess of 
the toxin protein (0.5 mg HSA versus approximately 4 to 5 nanograms of toxin).  Antibodies 
were not identified in the animal models used, thus it is not possible to comment on the 
relative occurrence of antibodies to HSA and to the toxin. 


 
 
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The hemolytic potential of BOTOX was evaluated in vitro in human whole blood and was 
found not to cause hemolysis up to 100 U/mL. 
Additionally, to examine the effects of potential inadvertent injection, monkeys have been 
given a single injection of 3.4 U/kg/site BOTOX into the prostatic urethra and proximal 
rectum (6.8 U/kg total) or 3.4 U/kg/site BOTOX into the urinary bladder wall (base) and left 
seminal vesicle (6.8 U/kg total).  No drug-related effects on clinical observations, physical 
examination, rectal temperature, clinical pathology, or histology were observed.  There was 
no evidence of local toxicity in any tissue and no signs of systemic toxicity.  Bladder stones 
were observed in one animal dosed into the prostatic urethra and proximal rectum.  Bladder 
stones are an uncommon finding in nonhuman primates.  Further studies were conducted as 
part of the Allergan’s benign prostatic hyperplasia program, and concluded that these findings 
were considered species specific and not relevant to human administration. 
BOTOX is approved in skeletal muscle indications for doses up to 360 U.  Based on the 
nonclinical toxicology, the IM (skeletal) repeat dose NOAEL of 8 to 16 U/kg in monkeys 
provides a safety margin of 96- to193-fold over the planned starting BOTOX total dose of 
5 U (0.083 U/kg).  In rats, the IM (skeletal) repeat dose NOAEL of 16 U/kg is 193-fold the 
starting dose of 5 U.  The highest BOTOX total dose proposed for the study is100 U 
(2.5 U/kg).  The safety margins in monkeys are 3.2 to 6.4 fold, and in rats 6.4-fold the 
maximum intended human dose for this indication. 
Further details regarding the nonclinical toxicology of BOTOX are contained in the 
Investigator’s Brochure.  
2. 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
To explore the safety and efficacy of a range of doses of BOTOX for the treatment of PE in 
male patients. 
2.2 
Clinical Hypotheses 
BOTOX injected bilaterally into the bulbospongiosus muscle has an acceptable safety profile 
and shows an efficacy signal in comparison to placebo, as demonstrated by an increased 
IELT.  


 
 
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3. 
Study Design 
This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled, single 
treatment, pilot study followed by an open-label observation period, to assess a range of 
BOTOX doses for the treatment of male patients with PE.  Patients will attend a minimum of 
6 or 7 clinic visits and also have 1 or 2 telephone visits in the randomized period:  screening, 
day 1 (treatment), day 2 (telephone visit for non-sentinel patients, clinic visit for sentinel 
patients, week 1 (telephone visit, and weeks 2, 4, 8, and 12/study exit).  Partners will need to 
either attend a clinic visit or participate on a video conference during the screening period to 
provide informed consent and to receive training on measurement and recording of the IELT.  
For the open-label period, patients will have 2 clinic visits (weeks 4 and 12/study exit), along 
with 3 telephone visits (day 2, weeks 2, and 8).  
For Cohorts 1-5, patients will be enrolled in cohorts of 10 patients.  Within each cohort, 
8 patients will receive BOTOX and 2 patients will receive placebo.  For Cohort 6, patients 
will be enrolled into the randomized period in a 1:1 ratio, with 12 patients receiving BOTOX 
 and 12 patients receiving placebo.  Cohort 6 patients may choose to participate in the 
open-label period where they will receive BOTOX 
  For each treatment, patients will 
receive one injection of study medication delivered by ultrasound guidance bilaterally to the 
bulbospongiosus muscle.  
Table 3–1 shows the planned dose escalation scheme; although, other interim doses may be 
recommended for investigation by the independent Data Review Committee (DRC) 
following data review.   


 
 
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Table 3–1 
Planned Dose Escalation Scheme 
Cohort 
Total Dose 
Sample Size 
Total Patients in Cohort 
1 
N = 8 
10 
Placebo 
N = 2 
2 
N = 8 
10 
Placebo 
N = 2 
3 
N = 8 
10 
Placebo 
N = 2 
4 
N = 8 
10 
Placebo 
N = 2 
5 
N = 8 
10 
Placebo 
N = 2 
6 
N = 12 
24 
Placebo 
N = 12 
Sentinel dosing will occur during Cohorts 1-5 (see Section 3.1).  When the full complement 
of 10 patients for the cohort has been enrolled, randomization will be halted to allow for 
observation of the cohort and DRC evaluation.  When all remaining patients from a cohort 
have week 4 data available, the DRC will evaluate the unblinded safety and efficacy data to 
provide study recommendations (see Section 3.2).  Cohort 6 will enroll 24 patients, based on 
the DRC recommendation of data analysis from Cohorts 1-5. 
3.1 
Sentinel Dosing (Cohorts 1-5 only) 
Two sentinel patients will be enrolled at the commencement of Cohort 1 and also for any 
subsequent cohort that escalates the dose.  The sentinel patients will receive double-blind 
study treatment administration with either BOTOX or placebo in a 1:1 ratio.  Prior to 
selection as a sentinel patient, the investigator must ensure the patient agrees to attempt 
masturbations (see Section 6.3.5) during the first week following study treatment as a safety 
assessment of ejaculation, and to record the outcome of each masturbation attempt on the 
masturbatory ejaculation record (
).  Sentinel patients are to be instructed to commence 
masturbations after 48 hours following study treatment and to attempt at least 
2 masturbations before the week 1 visit.  
At the week 1 visit, each sentinel patient will attend a clinic visit and will provide the 
completed
 for review and discussion with the investigator to assess ejaculations and to 
determine if the patient has experienced any adverse events after study treatment.  Vital signs 
and concurrent medications/procedures will also be recorded.  This information will be 
provided to the DRC.  If the DRC is satisfied that there are no significant safety concerns, 


 
 
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then the remainder of the cohort will be opened for enrollment.  If the DRC determine that 
there are safety concerns then the sentinel patients will be unblinded to the DRC.  The DRC 
may recommend opening of enrollment of the cohort, stopping further enrollment of the 
cohort, or enrolling additional sentinel patients within the cohort (maximum of 2 further 
sentinel patients) treated with BOTOX, prior to making a DRC recommendation to proceed.    
3.2 
Data Review Committee (Cohorts 1-5 only)  
In addition to reviewing safety data from the sentinel patients (see Section 3.1); the 
independent DRC will review cumulative unblinded safety and efficacy data when at least 
4 weeks of data are available for all patients remaining in a cohort.  The DRC will make 
recommendations for dose escalations, dose de-escalations, assessing alternative doses from 
the planned dose escalation scheme, repeating cohorts, and stopping the study.  
The review of safety data will be to ensure that it is appropriate to escalate to the subsequent 
dose.  Based on the risk/benefit profile, the DRC may also recommend stopping the study, 
based either on the safety data or on the efficacy data (if a signal of efficacy is achieved). 
The independent DRC will be composed of an external urologist and internal Allergan 
members who are independent of the study team.  Details of the DRC membership, data 
review procedures, frequency of review, stopping criteria, and communication between the 
DRC and other parties are detailed in the DRC charter. 
For Cohort 6, no data review will be conducted by the DRC as this will be the final cohort of 
the study. 
3.3 
Open Label Period (Cohort 6) 
At week 12, during the randomized period exit visit, patients who complete the double-blind 
period of the study will be eligible to enroll into the open-label period of the study. 
The patient must complete the double-blind portion of the study and have received the first 
injection at least 12 weeks prior before receiving the second injection in the open-label 
period. Day 1 of the open-label period may occur on the same day as the week-12 visit of the 
randomized period (provided the 1st injection occurred at least 12 weeks prior) and may 
occur up to 4 weeks following the week-12 visit of the randomized period, provided all 
inclusion/exclusion criteria are met on the day of treatment. 
If the Week 12 exit visit of the randomization period and the Day 1 treatment visit of the 
open-label period do not occur on the same day, the assessments of the Week 12 exit visit of 


 
 
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the randomization period should not be repeated at the Day 1 treatment visit of the open-label 
period, with the exception of recording AEs, concomitant medications/procedures, and vital 
signs.  
3.3.1 
Qualification for Open-Label Period  
To be able to enroll into the open-label period, the patient must meet these qualification 
criteria: 
1. The patient must request to continue his participation and inclusion into the 
open-label period 
2. The patient must complete the double-blind portion of the study and have received 
the first injection at least 12 weeks prior before receiving the second injection in the 
open-label period 
3. The patient must be free of ejaculatory adverse events 
4. The investigator deems that the open-label period treatment is medically appropriate 
and no condition or situation exists which, in the investigator’s opinion, puts the 
patient at significant risk from receiving a second treatment 
3.3.2 
Day 1 of Open-Label Period Injection 
Day 1 of the open-label period may occur on the same day as the week-12 visit of the 
randomized period (provided the 1st injection occurred at least 12 weeks prior) and may 
occur up to 4 weeks following the week-12 visit of the randomized period, provided all 
inclusion/exclusion criteria continue to be met on the day of treatment. Week 12 exit 
assessments of the randomization period should not be repeated at the Day 1 treatment visit 
of the open-label period, with the exception of recording AEs, concomitant 
medications/procedures, and vital signs.   
4. 
Study Population and Entry Criteria 
4.1 
Number of Patients  
Approximately 74 patients will be enrolled in the study. 
For Cohort 6, approximately 24 patients will be enrolled at approximately 15 sites in the US 
and UK.  


 
 
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4.2 
Study Population Characteristics 
Men aged between 18 and 60 years in a stable monogamous sexual relationship with a 
female partner, who have PE as defined by the 2008 ISSM guidelines and who meet the 
eligibility criteria for this protocol as specified in Sections 4.3 and 4.4.  
4.3 
Inclusion Criteria 
The following are requirements for entry into the study:  
 
 
 
 
 
 
 
3. male aged 18 to 60 years 
4. in a stable monogamous sexual relationship with a female partner for at least 6 months 
(with the intention to continue with the same partner for the duration of the study) 
5. diagnosed with lifelong PE (defined as symptoms starting at the time the patient became 
sexually active) 
 
  
 
 
 
 
 
 
 
  
 
 
   
 
 
  
 
   
 
 


 
 
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9. the patient has the ability to follow study instructions and complete study assessment 
tools, (eg, questionnaires) without any assistance or alteration to the assessment tools, 
except for the stopwatch and SID which may be completed with assistance from the 
female partner 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
Premature Ejaculation Exclusion Criteria 
1. any medical or surgical condition that could be associated with secondary (acquired) PE 
or patient has PE which is situational or attributable to relationship issues 


 
 
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4. patient reports pain on ejaculation 
 
   
 
 
 
  
Previous Medications/Treatments/Techniques Exclusion Criteria 
 
 
  
 
  
 
 
 
 
 
 
   
10. patient has had prior genital, prostatic or lower urinary tract surgery (other than 
vasectomy or circumcision) 
11. circumcision within 6 months of screening  
12. current enrollment in an investigational drug or experimental medical device study; or 
use of an investigational drug or experimental medical device within 1 month of 
screening 


 
 
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Partner Exclusion Criteria 
 
 
 
 
 
 
General Medical/Surgical Exclusion Criteria 
  
 
 
 
 
 
 
 
 
22.
  
 
 
 
 
 
 


 
 
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BOTOX-specific Exclusion Criteria 
30. any previous or current usage of botulinum toxin therapy of any serotype for any 
urological condition (eg, prostatic, detrusor, urethral, sphincteric, or pelvic floor 
injection therapy)  
31. botulinum toxin therapy of any serotype for any nonurological condition or usage (eg, 
cosmetic, chronic migraine) during the 12 weeks prior to screening, or planned usage 
during the course of this study 
 
 
 
34. any medical condition that may put the patient at increased risk with exposure to 
BOTOX including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic 
lateral sclerosis, or any other condition that might interfere with neuromuscular function 
4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
Patients must continue stable usage of concomitant therapies (except for prohibited 
medications/treatments; see Section 4.5.2) for the duration of the study.   
As needed sleeping medications may be used, but should be avoided in the 12 hours prior to 
intended vaginal intercourse with their female partner (if a patient does use a sleeping 
medication within 12 hours of vaginal intercourse, this will not be considered a deviation to 
the protocol).   
Medications/treatments considered necessary for the patient’s welfare may be given at the 
discretion of the investigator.  If the permissibility of a specific medication/treatment is in 
question, please contact Allergan. 


 
 
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4.5.1.1 
Acceptable Contraceptive Methods  
If the female partner is of childbearing potential then a reliable method of contraception must 
be used. 
 
 
  
The following methods of contraception, if properly used, are generally considered reliable 
for the female partner:  oral contraceptives, patch contraceptives, injection contraceptives, 
diaphragm or cervical cap with spermicide, vaginal contraceptive ring, intrauterine device, 
surgical sterilization (bilateral tubal ligation or hysterectomy), or male patient has had a 
vasectomy.   
The investigator will discuss contraception methods with each couple and each couple will 
determine the appropriate method of contraception to be used during their participation in the 
study. 
If a study patient’s female partner becomes pregnant during the study, the investigator will 
notify the sponsor immediately after the pregnancy is confirmed.  The investigator will (1) 
notify the female partner’s physician that the patient was being treated with an investigational 
drug, and (2) follow the progress of the pregnancy.  The investigator must document the 
outcome of the pregnancy and provide a copy of the documentation to Allergan. 
4.5.2 
Prohibited Medications/Treatments/Techniques 
No new medications or therapies (including behavioral therapy) for PE may be commenced 
during the study.  
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration.  When possible, Allergan are to be notified 
before a prohibited medication/treatment is administered. 
 
 
 
 
 
  


 
 
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Botulinum toxin therapy of any serotype for any indication is prohibited during the study.  
Patients who have used a botulinum toxin for any (nonurological) indication prior to study 
entry must not undergo screening until 12 weeks have elapsed since their previous botulinum 
toxin administration. 
4.5.3 
Anticoagulant and Antiplatelet Medications 
The following classes of medications are prohibited at least 3 days immediately preceding 
the treatment visit: 
• Anticoagulants, antiplatelet medications, or medications with anticoagulative effects 
which include the following:   
o 
warfarin and other coumadin derivatives 


 
 
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o 
acetylsalicylic acid (including low dose aspirin) 
o 
clopidogrel 
o 
ticlopidine 
o 
nonsteroidal anti-inflammatory drugs  
These may be prohibited for longer than 3 days prior to a treatment visit, according to the 
clinical judgment of the investigator.   
These may be reinstituted on the day following study treatment administration.   
Please note, if medically indicated, low molecular weight heparins (eg, enoxaparin) are 
permitted with the last dose of administration 24 hours prior to study medication 
administration. 
4.6 
Sexual Activity and Practices 
Patient and female partner must be willing and able to engage in vaginal intercourse at a 
minimum of 4 times per month for the randomized period of  the study (see Section 4.3).  
 
 
 
 
 
The patient and their female partner must be advised: 
• not to significantly alter their usual sexual practices (eg, amount of foreplay, use of 
lubrication, and/or sexual position, etc) during the screening period or the posttreatment 
period)  
• that any behavioral techniques for PE must also be continued consistently throughout the 
screening period and during the posttreatment period  
 
 
• that alcohol usage must also remain consistent during the screening period and 
throughout the posttreatment period  


 
 
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Note:  if the couple are not able to provide at least 4 evaluable events per month; if they alter 
their sexual practices; if they alter any behavioral techniques for PE; or if the patient alters 
alcohol consumption, these will not be considered deviations from the protocol. 
5. 
Study Treatments  
5.1 
Study Treatments and Formulations 
 
 
 
 
 
 
5.2 
Control Treatment  
Each vial of placebo (formulation number:  
 contains 0.9 mg sodium chloride in a 
sterile, vacuum-dried form without preservatives.  The diluent will be 0.9% sterile saline 
(without preservatives) for injection of placebo. 
5.3 
Methods for Blinding 
To maintain the double blind, the BOTOX and placebo vials and kits will be identically 
labeled.   
5.4 
Treatment Allocation Ratio and Stratification  
Patients will be randomly allocated (based on a randomization schedule, prepared by 
Allergan biostatistics) to BOTOX or placebo.  
Study medication allocation will be performed using the interactive voice response system 
(IVRS) or the interactive web response system (IWRS). 
For Cohorts 1-5, the allocation ratio for sentinel patients will be 1:1 BOTOX to placebo.  The 
allocation ratio for subsequent patients will be 7:1 BOTOX to placebo.  Two additional 
sentinel patients can be enrolled if requested by the DRC; further sentinel patients will be 
treated with BOTOX and will be in addition to the 10 planned patients within a cohort. 


 
 
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For Cohort 6, no sentinel dosing will occur. Twenty-four patients will be randomized at a 
ratio of 1:1 to receive either BOTOX 
 or placebo.  Patients who choose to participate in 
the open-label period will receive treatment with 
 BOTOX. 
There will be no stratification performed in the study. 
5.5 
Method for Assignment to Treatment Groups/Randomization 
Prior to initiation of study treatment, each patient who provides informed consent will be 
assigned a screening number that will serve as the patient number on all study documents. 
Randomization will occur on the same day as, and prior to study treatment 
reconstitution/administration.  At the time of randomization, eligible patients will be 
randomly assigned to receive BOTOX or placebo as described in Section 5.4.   
In Cohorts 1-5, the dose of BOTOX received will be determined by the dose being assessed 
in the cohort in which the patient is enrolled; see Table 3–1 showing the planned dose 
escalations. 
Randomized patients who exit the study prior to receiving study treatment may be replaced to 
ensure that the expected number of patients within a cohort receive treatment. 
An automated IVRS/IWRS will be used to assign patient numbers, patient initials, and 
randomize patients.  Treatment assignment is based on a randomization scheme prepared by 
Allergan biostatistics.  Central randomization will occur.  
Study medication will be labeled with medication kit numbers.  The IVRS/IWRS system will 
provide the site with the specific medication kit number(s) for each randomized patient at the 
time of randomization.  Sites will dispense study medication according to the IVRS/IWRS 
instructions.  Sites will receive IVRS/IWRS confirmation notifications for each transaction.  
All notifications are to be maintained with the study source documents. 
5.6 
Treatment Regimen and Dosing 
 
   
 
 


 
 
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5.6.1 
Treatment Regimen/Dosage Adjustments (Cohorts 1-5 only) 
Following unblinded evaluation by the DRC of at least 4 weeks of data from all remaining 
patients in the preceding cohort along with cumulative data from earlier cohorts, the DRC 
will recommend the appropriate dose for investigation in the subsequent cohort, or to stop the 
study.  The planned dose escalation scheme is provided in Table 3–1, although the DRC may 
recommend alterations to the scheme including repeating cohorts, de-escalating or assessing 
alternative doses. 
5.7 
Storage of Study Medications/Treatments 
The study medication must be stored in a secure area and administered only to patients 
entered into the clinical study, at no cost to the patient, in accordance with the conditions 
specified in this protocol. 
 
  Refer to the Pharmacy Manual for guidelines on acceptable variances and 
instructions for reporting to Allergan.   
 
 
 
 
 
   
Storage conditions of vacuum-dried and reconstituted study medication will be documented. 
Used investigational product vials may be stored at room temperature in a secure designated 
area until shipped for destruction by the site monitor. 
5.8 
Preparation of Study Medications/Treatments  
Training and instructions for reconstitution of the study drug will be provided to study sites 
and detailed in the Pharmacy Manual. 


 
 
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The following must be completed prior to reconstitution of 
study medication and treatment administration: 
• Final eligibility must be fully satisfied, including satisfying all inclusion and exclusion 
criteria (see Sections 4.3 and 4.4) 
• The IVRS/IWRS will be used for randomization to allocate a drug kit number(s) 
associated with a box(es) of study medication.  Each box will contain labeled vial of 
study medication.  Study medication must be prepared by the DR from the specific kit(s) 
corresponding to the number assigned by IVRS/IWRS.   
• The DR must review the relevant reconstitution instructions  
• Study site personnel must notify Allergan or its designee immediately to advise of any 
situation in which the study medication vials are defective or diluted improperly (refer to 
the Pharmacy Manual) 
The DR will prepare 1 mL of study medication to be provided to the investigator in 
2 syringes of 0.5mL each. 
5.9 
Treatment Administration 
Treatment administration must be performed by a urologist or other appropriately qualified 
physician who has received study-specific training on how to perform the 
 
 
   
5.9.1 
Anesthesia and Sedation  
The following options are permitted either alone or in combination before treatment 
administration: 
• no anesthesia 
• topical local anesthesia 


 
 
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o sterile local anesthetic topical preparation (eg, lidocaine cream) may be 
applied to the skin around the injection site  
• local anesthetic injections to skin 
o sterile local anesthetic solution (eg, lidocaine solution) may be injected to 
the skin overlying the injection site  
• Sedation 
o if it is clinically indicated, may be administered to the patient at the 
investigator’s discretion  
The type of anesthesia/sedation used and the administration method must be recorded.  All 
local anesthesia and sedation must be administered according to local site practice and it 
must be confirmed prior to administration that the patient is not allergic to the 
anesthetic/sedative drug(s) (see study manual for additional details regarding anesthesia and 
sedation usage).   
5.9.2 
Bulbospongiosus Injection Technique 
Step-by-step details of the bulbospongiosus injection technique (including diagrams of the 
appropriate injection site) are provided in the study manual.   
A diagram of the location of the bulbospongiosus muscle is provided in Attachment 12.4. 
5.9.3 
Posttreatment Observation Period 
The patient must be observed for at least 30 minutes post injection, and allowed to leave the 
clinic at the discretion of the investigator. 
During the posttreatment observation period: 
• vital signs must be collected prior to patient leaving the clinic 
• any adverse events must be recorded 
• any concomitant procedures/treatments performed post-injection must be recorded 


 
 
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5.9.4 
Posttreatment Instructions for Patients 
Instructions For All Patients 
Prior to leaving the site, all patients  will be instructed to: 
• refrain from having intercourse with their female partner for at least 48 hours 
• aim for a minimum of 4 evaluable sexual events per month for the remainder of the 
randomized period of the study  
• record all sexual events in the SID.  Patients will be reminded what constitutes an 
evaluable event, how to measure the IELT and how to record the information in the SID 
(see Section 6.3.4 and Attachment 12.2) 
• not alter their usual sexual practices (see Section 4.6) 
• bring the SID to all study visits  
• report any posttreatment adverse events including ejaculation adverse events 
• seek immediate medical care and to contact the investigative site immediately if they 
develop priapism, significant bleeding, or signs of infection around the injection site  
• contact the study site (or have a family member or friend contact the study site) to report 
any hospitalizations 
• maintain the dose of any concomitant medication.  If there are any changes to 
medications, dosages, or frequency, the changes must be reported to the investigator at 
the next study visit 
• maintain the frequency of any concomitant procedure 
• refrain from commencing any new medication or therapies (including behavioral therapy) 
for PE during the study (see Section 4.5.2) 
• contact the site if they are having any difficulty with following and/or conducting study 
procedures (eg, the stopwatch assessment and SID completion) 
• contact the study site as soon as possible if they cannot make their next scheduled study 
visit in order to reschedule 


 
 
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• receive a telephone call from the site the day after treatment 
Instructions For Sentinel Patients Only (Cohorts 1-5) 
Prior to leaving the site, sentinel patients will also be instructed to: 
 
 
  
 
 
• attend a clinic visit 1 week following treatment 
 
 and SID to the week 1 clinic visit 
6. 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.1.1 
Primary Efficacy Measure 
The primary efficacy measure is IELT as measured by stopwatch.  
The IELT is captured on the SID and provides an objective assessment of the pharmacologic 
effects of study treatment on PE. 
The primary efficacy variable will be change from baseline in the logarithm value of 
individual patient’s geometric mean IELT across all the evaluable ejaculatory attempts 
recorded in the SIDs at the end of the randomized 12 week follow-up period.   
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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6.3 
Examination Procedures, Tests, Equipment, and Techniques   
Study evaluations and treatments must be performed by the same investigator/sub-
investigator throughout the study whenever possible (see Table 1 and Table 2).  If it is not 
possible for the same individual to follow the patient, then an attempt should be made to have 
visits overlap (examine the patient together and discuss findings) for at least one visit. 
6.3.1 
Medical History, Physical Examination, and Vital Signs  
6.3.1.1 
Medical History  
A standard medical history (including all relevant conditions that the patient has had in the 
past or currently has) must be obtained at screening and before randomization at the 
treatment visit (day 1). 
A sexual history must also be obtained including usage and duration of usage of all previous 
self-initiated or health-care-professional prescribed treatments/therapies/techniques for PE 
(may include, but not limited to behavioral therapies, distraction techniques, topical or oral 
therapies, use of condoms, etc). 
All medical and surgical procedures must have an associated medical history entry.   


 
 
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6.3.1.2 
Physical Examination  
A physical examination will be performed at screening and at week 12 (exit visit) of the 
randomized period and at week 12 of the open-label period of Cohort 6 (study exit for open 
label).  The investigator will examine the patient for any physical abnormality of the 
following systems:  general appearance; head, eyes, ears, nose, and throat; 
heart/cardiovascular; lungs; abdomen; neurologic; extremities; back; musculoskeletal; 
lymphatic; skin; genitourinary; and rectal.  The patient’s weight will also be measured.  The 
patient’s height will only be measured at the screening visit.  
6.3.1.3 
Vital Signs 
Vital signs will be measured at screening, treatment/day 1 (prior to injection and prior to 
leaving the clinic), and all follow-up clinic visits.  The following vital signs will be 
measured: 
• pulse rate (beats per minute):  the patient should be resting in a seated position for a 
minimum of 5 minutes prior to measurement.  Pulse rate is then counted over 30 seconds 
(× 2). 
• blood pressure (mm Hg):  the patient must be resting in a seated position for a minimum 
of 5 minutes prior to measurement.  Systolic/diastolic blood pressure will be measured 
with a sphygmomanometer. 
• temperature (°C/°F):  temperature assessment method must be performed consistently 
throughout the study. 
6.3.2 
Blood Specimen Procedures 
Blood samples will be obtained for the analyses of hematology and non-fasting serum 
chemistry. 
A central laboratory will be used to analyze all blood specimens, including any repeat 
laboratory tests.  Instructions for the collection, processing, shipment, and storage of blood 
samples are provided in the central laboratory manual. 
All hematology and serum chemistry laboratory test results will be: 
• forwarded from the central laboratory to the study site and to Allergan or its designee   


 
 
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• reviewed by the investigator for the clinical significance of any abnormalities   
• evaluated and managed, if the laboratory result is abnormal, and conducted according to 
local site practice   
• recorded on an adverse event electronic case report form (eCRF) page, for any clinically 
significant abnormalities 
The laboratory results from the screening period must be reviewed prior to randomization  
(including the most recent results if any investigations were repeated), and 
randomization/treatment administration must only be performed if the investigator deems the 
results to be acceptable.  
6.3.2.1 
Hematology  
Hematology blood samples are to be collected at screening, week 4, and week 12 of both the 
randomized period and the open-label period. 
Hematology measures are as follows:  hematocrit, hemoglobin, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume (MCV), 
platelets, red blood cell (RBC) count, RBC morphology, total white blood cell (WBC) count 
and differential (eg, neutrophils, bands, lymphocytes, monocytes, basophils, and 
eosinophils). 
6.3.2.2 
Serum Chemistry  
Nonfasting serum chemistry blood samples are to be collected at screening, and weeks 4 
and 12 of both the randomized period and the open-label period. 
Serum chemistry measures are as follows:  albumin, alkaline phosphatase, alanine 
transaminase, aspartate transaminase, bicarbonate, calcium, chloride, creatinine, creatine 
kinase, direct bilirubin, non-fasting glucose, indirect bilirubin, magnesium, phosphorous, 
potassium, sodium, total bilirubin, total cholesterol, total protein, urea nitrogen, and uric acid.  
6.3.3 
Urine Specimen Procedures 
Urine samples will be obtained for central laboratory urine analysis and for urine culture and 
sensitivity. 


 
 
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A central laboratory will be used to analyze all urine specimens, including any repeat 
laboratory tests.  Instructions for the collection, processing, shipment, and storage of urine 
samples are provided in the central laboratory manual. 
All urine laboratory test results will be: 
• forwarded from the central laboratory to the study site and to Allergan or its designee   
• reviewed by the investigator for the clinical significance of any abnormalities   
• evaluated and managed, if the laboratory result is abnormal, and conducted according to 
local site practice   
• recorded on an adverse event eCRF page, for any clinically significant abnormalities 
The laboratory results from the screening period must be reviewed prior to randomization 
(including the most recent results if any investigations were repeated), and 
randomization/treatment administration must only be performed if the investigator deems the 
results to be acceptable.  
6.3.3.1 
Central Laboratory Urine Analysis 
Urine samples are to be collected at screening, and weeks 4 and 12 of both the randomized 
period and the open-label period. 
The urine will be analyzed for clarity, color, bilirubin, blood, glucose, ketones, leukocyte 
esterase, nitrite, pH, protein, specific gravity, urobilinogen, microscopic sediment (WBCs, 
RBCs, casts, bacteria, crystals, and epithelial cells).   
6.3.3.2 
Urine Culture and Sensitivity 
The urine culture and sensitivity sample will be analyzed as a reflex (automatic) test by the 
central laboratory when the central laboratory urine analysis results are suggestive of a 
urinary tract infection (eg, positive leukocyte esterase, nitrites, blood, or microscopic 
sediments such as WBCs, RBCs, and/or bacteria).   
6.3.4 
Intravaginal Ejaculatory Latency Time 
Patients will document sexual activities in the SID during screening and for 12 weeks 
following treatment to provide baseline and posttreatment IELT data.  


 
 
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Either the patient or female partner may operate the stopwatch, although the preference is for 
the female partner to operate the stopwatch.  The stopwatch operator must be consistent 
throughout screening and the posttreatment period.  
In the SID, patients will be asked to record the date and start time of each sexual encounter, 
the duration of intercourse (ie, the time from vaginal penetration until ejaculation, measured 
with a stopwatch), and a description of when the ejaculation occurred (ie, prior to 
penetration, intravaginal, did not occur, or after withdrawal) for all sexual intercourse 
attempts.   
Patients must be instructed: 
• that any behavioral techniques that were performed prior to screening should also be 
continued consistently for the duration of the study 
• that the patient and female partner must not significantly alter their normal sexual 
practices during the course of the study (eg, amount of foreplay, use of lubrication, or 
position). 
• that condoms must not be used during the study 
• not to withdraw the penis from the vagina during intercourse as this would make the 
event nonevaluable  
• to record all sexual intercourse events that constitute an attempt at penile penetration of 
the vagina, including any ejaculation that occurs before, during, or after the act of vaginal 
penetration  
• that if ejaculation does not occur during intercourse and a new vaginal penetration is 
attempted, these separate vaginal penetrations must be recorded on the SID as 2 separate 
events 
Additional study site instructions regarding the SID are provided in Attachment 12.2. 
Sexual events recorded on the SID will be reviewed by the site and/or Allergan (or designee) 
to determine if the events are evaluable.   


 
 
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6.3.4.1 
Definition of Evaluable Intravaginal Ejaculatory Latency Time 
Events 
An evaluable event is defined as: 
• an event in which the patient and his female partner had vaginal intercourse, and the 
couple have recorded that the ejaculation occurred ‘intravaginally’ and duration of time 
from penetration to ejaculation has been recorded 
OR 
• an event in which the patient and his female partner attempted to have vaginal 
intercourse.  However, the couple have recorded that ejaculation occurred “prior to 
vaginal penetration”.  In this scenario, the duration of time will be recorded as zero for 
the purpose of calculating the average IELT.   
Any other scenarios will not be considered as evaluable and must not be included in the 
screening average IELT calculation.  
6.3.4.2 
Screening Intravaginal Ejaculatory Latency Time Collection 
The patient will receive a stopwatch, the SID and written instructions during screening.  The 
site will also provide training on the usage of the stopwatch and SID to the patient and 
female partner.   
Patients who are taking medications that require a washout must be instructed not to 
commence IELT data collection until the day after the washout period has completed.  
 
   
The couple must be instructed to record at least 4 evaluable attempts at vaginal sexual 
intercourse during a maximum of  28 days.  Patients who do not record 4 evaluable events in 
a period of 28 days will not be eligible for study entry.  Sites may contact the patient via 
telephone (at the sites discretion) to determine if the patient has achieved 4 evaluable events 
prior to the patient returning to the site for review of the SID and determination of eligibility.  
There is no minimum time period to collect the 4 evaluable events (more than 4 evaluable 
can be collected).  
Eligibility will be determined from the 4 most recent evaluable events recorded on the SID 
during the screening period (see Section 4.3).  


 
 
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• The mean (average) IELT of these 4 most recent evaluable events must be ≤ 1minute.   
• None of these 4 most recent evaluable events can have an IELT ≥ 2 minutes.  If any one 
of the 4 most recent evaluable events is ≥ 2 minutes, the patient is ineligible for study 
participation. 
The site should determine which events are evaluable using the definitions in Section 6.3.4.1.  
If there is any ambiguity regarding if an event is evaluable the site should contact Allergan 
for clarification.  Allergan will confirm the average IELT prior to patient randomization. 
Note:  if > 4 events have been recorded during screening then all events must be reported on 
the eCRF whether or not the event is evaluable; although, only the 4 most recent evaluable 
events will be used to determine eligibility as described above.  
6.3.4.3 
Posttreatment Intravaginal Ejaculatory Latency Time 
Collection 
Patients will be instructed to refrain from having intercourse for at least 48 hours 
posttreatment.  Patients will be reminded of the correct collection of IELT data and 
completion of the SID. 
The couple will be instructed to record all posttreatment sexual intercourse events in the 
same manner as for the screening assessment, until they exit the study.   
The couple will be instructed to aim for a minimum of 4 evaluable events per month and 
their sexual practices must remain consistent with their practices prior to study entry and 
during the screening period (see Section 4.6). 
Patients are to be reminded to bring the SID to all study clinic visits.  The site must record all 
available events (evaluable and not evaluable) in the eCRF. 
6.3.5 
Masturbatory Events  
Sentinel Patients (Cohorts 1-5) must attempt at least 2 masturbations (starting 48 hours after 
treatment) prior to the week 1 visit.  These masturbations are to be 
, so 
that any safety issues related to ejaculation can be identified early and reported to the DRC 
prior to opening the remainder of the cohort for enrollment (see Section 3.1). 


 
 
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Nonsentinel Patients (Cohorts 1-6) are not required to perform masturbation nor complete 
the 
 unless they complain of difficulty or an adverse event related to ejaculation (see 
Section 6.3.5.2). 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
      
 
 
 
 
 
  
 
 
 
 


 
 
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6.3.5.2 
Ejaculation Adverse Events 
Adverse events related to ejaculation are whenever possible to be based on findings during 
masturbation.  If the patient complains of an ejaculation issue during nonmasturbatory 
situations (eg, vaginal intercourse), the site must ask the patient to confirm the findings 
during masturbation (if possible) and to record the finding on the 
, prior to reporting the 
finding as an adverse event.  If the patient declines to perform a masturbation and/or 
completion of the 
, this should be recorded in the source documentation. 
If the patient was unable to ejaculate despite sufficient manual stimulation and sufficient 
sexual arousal (in the patient’s opinion) and the patient did not feel that with continued 
stimulation that ejaculation could be achieved then this must be recorded as: 
• an adverse event of “delayed ejaculation” if the period of manual stimulation was 
< 30 minutes 
• an adverse event of “anejaculation” if the period of manual stimulation was ≥ 30 minutes 
For other ejaculation difficulties during masturbation this must be recorded as: 
• an adverse event of “retrograde ejaculation”, if the patient felt that ejaculation/orgasm 
occurred but no semen was expelled during or immediately following ejaculation 
• an adverse event of “weak ejaculation”, if ejaculation/orgasm occurred but the perceived 
force/strength of the ejaculation was noticeably reduced 
• an adverse event of “dribbling ejaculation”, if ejaculation occurred but the semen only 
dribbled out during the ejaculation or shortly after the ejaculation 
• an adverse event of “painful ejaculation”, if ejaculation occurred and was associated with 
pain for the patient 
If the patient is unable or unwilling to attempt masturbations (due to religious or other 
reasons) then the investigator must attempt to determine the character of the ejaculatory 
abnormality by taking a detailed history from the patient (eg, regarding ejaculation during 
vaginal intercourse).  In such situations, the investigator will categorize the adverse event 
based on their best judgment. 


 
 
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6.3.6 
Questionnaire Assessments 
The versions of the questionnaires provided in Attachment 12.1 of this protocol are examples 
and in practice will be replaced with the appropriate versions for the country where the 
questionnaire will be administered. 
Questionnaires must be administered prior to the patient undergoing any procedures at the 
study visit.   
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  


 
 
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6.4 
Other Study Supplies 
The following will be provided by Allergan: 
• all supplies needed for blood and urine sampling (except syringes and needles)  
• needles for injection of study medication 


 
 
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• materials for shipment of laboratory samples to central laboratory 
• stopwatches 
• paper data collection materials (eg, questionnaires, SID, 
 etc) 
The following will be provided by the investigator: 
• syringes and needles (for reconstitution of study medication, blood sampling, and local 
anesthetic administration, if applicable) 
• equipment for ultrasound guided treatment administration (eg, ultrasound machine, 
suitable ultrasound probe, ultrasound gel, and if applicable needle guides); 
Note:  ultrasound equipment may be provided by Allergan if requested by the site 
• sterile pads 
• antiseptic solution/wipes for cleaning treatment injection area 
• local anesthetic medication and sedation (if applicable)  
 
 
• sterile saline (0.9% without preservative) as diluents 
• appropriate electronic connections to access study-related systems (eg, high-speed 
internet, telephone) 
6.5 
Summary of Methods of Data Collection 
An IVRS/IWRS will be used to assign patient identification numbers, patient initials, 
randomize patients, and manage study medication inventory.   
Data for this study will be collected using eCRFs via an electronic data capture system.   
Source documents will be used at the sites and may include, but are not limited to, a patient’s 
medical record, hospital charts, clinic charts, the investigator’s patient study files, still 
capture images and video recordings as well as the results of diagnostic tests such as 
laboratory tests.   
A qualified central laboratory will be used for the analysis of all blood and urine samples.  
Laboratory data will be transferred to Allergan on a periodic basis throughout the study. 


 
 
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7. 
Statistical Procedures 
The final analysis will be performed when all patients have completed or exited the study.  A 
detailed analysis plan will be finalized prior to the study database lock. 
7.1 
Analysis Populations 
There are 3 analysis populations:  modified  intent-to-treat (mITT), per protocol (PP) and 
safety:   
• The mITT population will be used to analyze all efficacy variables; the mITT population 
is defined as all randomized patients that have received study medication and have 
postbaseline IELT data available.  Analyses on the mITT population will be based on the 
dose actually received by the patient.   
• The PP population includes patients in the mITT population who have had no significant 
protocol deviations and will also be used for analyzing the primary efficacy variable and 
summarizing baseline characteristics. 
• The safety population includes all treated patients and will be used in the analysis of all 
safety data.   
7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
7.2.1 
Primary Efficacy Variable  
The primary variable for assessing the efficacy of BOTOX versus placebo will be the change 
from baseline in logarithm value of the individual patient’s geometric mean IELT for the 
entire 12 weeks of the randomized period of the study.  Only evaluable events on the logs 
will be used to calculate the geometric mean IELT.  Nonevaluable events will not form part 
of the calculation.  Data handling conventions including missing data imputation will be 
discussed in detail in the statistical analysis plan.  
7.2.2 
Secondary Efficacy Variables 
• geometric mean IELT up to week 2, 4, 6, 8, and 10, respectively 
• average IELT up to week 2, 4, 6, 8, 10, and 12, respectively  


 
 
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7.3 
Hypothesis and Methods of Analysis 
7.3.1 
Primary Efficacy Analyses 
The primary timepoint for analysis is week 12. 
The primary null hypothesis:  At the primary efficacy timepoint the difference in mean 
change from baseline in logarithm value of the geometric mean IELT between placebo and 
BOTOX is at zero; and there is no dose response shown in the change from baseline in 
logarithm value of the geometric mean IELT.  
The primary alternative hypothesis:   At the primary efficacy timepoint the difference in 
mean change from baseline in logarithm value of the geometric mean IELT between placebo 
and BOTOX is not equal to zero; or there is a dose-response in the change from baseline in 
logarithm value of the geometric mean IELT.  
The primary efficacy variable (change from baseline in the logarithm value of individual 
patient’s geometric mean IELT) in relation to dose levels will be analyzed using an analysis 
of covariance (ANCOVA) model with treatment as the fixed effect and baseline logarithm 
value in geometric mean IELT as the covariate to assess the relationship of response across 
the BOTOX dose levels.  Geometric means of the IELT up to week 12 will be 
log-transformed prior to analysis.     
No multiplicity adjustment will be taken. 
Analysis of the primary efficacy variable using a PP population will also be performed. 
The log-transformed primary efficacy variable will also be analyzed with a linear regression 
model to assess the dose-response of the active treatments.   
Details will be specified in the statistical analysis plan. 
7.3.2 
Secondary Efficacy Analyses  
The following key secondary efficacy variables will be analyzed using ANCOVA, with the 
treatment as factor and with baseline value as a covariate:  
• log-transformed geometric mean IELT up to week 2, 4, 6, 8, and 10, respectively 
• average IELT up to week 2, 4, 6, 8, 10, and 12, respectively  


 
 
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• interval-based geometric mean IELT and average IELT for week 4, 8, and 12 (ie, events 
between baseline and week 4, between week 4 and week 8, and between week 8 and 
week 12) 
Responder analyses using the fold-change threshold of 3, 4, 5, 6, 7, and 8 in the geometric 
mean IELT will also be conducted. 
In addition, geometric mean IELT at visits will be analyzed using a likelihood-based Z-score, 
as well as a bootstrap test for pair-wise comparisons between each active treatment group and 
the placebo (Zhou et al, 1997).  Nonparametric analysis including, but not limited to the 
Wilcoxon rank-sum test will also be performed on the geometric mean IELT.  Details will be 
provided in the statistical analysis plan.   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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7.4 
Subgroup Analyses 
No subgroup analysis is planned, but may be included in the final statistical analysis plan if 
deemed necessary. 
7.5 
Sample Size Calculation 
For this exploratory study, an empirical sample size is used.  For Cohorts 1-5, 8 patients will 
be randomized to receive BOTOX and 2 patients to placebo. In Cohort 6, 24 patients will be 
randomized in a 1:1 ratio.   The power  for detecting 2, 3 and 4-fold change (the ratio 
between groups) with differing values for the coefficient of variation (CV) assuming the 
IELT is log-normally distributed, using a 2-group t-test with a 1-sided 0.10 significance level 
are presented in Table 7–1.  The CV assumption is estimated from the pooled analysis of 
week 12 data from Priligy (dapoxetine hydrochloride) film-coated tablets, 30 and 60 mg 
(Public Assessment Report Scientific Discussion of  Priligy, 2008) (Table 7–2).  The CV in 
the pivotal studies at week 12 ranges from 0.85 to 1.64.  The commercial 
 
Guide 5.1 (procedure 
) was used for the power calculation. 


 
 
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Table 7–1 
Power Calculation with Different Expected Fold-change 
Comparison Ratio and Coefficient of Variations 
Expected Fold-change 
BOTOX versus 
Placebo
Coefficient of Variation
Power 
2 
8 versus 2 
1
38% 
1.5
30% 
2
26% 
2 
8 versus 8 
1
63% 
1.5
48% 
2
41% 
3 
8 versus 2 
1
61% 
1.5
47% 
2
40% 
3 
8 versus 8 
1
89% 
1.5
75% 
2
65% 
4 
8 versus 2 
1
76% 
1.5
59% 
2
51% 
4 
8 versus 8 
1
97% 
1.5
88% 
2
79% 
 
 
1 
76% 
2 
12 versus 12 
1.5 
60% 
 
 
2 
51% 
 
 
1 
97% 
3 
12 versus 12 
1.5 
88% 
 
 
2 
79% 
 
 
1 
>99% 
4 
12 versus 12 
1.5 
96% 
 
 
2 
91% 
Table 7–2 
Coefficient of Variation at Week 12 in Priligy Pivotal Studies 
Study 
Treatment Group
Mean (SD)
Coefficient of Variation
C-20052-012 
Placebo
DPX 30 mg PRN 
DPX 60mg PRN
1.7 (2.09)
2.9 (3.59) 
3.4 (3.97)
1.23 
1.24 
1.17 
C-2002-013 
Placebo
DPX 30 mg PRN 
DPX 60mg PRN
1.8 (2.33)
2.7 (3.39) 
3.3 (3.40)
1.29 
1.26 
1.03 
PRE-3001 
Placebo
DPX 30 mg PRN 
DPX 60mg PRN
1.9 (3.11)
3.2 (4.61) 
3.5 (4.04)
1.64 
1.44 
1.15 
PRE-3003 
Placebo
DPX 30 mg PRN 
DPX 60mg PRN
2.4 (2.05)
3.9 (3.95) 
4.2 (3.97)
0.85 
1.01 
0.95 
Pooled 
Placebo
DPX 30 mg PRN 
DPX 60mg PRN 
1.9 (2.43)
3.1 (3.91) 
3.6 (3.85) 
1.28 
1.26 
1.07 
DPX = dapoxetine hydrochloride; PRN = as needed; SD = standard deviation 


 
 
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7.6 
Interim Analyses 
No interim analysis is planned for this study. 
8. 
Study Visit Schedule and Procedures 
Please see Table 1 and Table 2 for the schedules of visits and procedures and Section 6.3 for 
detailed information on study procedures, tests, equipment, and techniques. 
8.1 
Patient Entry Procedures  
8.1.1 
Overview of Entry Procedures 
Prospective patients as defined by the criteria in Sections 4.3 and 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study. 
8.1.2 
Informed Consent and Patient Privacy 
The study will be discussed with the patient and their female partner and both must be 
willing to participate and give informed consent.  The patient must give informed consent 
prior to any study-related procedures or change in treatment.  The patient and their female 
partner must also give authorization (US only), data protection consent (UK only), and other 
written documentation in accordance with the relevant country and local privacy 
requirements (where applicable).  The patient must give patient privacy authorization prior to 
any study-related procedures or change in treatment. 
Each patient that provides informed consent will be assigned a patient number that will be 
used on patient documentation throughout the study. 
If the female partner does not provide consent or privacy authorization, the patient will be 
considered a screen failure.  The female partner will not be assigned a separate screening 
number as no data will be collected from/about the partner. 
8.2 
Washout of Prohibited Medications 
If washout is required for the purposes of this study then the patient must sign the informed 
consent before the washout is commenced.  
Patients taking prohibited medications must undergo a washout of the medications for at least 
28 days prior to performing screening efficacy assessments (eg, stopwatch IELT 
measurements, SID, and health outcomes questionnaires).  Any screening IELT data collected 


 
 
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prior to washout completion will not be considered as evaluable.  The screening period may 
occur over several visits if needed.  
A full list of prohibited medications requiring washout is provided in Section 4.5.2. 
8.3 
Procedures for Final Study Entry 
A patient is considered to have enrolled in the study upon randomization after the 
investigator  re-verifies the patient has met all the inclusion/exclusion criteria for study entry.  
The investigator should also confirm that blood and urine results are acceptable prior to 
randomization.  The treatment visit (day 1) can occur on the same day as the final screening 
visit if all eligibility criteria are met, depending on site and patient preference. 
See Section 5.5 for the method for assignment to treatment groups/randomization. 
8.3.1 
Extended Screening Period 
In some instances, a patient may remain in the screening period beyond 70 days (10 weeks) 
(maximum of 42 days of screening plus 28 days for washout, if applicable).  Examples may 
include a randomization halt in support of DRC data review or other reason as approved by 
Allergan.   
With the approval of the Allergan study manager, the screening period may be extended and 
the following procedures repeated to confirm the patient’s continued eligibility for 
participation in the study (information may be collected by telephone): 
• inclusion/exclusion criteria 
• medical history  
• concomitant medications/procedures 
• adverse events 
At the investigator’s discretion or on request by Allergan, other assessments (eg, blood tests, 
urine tests, vital signs, IELT assessment, or questionnaires) may also be repeated to ensure 
the patient’s continued eligibility in the study. 


 
 
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8.4 
Visits and Associated Procedures  
For summaries of the procedures to be performed, see Table 1 and Table 2 (Schedules of 
Visits and Procedures).  A description of individual procedures is provided in Section 6.3.  
Evaluations should be performed by the same evaluator throughout the study whenever 
possible.  During the study, every effort should be made to perform the study procedures as 
described in Table 1 and Table 2. 
8.5 
Instructions for the Patients 
All patients and their female partners will be instructed to: 
• attempt vaginal intercourse at a minimum of 4 times per month and to use the stopwatch 
and complete the SID as instructed 
• not to change their usual sexual practices (see Section 4.6)   
• refrain from condom use (see Section 4.5.1.1) 
• refrain from use of prohibited medications (see Section 4.5.2) 
• continue use of any ongoing medications or therapies.  Any changes in dose or frequency 
or stoppage should be reported during a scheduled clinic visit. 
• bring the SID and 
 to the study site at each scheduled clinic visit 
• call the study site if any of the following occur 
o the patient experiences any difficulties following the study treatment 
administration or study procedures 
o the patient has any questions on completion of the SID or 
 
o the patient is hospitalized 
o the patient’s female partner becomes pregnant 
o the patient and their female partner are no longer in a stable monogamous 
sexual relationship 


 
 
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o the patient is unable to attend a scheduled clinic visit in order to 
reschedule the visit 
For sentinel patients in Cohorts 1-5 only, the patient will be instructed to attempt and record a 
minimum of 2 masturbations (starting 48 hours after study treatment administration) on the 
 prior to attending the week 1 clinic visit. 
8.6 
Unscheduled Visits 
Unscheduled visits can be performed if safety concerns arise and at the discretion of the 
investigator.  Additional examinations may be performed as necessary to ensure the safety 
and wellbeing of patients during the study. 
8.7 
Compliance with Protocol 
Participating patients should be able to attend all clinic visits and to adhere to the SID 
completion, appropriate stopwatch use, and testing parameters (patient only) as described in 
this protocol. 
Data will be recorded on the appropriate eCRF supported by appropriate source 
documentation.  At each visit, patients should be asked if any concomitant medications had 
been used, if they had undergone any concurrent procedures (nonstudy procedures), and their 
compliance with the protocol since the previous visit. 
8.8 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time. 
Notification of early patient discontinuation from the study and the reason for discontinuation 
will be made to Allergan and will be clearly documented on the appropriate eCRF.  If a 
patient exits the study prior to completion, whenever possible all week 12 exit visit 
assessments should be performed at the time of exit. 
8.9 
Withdrawal Criteria 
Patients have the right to withdraw from the study at any time and for any reason without 
prejudice to his future medical care by the physician or institution.  The investigator and 
Allergan also have the right to withdraw a patient from the study at any time for any reason. 
Where possible, the decision to withdraw a patient from the study should be discussed with 
Allergan. 


 
 
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Patients should be discontinued from the study if any of the following criteria are met.   
• patient develops (or has an exacerbation of) any medical condition that, in the opinion of 
the investigator, would put the patient at an unacceptable medical risk or compromises 
the patient’s ability to participate in the study 
• patient or their female partner is unwilling or unable to continue to comply with the study 
procedures 
8.10 
Study Termination 
The study may be stopped at his/her study site at any time by the site investigator.  Allergan 
may stop the study (and/or the study site) for any reason with appropriate notification.  
8.11 
Definition of Study End 
The end of the study is defined as the date of the last visit of the last patient participating in 
the study. 
9. 
Adverse Events  
Adverse events occurring during the study will be recorded on an adverse event case report 
form including seriousness, severity, action taken, and relationship to study medication or 
injection procedure.  If adverse events occur, the first concern will be the safety of the study 
participants.  
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this  treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product.   
Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study drug. 


 
 
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Adverse events will be assessed, documented, and recorded in the eCRF throughout the study 
(ie, after informed consent has been obtained).  At each visit, the investigator will begin by 
querying for adverse events by asking each patient a general, nondirected question such as 
“How have you been feeling since the last visit?”  Directed questioning and examination will 
then be done as appropriate.  All reported adverse events will be documented on the 
appropriate eCRF.  
9.1.2 
 Definition of Ejaculation Adverse Events 
Study-specific definitions for ejaculation adverse events are provided in Section 6.3.5.2. 
In addition, all patients who report an ejaculatory adverse event should be encouraged by the 
site to attempt a masturbation and record the results on the 
 (both sentinel and 
nonsentinel patients) to help the investigator accurately characterize the event. 
9.1.3 
Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  (see Section 9.3 for procedures for reporting a serious adverse event.) 
Allergan considers all cancer adverse events as serious adverse events.  In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event. 
Preplanned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event. 
Any preplanned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 
study.  If it has not been documented at the time of the patient’s entry into the study, then it 
should be documented as a serious adverse event and reported to Allergan. 


 
 
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9.1.4 
Severity 
A clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
Not applicable In some cases, an adverse event may be an ‘all or nothing’ finding 
which cannot be graded. 
 
9.1.5 
Relationship to Study Medication or Study Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study medication or study procedure, as applicable.  A causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the study medication or study procedure.  
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate eCRF. 
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator's Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local 
regulations, and the governing health authorities.  Any adverse event that is marked ‘ongoing’ 
at the exit visit must be followed-up as appropriate. 
9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 28 days after the last dose of study medication must be immediately 
reported but no later than 24 hours after learning of a serious adverse event.  Serious adverse 
events  must be reported to Allergan (or Agent of Allergan) as listed on the Allergan Study 
Contacts Sheet and recorded on the serious adverse event form.  All patients with a serious 
adverse event must be followed up and the outcomes reported.  The investigator must supply 


 
 
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Allergan and the IRB/IEC with any additional requested information (eg, autopsy reports and 
discharge summaries).  
In the event of a serious adverse event, the investigator must: 
1. notify Allergan immediately by fax or email using the  serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form, phone 
numbers and relevant Allergan personnel contacts are also on the front page of 
protocol and Study Contacts Page. 
2. obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 
3. provide Allergan with a complete, written description of the adverse event(s) on the 
serious adverse event form describing the event chronologically, including any 
treatment given (eg, medications administered, procedures performed) for the adverse 
event(s).  Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality which includes a statement as 
to whether the event was or was not related to the use of the investigational drug. 
4. promptly inform the governing IRB/IEC of the serious adverse event as required by 
the IRB/IEC, local regulations, and the governing health authorities. 
9.4 
Procedures for Unblinding of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
unblind the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, the sponsor (Allergan Medical 
Safety Physician) should be notified prior to unblinding study medication.  The investigator 
must inform the sponsor (Allergan Medical Safety Physician) of the unblinding if there is no 
notification prior to the unblinding.   
The treatment assignment for the patient can be determined by designated site personnel 
calling into the IVRS or IWRS system via password protected access.  The reason for 
breaking the code must be recorded in the patient’s source documents. 


 
 
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10. 
Administrative Items 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the ICH Guideline on GCP. 
10.1 
Protection of Human Patients 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations 
Written informed consent is to be obtained from each patient prior to any study-related 
activities or procedures in the study. 
10.1.2 
Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan. 
10.1.3 
Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.  
10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
10.2 
Changes to the Protocol 
The investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 


 
 
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10.3 
Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient’s name may be 
disclosed to the Sponsor of the study, Allergan, or the governing health authorities or the 
US FDA if they inspect the study records.  Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
10.3.1 
Patient Privacy 
Written authorization (US sites only), data protection consent (UK sites only), and other 
documentation in accordance with the relevant country and local privacy requirements 
(where applicable) is to be obtained from each patient prior to enrollment into the study, in 
accordance with the applicable privacy requirements (eg, the Health Insurance Portability 
and Accountability Act Standards for Privacy of Individually Identifiable Health Information 
(“HIPAA”), European Union Data Protection Directive 95/46/EC [“EU Directive”]). 
In accordance with HIPAA requirements, additional purposes of this study include the 
following: 
•  to publish anonymous patient data from the study; and  
•  to create and maintain a data repository 
10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include, but is not limited to, a patient’s medical records, hospital 
charts, clinic charts, the investigator's patient study files, as well as the results of diagnostic 
tests such as ultrasound visualizations, x-rays, laboratory tests, and electrocardiograms.  Any 
document, paper or electronic, that contains patient related information, whether the 
information is transcribed into the eCRF or not, is considered source documentation.  The 
investigator's copy of the eCRFs serves as part of the investigator's record of a patient’s 
study-related data.   
At a minimum the following information should be entered into the patient’s medical record: 
• patient’s name 


 
 
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• patient’s contact information 
• date that the patient entered the study, patient number, and patient randomization number 
along with anonymous patient identification and date of birth used in the eCRF 
• study title and/or the protocol number of the study and the name of Allergan 
• a statement that informed consent was obtained (including the date), treatment 
risk/benefits discussed, study related questions answered, and a copy provided to the 
patient  
• a statement that informed consent was obtained from the female partner, study related 
question answered, and a copy provided to the patient/female partner 
• a statement that written authorization (US sites only), data protection consent (UK sites 
only), or other country and local patient privacy required documentation for this study 
has been obtained (including the date) for both the patient and the female partner 
• dates of all patient visits 
• progress notes summarizing all patient visits 
• medical and surgical history (including sexual history and all prior therapies and 
medications for treatment of PE or other previous sexual conditions) 
• injection procedure with details on dosage and time of injection, and any local anesthesia 
or sedation used and route of administration of the anesthetic 
• all concurrent medications, concurrent procedures, and behavioral therapies and other PE 
interventions (list all prescription and nonprescription medications/techniques being 
taken/done at the time of enrollment.  At each subsequent visit, changes to the list of 
medications should be recorded). 
• occurrence and status of any adverse events (including any procedure-related adverse 
events) 
• date the patient exited the study, and a notation as to whether the patient completed the 
study or reason for discontinuation 
• the results of laboratory tests performed by the central laboratory 


 
 
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• results of laboratory tests performed by the site (eg, urine pregnancy test [female 
partner]) 
• concurrent procedures performed during the study 
• vital signs and physical examination findings 
• height and weight 
• key study variables 
• details of training including topic (eg, IELT/SID or 
, trainer (eg, investigator), 
trainee (eg, patient and/or female partner), and date conducted  
The responses to the following questionnaires/assessments entered directly onto the 
appropriate form will be considered source data: 
 
• SID 
 
 
 
 
 
 
 
In addition, study drug accountability and reconstitution records will be retained as source 
documentation. 
10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each patient’s 
eCRF and related documents.  An investigator who has signed the protocol signature page 
will electronically sign the Data Review Form in the eCRF to indicate the observations and 
findings are recorded on the eCRFs correctly and completely.  The eCRFs are to be submitted 
to Allergan in a timely manner at the completion of the study, or as otherwise specified by 
Allergan. 


 
 
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10.4.3 
Study Summary 
An investigator's summary will be provided to Allergan within a short time after the 
completion of the study, or as designated by Allergan.  A summary is also to be provided to 
the responsible IRB/IEC. 
10.4.4 
Retention of Documentation 
All study related correspondence, patient records (ie, source documents listed in 
Section 10.4.1), consent forms, patient privacy documentation, records of the distribution and 
use of all investigational products, questionnaires, SIDs, 
, correspondence with the 
IRB/IEC, copies of eCRFs, and other essential documents should be maintained on file. 
For countries falling within the scope of the ICH guidelines, Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by the sponsor. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
The investigational materials will be packaged and labeled in identically appearing vials.  
The study treatment will be identified as an investigational compound.  The study number 
and kit number will be identified on the unit label. 


 
 
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10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed to the patients, the number of units returned to the 
investigator by the patient, and the number of units returned to Allergan during and at the 
completion of the study.  A detailed inventory must be completed for the study medication.  
The study medication must be dispensed only by an appropriately qualified person to patients 
in the study.  The medication is to be used in accordance with the protocol by patients who 
are under the direct supervision of an investigator. 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All clinical study medications/treatments will be returned to Allergan or Allergan designee 
for destruction. 
10.6 
Monitoring by the Sponsor 
A representative of Allergan will monitor the study on a periodic basis.  The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study.   
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents.  These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
10.7 
Handling of Biological Specimens 
Samples of blood and urine for evaluation of hematology, chemistries, and urinalysis will be 
analyzed at a centralized clinical laboratory with certification from a recognized accreditation 
agency (eg, College of American Pathology [CAP] or Clinical Laboratory Improvement 
Amendments [CLIA] certification).  
The central laboratory manual provides details regarding the laboratory collection and 
shipment procedures for blood and urine samples in this study. 


 
 
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10.8 
Publications 
Allergan as the sponsor, has proprietary interest in this study.  Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.  As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.   
10.9 
Coordinating Investigator 
A signatory coordinating investigator will be designated prior to the writing of the clinical 
study report.


 
 
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11. 
References 
Althof SE.  Prevalence, characteristics and implications of premature ejaculation/rapid 
ejaculation.  J Urol.  2006;175:842-848. 
Giuliano F and Clèment P.  Pharmacology for the treatment of premature ejaculation.  
Pharmacol Rev.  2012;64(3):621-644. 
Godpodinoff ML.  Premature ejaculation: clinical subgroups and etiology.  J Sex Marital 
Ther.  1989;15(2):130-134. 
Gottsch HP, Yang CC, Berger RE.  A pilot study of botulinum toxin A for male chronic pelvic 
pain syndrome.  Scand J Urol Nephrol.  2011;45(1):72-76. 
Graziottin A and Althof S.  What does premature ejaculation mean to the man, the woman, 
and the couple?  J Sex Med.  2011;Suppl 4:304-309. 
ICH Harmonised Tripartite Guideline.  Guideline on the need for carcinogenicity studies of 
pharmaceuticals S1A.  1995. 
Hawton K, Catalan J, Martin P, Fagg J.  Long-term outcome of sex therapy.  Behav Res Ther.  
1986;24(6):665-675. 
Hutchinson K, Cruickshank K, Wylie K.  A benefit-risk assessment of dapoxetine in the 
treatment of premature ejaculation.  Drug Safety.  2012;35(5):359-372. 
Janssen PK, Bakker SC, Réthelyi J, Zwinderman AH, Touw DJ, Olivier B, et al.  Serotonin 
transporter promoter region (5-HTTLPR) polymorphism is associated with the intravaginal 
ejaculation latency time in Dutch men with lifelong premature ejaculation.  J Sex Med.  
2009;6(1):276-284. 
Laumann EO, Nicolosi A, Glasser DB, Paik A, Gingell C, Moreira E, et al.  Sexual problems 
among women and men aged 40-80 y:  prevalence and correlates identified in the Global 
Study of Sexual Attitudes and Behaviours.  Intl J Impt Res. 2005;17(1):39-57. 
Masters WH and Johnson VE.  Human sexual inadequacy.  Boston, Massachusets:  Little and 
Brown; 1970. 
McMahon CG, Althof SE, Waldinger MD, Porst H, Dean J, Sharlip ID, et al.  An 
evidence-based definition of lifelong premature ejaculation: report of the International 


 
 
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Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature 
ejaculation.  J Sex Med.  2008;5(7):1590-1606. 
Morales A.  Evolving therapeutic strategies for premature ejaculation: The search for 
on-demand treatment - topical versus systemic.  Can Urol Assoc J.  2012;6(5):380-385. 
Patrick DL, Althof SE, Pryor JL, Rosen R, Rowland DL, Ho KF, et al. Premature ejaculation:  
an observational study of men and their partners.  J Sex Med.  2005;2(3):358-367. 
Porst H, Montorsi F, Rosen RC, Gaynor L, Grupe S, Alexander J.  The premature ejaculation 
prevalence and attitudes (PEPA) survey:  prevalence, comorbidities, and professional 
help-seeking.  Eur Urol.  2007;51(3):816-824. 
Priligy™.  Public Assessment Report Scientific Discussion, 2008. 
Rosen RC, Althof S.  Impact of premature ejaculation: the psychological, quality of life, and 
sexual relationship consequences.  J Sex Med.  2008;5(6):1296-1307. 
Rowland DL, Patrick DL, Rothman M, Gagnon DD.  The psychological burden of premature 
ejaculation.  J Urol.  2007;177(3):1065-1070. 
Sadeghi-Nejad H, Watson R.  Premature ejaculation: current medical treatment and new 
directions (CME).  J Sex Med.  2008;5(5):1037-1050. 
Semans JH.  Premature ejaculation:  a new approach.  Southern Med J.  1956;49(4):353-358. 
Serefoglu EC, Hawley W, Lasker G, Grissom E, Sikka S, Dohanich G, et al.  Effect of 
botulinum-A toxin injection into bulbospongiosus muscle on ejaculatory latency time in male 
rats [abstract].  J Sex Med.  2012;9(Suppl 5):305-335. 
Symonds T, Roblin D, Hart K, Althof S.  How does premature ejaculation impact a man’s 
life?  J Sex Marital Ther.  2003;29:361-370. 
Waldinger MD.  The neurobiological approach to premature ejaculation.  J Urol.  
2002;168(6):2359-2367. 
Waldinger MD, Quinn P, Dilleen M, Mundayat R, Schweitzer DH, Boolell M.  A 
multinational population survey of intravaginal ejaculation latency time.  J Sex Med.  
2005a;2(4):492-497. 


 
 
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Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH.  Proposal for a definition of 
lifelong premature ejaculation based on epidemiological stopwatch data.  J Sex Med.  
2005b;2(4):498-507. 
Waldinger MD.  Premature ejaculation: different pathophysiologies and etiologies determine 
its treatment.  J Sex Marital Ther.  2008;34(1):1-13. 
Zhou XH, Gao S, Hui SL.  Method for comparing the means of two independent log-normal 
samples.  Biometrics.  1997;53(3):1129-1135. 
 


 
 
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12. 
Attachments 
12.1 
Patient Questionnaires and Instructions for Administration 
Study sites should adhere to the following instructions for all patient questionnaires: 
• administered to patients prior to having any other study procedure performed at the study 
visit (including prior to interview procedures, such as concurrent medications, concurrent 
procedures, adverse event review, etc)  
• completed only by the patient (no outside influences such as family/female partner or 
study personnel) using a black, ball point pen on a firm writing surface  
• administered in a quiet place with ample time for the patient to complete the 
questionnaire 
• filled out completely by the patient (every question must be answered) 
• initialed and dated on the last page by the patient completing the questionnaire 
• completed only at the protocol-specific study visits (no attempt should be made at any 
subsequent visit to administer missed questionnaires) 
• Photocopies or protocol attachment examples of blank questionnaires must not be used 
by patients (only originals provided by Allergan are to be provided to the patient). 
• checked for completeness, and not content, by the study site personnel in the patient’s 
presence.  Study site personnel will verify that all corrections made by the patient are 
initialed/dated by the patient.  Study site personnel should not change responses on the 
questionnaires. 
Examples of each patient questionnaire to be used during this study are provided in the 
sections below. 


 
 
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12.2 
Sexual Intercourse Diary 
The SID will be completed by the patient and/or their female partner after any vaginal sexual 
activity during the screening visit and for 12 weeks following study treatment.   
Study sites should adhere to the following general instructions: 
• at each clinic visit, the SID is collected and reviewed for completeness and not content by 
the study site personnel in the patient’s presence.  Study site personnel will verify that all 
corrections made by the patient are initialed/dated by the patient.  Study site personnel 
should not change information on the diary. 
• review of SID is to occur after completion of questionnaires  
• if information is not completely filled out in the diary, the patient/female partner should 
not be asked to recall the information 
• instruct patients to refrain from altering their sexual activities (see Section 4.6) and 
refrain from condom usage (see Section 4.5.1.1) 
• at the screening visit and each posttreatment clinic visit, the collected SID is filed as 
source document at the site  
• completed only by the patient and/or female partner (no other outside influences such as 
family or study personnel)  
• initialed and dated by the patient completing the diary 
• completed for all attempted vaginal intercourse events 
• completed only for vaginal intercourse events  
• patient/female partner should call the site with any questions concerning completion of 
SID 


 
 
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Study sites should adhere to the following instructions during the screening period: 
• provide initial stopwatch and SID training during the screening visit  
• remind patient not to begin recording IELT in SID until after 28 days of washout has been 
completed (if applicable) 
• instruct patients to provide at least 4 evaluable events (in a maximum of 28 days) during 
screening collection period  
Study sites should adhere to the following instructions posttreatment: 
• at the treatment visit and at each posttreatment clinic visit, SID and stopwatch training 
should be provided, as applicable, with emphasis on addressing corrective actions on any 
errors that were noted during SID review 
• remind patient to wait at least 48 hours after treatment before engaging in vaginal 
intercourse 
• instruct patients to aim for a minimum of 4 vaginal intercourse events per month for the 
duration of the study.  For the open-label portion of the study, no minimum number of 
events per month is needed. 
See Section 6.3.4 for additional details for patients for completing and reviewing the SID for 
IELT assessment.


 
 
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View shows patient in lithotomy position


 
 
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12.5 
Package Insert 
The appropriate Package Insert/Summary of Product Characteristics will be supplied to 
investigators in countries where the product is marketed. 


 
 
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12.6 
Glossary of Abbreviations 
Term/Abbreviation 
Definition 
ANCOVA 
analysis of covariance 
BOTOX 
Botulinum Toxin Type A Purified Neurotoxin Complex (US Adopted Name is 
OnabotulinumtoxinA) 
BSM 
bulbospongiosus muscle 
 
 
DRC 
Data Review Committee 
eCRF 
electronic case report form 
CV 
coefficient of variation 
DR 
drug reconstitutor 
ED 
erectile dysfunction 
GCP 
Good Clinical Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
HSA 
human serum albumin 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IELT 
intravaginal ejaculatory latency time 
 
  
IM 
intramuscular 
IRB 
Institutional Review Board 
ISSM 
International Society of Sexual Medicine 
IV 
intravenously 
 
 
 
 
LOAEL 
lowest observable adverse effect level 
mITT 
modified intent-to-treat 
 
 
 
 
NOAEL 
no observed adverse effect level 
PDE-5 
phosphodiesterase type 5 
PE 
premature ejaculation 
 
 
PP 
per protocol 
RBC 
red blood cell 
SID 
sexual intercourse diary 
SNRI 
serotonin norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
UK 
United Kingdom 
US 
United States 


 
 
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US FDA 
United States Food and Drug Administration 
WBC 
white blood cell 
 
 


 
 
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12.7 
Protocol Amendment 1 Summary 
Protocol 191622-133 Amendment 1 
Date of amendment:  April 2015 
The rationale for this amendment is to assess and visualize the direct effect on the 
bulbospongiosus muscle’s ability to contract at baseline and then after the injection.   
The following table summarizes changes to Protocol 191622-133.  It includes 
content-oriented changes that were made to each section of the protocol and a brief rationale 
for these changes.  Minor editorial and document formatting revisions are not summarized in 
the table. 
Section 
Revision 
Rationale 
Title Page 
Revised emergency telephone 
numbers 
Administrative change 
 
Revised name and contact 
information for Allergan 
Medical Safety Physician 
Administrative change 
Protocol Summary/ 
Response Measures/ 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Same as above 
 
 
 
 
 
Same as above 
6.5 
Summary of Methods 
of Data Collection 
 
 
Same as above 


 
 
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Section 
Revision 
Rationale 
7.2.2 
Secondary Efficacy 
Variables 
 
 
Same as above 
 
 
 
 
Same as above 


 
 
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12.8 
Protocol Amendment 2 Summary 
Protocol 191622-133 Amendment 2 
Date of amendment:  July 2016 
The rationale for this amendment is to 1) specify Cohort 6 with 24 patients (no sentinel 
dosing) randomized 1:1 to receive BTX 
 or placebo, 2) add an open-label period 
following the 12-week randomized period, 3) increase the maximum inclusion age from 50 to 
60 years, 4) add additional study sites in the United States, and 5) remove
 
  
The following table summarizes changes to Protocol 191622-133 Amendment 1.  It includes 
content-oriented changes that were made to each section of the protocol and a brief rationale 
for these changes.  Minor editorial and document formatting revisions including the addition 
of wording such as “ (Cohorts 1-5 only)” and clarification that “partner” refers to a “female 
partner” were added throughout the document for clarity and are not summarized in the table.  
Section 
Revision 
Rationale 
Title Page 
Revised sponsor’s address  
Administrative change 
Investigator Signature 
Page 
Revised to current company 
wording 
Updated to current template 
wording 
Protocol Summary, 
Section 3 (Study 
Design) 
 
The study design was updated 
to include an open-label period 
and study visits during the 
randomized period and the 
open-label period were 
clarified  
To address DRC request to 
change dosing and sample size 
for Cohort 6 
Protocol Summary 
Changed the study duration 
from up to 12 weeks to up to 
24 weeks 
To add an open-label period for 
Cohort 6 
Protocol Summary, 
Section 5.6 (Treatment 
Regimen and Dosing) 
Changed the maximum 
BOTOX total dose from 
 
 
To address DRC request to 
change dosing 


 
 
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Section 
Revision 
Rationale 
Protocol Summary, 
Section 3 (Study 
Design), Table 3-1, 
Section 5.4 (Treatment 
Allocation Ratio and 
Stratification) 
 
Added dosing information for 
Cohort 6 where 24 subjects 
will be randomized 1:1 to 
receive a single dose of 
BOTOX 
 or placebo  
 
To address DRC request to 
change dosing and sample size 
for Cohort 6 
Protocol Summary 
Added a visit schedule for 
Cohort 6 during the 
randomized period and the 
open-label period 
To accommodate the added 
open- label period  
Protocol Summary, 
Section 4.1 (Number of 
Patients) 
Updated the anticipated total 
number of subjects from 60 to 
74 
To address DRC request to 
change sample size of Cohort 6 
Protocol Summary, 
Section 4.2 (Study 
Population 
Characteristics), 
Section 4.3 (Inclusion 
Criteria) 
Changed the maximum patient 
age from 50 years to 60 years 
Required to enroll a sufficient 
number of subjects 
Protocol Summary, 
Section 4.6 (Sexual 
Activity and Practices), 
Section 5.9.4 
(Posttreatment 
Instructions for 
Patients) 
 
 
 
 
 
 
 
 
Protocol Summary, 
Section 4.4 (Exclusion 
Criteria) 
 
 
  
To accurately define the 
exclusion criteria 
Protocol Summary, 
Section 6.1.3 
(Exploratory Measure), 
Section 6.3.6.4 
(Clinical Global 
Impression of Change), 
Section 7.3.5 
(Exploratory Analyses) 
 
 
 
 
  
 
 
 
 
 


 
 
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Section 
Revision 
Rationale 
Protocol Summary 
Clarified that the safety 
response measures will be 
assessed in both randomized 
and open-label periods 
To confirm that safety measures 
do not change regardless of the 
cohort or the period of the study 
Protocol Summary, 
Section 7.5 (Sample 
Size Calculation) 
Specified the number of 
subjects to be enrolled by 
cohort 
To address DRC request to 
change sample size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 3.2 (Data 
Review Committee) 
Added that no data review of 
Cohort 6 will be conducted by 
the data review committee 
To clarify that the DRC is not 
scheduled to review Cohort 6 as 
this is the final cohort 
Section 3.3 (Open-label 
Period) 
Added that at week 12, during 
the randomized period exit 
visit, patients who complete 
the double-blind period of the 
study will be eligible to enroll 
into the open-label period of 
the study 
To clarify the criteria for entry 
into the open-label period for 
Cohort 6 and the dosing 
information 
Section 4.1 (Number of 
Patients) 
Updated the total number of 
study sites from 10 to 15 
To support enrollment 
Section 6.3.1.2 
(Physical 
Examiniation) 
Added wording for the 
physical exam of Cohort 6 to 
be performed at week 12 of the 
open-label period 
To accommodate Cohort 6 
activities and timelines 
Section 6.3.2.1 
(Hematology), Section 
6.3.2.2 (Serum 
Chemistry), Section 
6.3.3.1 (Central 
Laboratory Urine 
Analysis) 
Added clarification that 
hematology, serum chemistry, 
and urine samples will be 
collected at both the 
randomized period and the 
open-label period 
For clarity 


 
 
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Section 
Revision 
Rationale 
Section 6.3.6.1 
(International Index of 
Erectile Function - 
Erectile Function) 
 
 
To accurately define the 
exclusion criteria 
Section 7.2.1 (Primary 
Efficacy Variable) 
Adding wording to clarify that 
IELT was assessed during the 
randomized period of the study 
only 
To clarify the primary endpoint 
timelines 
Section 7.6 (Interim 
Analyses) 
Deleted that a data review 
committee will perform 
ongoing unblinded review of 
safety and efficacy 
To clarify that no additional 
DRC activities are scheduled 
Attachment 12.2 
(Sexual Intercourse 
Diary) 
Updated the diary instructions 
to clarify that no minimum 
number of events per month is 
needed for the open-label 
period 
To clarify that there is no need 
for a minimum of vaginal 
intercourses for the open-label 
period 
 


 
 
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Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 191622-133 Amd 2

SAP_001.pdf: 
NCT01917006 
 
Study ID: 191622‐133 
 
Title: An Exploratory Study of the Safety and Efficacy of BOTOX® for the Treatment of Premature 
Ejaculation 
 
Statistical Analysis Plan Date: 08 Nov 2016 


Allergan Confidential
 191622-133Analysis Plan 
Study 191622-133 (final) Analysis Plan 
GDD-BSP-T-001 v2014.6 
1 
   
   
 
 
Allergan 
Biostatistics 
Analysis Plan – Clinical Study Report 
 
Study ID:   191622-133 
 
Study Title:  An Exploratory Study of the Safety and Efficacy of BOTOX
® for 
the Treatment of Premature Ejaculation 
 


Allergan Confidential
 191622-133Analysis Plan 
Study 191622-133 (final) Analysis Plan 
GDD-BSP-T-001 v2014.6 
2 
Table of Contents 
1. Introduction 
........................................................................................................................ 4
 
1.1  Primary Study Objectives and Design ..................................................................... 4 
1.2  Secondary and Other Objectives 
.............................................................................. 5 
1.3  Sample Size 
.............................................................................................................. 5 
1.4  Experimental Unit and Analysis Unit ...................................................................... 5 
2. Analysis Populations and Data Conventions 
..................................................................... 5 
2.1  Analysis Populations 
................................................................................................ 5 
2.1.1 Handling Mis-randomization and Mis-stratification 
.................................... 6 
2.2  Analysis Visit Windows 
........................................................................................... 6 
2.3  Data Conventions 
..................................................................................................... 7 
3. Disposition and Exit Status 
................................................................................................ 8 
3.1  Screening Log Data 
.................................................................................................. 8 
3.2  Disposition and Exit Status 
...................................................................................... 8 
3.3  Study Duration 
......................................................................................................... 9 
3.4  Protocol Deviations 
.................................................................................................. 9 
4. Demographics and Other Baseline Characteristics 
............................................................ 9 
4.1  Demographics .......................................................................................................... 9 
4.2  Disease Characteristics........................................................................................... 10 
4.3  Prior Medications 
................................................................................................... 10 
4.4  Concomitant Medications/Procedures ................................................................... 10 
4.5  Past Medical History 
.............................................................................................. 10 
5. Efficacy Analyses ............................................................................................................ 11 
5.1  Collection of Primary Efficacy Measurement(s) and Derivation of Primary 
Efficacy Variable(s) 
................................................................................................ 11 
5.2  Primary Efficacy Analyses 
..................................................................................... 12 
5.2.1 Primary Analyses of Primary Efficacy Variable(s) 
.................................... 12 
5.2.2 Other Analyses of Primary Efficacy Variable(s) 
........................................ 12 
5.3  Secondary Efficacy Analyses 
................................................................................. 13 
5.3.1 Secondary Efficacy Analysis 
...................................................................... 13 
5.3.2 Multiplicity Consideration among Secondary Efficacy Analyses ............. 14 
 
 
 
 


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Study 191622-133 (final) Analysis Plan 
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3 
 
 
 
 
5.6  Subgroup Analyses for Efficacy Variables 
............................................................. 16 
6. Safety Analyses 
................................................................................................................ 16
 
6.1  Study Treatment – Exposure and Administration .................................................. 17 
6.1.1 Exposure to Study Treatment(s) 
................................................................. 17 
6.1.2 Administration of Study Treatment(s) ....................................................... 17 
6.2  Pre-Treatment Adverse Events 
............................................................................... 17 
6.3  Pre-Treatment Serious Adverse Events 
.................................................................. 18 
6.4  Adverse Events ...................................................................................................... 18 
6.4.1 Potential Distant Spread of Toxin Adverse Events (applicable to BOTOX® 
studies only) 
............................................................................................... 19 
6.5  Serious Adverse Events 
.......................................................................................... 20 
6.6  Clinical Laboratory Evaluations ............................................................................ 20 
6.7  Vital Signs 
.............................................................................................................. 21 
 
 
 
 
 
 
 
 
6.9  Subgroup Analyses for Safety Variables 
................................................................ 22 
7. Pharmacokinetic, Biomarker, Genomic, or Immunogenicity Data Analyses 
.................. 22
 
 
 
 
 
 
 
 
 
 
 
9. Interim Analyses 
.............................................................................................................. 24
 
10. Analysis for US FDA 
....................................................................................................... 24 
11. Data Collected but not Analyzed 
..................................................................................... 24 
12. Deviations from Protocol 
................................................................................................. 25 
13. References 
........................................................................................................................ 25
 
14. Amendment(s) ................................................................................................................. 25 
 


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Study 191622-133 (final) Analysis Plan 
GDD-BSP-T-001 v2014.6 
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1.  Introduction 
This document describes the statistical analysis plan for study 191622-133, an exploratory 
study of the safety and efficacy of BOTOX
® for the treatment of premature ejaculation (PE).  
Patients will receive only 1 treatment of BOTOX® or placebo during the study and are 
followed up to 24 weeks for safety and efficacy assessments. The final statistical analysis 
will be conducted after database lock, when all patients have completed or exited the study. 
No interim analysis is planned for this study. An independent DRC will review cumulative, 
un-blinded safety and efficacy data. Details of analyses conducted for the DRC review can be 
found in the DRC statistical analysis plan. 
 
1.1  Primary Study Objectives and Design 
The primary study objectives are to explore the safety and efficacy of a range of doses of 
BOTOX® for the treatment of PE in male patients. This is a phase 2a, multicenter, 
randomized, double-blind, placebo-controlled, single treatment, pilot study, followed by an 
open-label observation period, to assess a range of BOTOX
® doses for the treatment of male 
patients with PE. Patients will attend a minimum of 6 or 7 clinic visits and also have 1 or 2 
telephone visits in the randomization period: screening, day 1 (treatment), day 2 (telephone 
visit), week 1 (phone/clinic visit), and weeks 2, 4, 8 and 12/study exit. For the open-label 
period, patients will have 2 clinic visits (weeks 4 and 12/study exit), along with 3 telephone 
visits (day 2, weeks 2, and 8). 
For Cohorts 1-5, patients will be enrolled in cohorts of 10 patients. Within each cohort, 8 
patients will receive BOTOX® and 2 patients will receive placebo. Patients will receive a 
single treatment of the study medication, with the total BOTOX
® dose ranging from   
 
The possible doses are 
, as well as any interim doses that 
are recommended by the DRC. Sentinel dosing of the first 2 patients (1 BOTOX
®, 1 placebo) 
will occur during cohort 1 and also for any subsequent cohort that escalates the dose. Up to 2 
additional sentinel patients might be enrolled to be treated with BOTOX
®, prior to enrolling 
more patients in the dose level. These additional sentinel patients are not considered as 
randomized patients. For Cohorts 1-5, DRC will review cumulative unblinded safety and 
efficacy data when at least 4 weeks of data are available for all patients remaining in a 
cohort. The DRC will make recommendations for dose escalations, dose de-escalations, 
assessing alternative doses from the planned dose escalation scheme, repeating cohorts, and 


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stopping the study. 
Based on DRC recommendations, Cohort 6 is added, where patients will be enrolled into the 
randomized period in a 1:1 ratio, with 12 patients receiving a single treatment of BOTOX
® 
 and 12 patients receiving placebo. Cohort 6 patients may choose to participate in the 
open-label period where they will receive BOTOX®    For Cohort 6, no data review will 
be conducted by the DRC as this will be the final cohort of the study. 
 
1.2  Secondary and Other Objectives 
None. 
 
1.3  Sample Size   
Sample size calculation and power consideration is discussed in Section 7.5 of the study 
protocol. 
 
1.4  Experimental Unit and Analysis Unit 
Both the experimental unit and the analysis unit are the study subject. 
 
2.  Analysis Populations and Data Conventions 
2.1  Analysis Populations 
There are 3 analysis populations defined in this study: modified intent-to-treat (mITT), per 
protocol (PP), and safety: 
• The mITT population will be used to analyze all efficacy variables and summarize 
baseline characteristics.  The mITT population is defined as all randomized patients 
that have received study medication and have both baseline and postbaseline IELT 
data available.  Analyses on the mITT population will be based on the dose actually 
received by the patient. 
• The PP population includes patients in the mITT population who have had no 
protocol deviations that affect the primary efficacy variable.  The PP population will 
be used for analyzing the primary efficacy variable and summarizing baseline 
characteristics based on the dose received by the patient.  
• The safety population includes all treated patients and will be used in the analysis of 
all safety data.  Analyses on the safety population will be based on the dose received 
by the patient. 




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observations are equidistant from the target date, then the latter observation will be used for 
the window
.  The only exception is for clinical laboratory variables, where the last non-
missing observation will be used.  Because re-runs of laboratory variables may only involve 
one or a few variables, leaving the rest missing, this rule will be applied separately for each 
variable for non-missing data only
.  
A
 separate window for the PP population would not be generated as the population is only 
used to analyze IELT data, which is not window-based.    
 
2.3  Data Conventions 
• A
 one-sided, alpha=0.1 significance level will be used for this study for treatment 
comparisons, i.e., treatment differences are considered significant if the 1-sided p-
value of the test used in the comparison is less than or equal to 0.1. 
• Data will be pooled across centers in all analyses.  Placebo patients from different 
cohorts will also be pooled to form the placebo treatment group in all analyses. 
• Day 1 is defined as the day of the first study medication administration.  Study day is 
calculated as: Study day=visit date-day 1 date +1 for visits occurred after day 1 and 
study=visit date -day 1 date for visits occurred before day 1.  
• The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all 
adverse events and medical history
. 
• Medications will be coded by the World Health Organization Drug Dictionary 
Enhanced (WHO DDE) preferred name for the medication’s name and MedDRA
 for 
the medication’s indication.   
• All adverse events/medications with missing onset/stop dates will be identified and 
the missing dates will be imputed as follows: 
a) For adverse event onset date: if day and month are missing but year is available 
then the imputed date would be January 1
st of that year, or day 1 if they are in the 
same year
.  If day is missing but month and year are available then the imputed 
day will be the first day of the month or day 1 if they are in the same month and 
year
. 
b) For adverse event stop date:  if day and month are missing but year is available 
then the imputed day will be December 31
st of that year, or the study exit date if 
they are in the same year
.  If only day is missing but moth and year are available 
then the imputed day will be the last day of the month of the year, or the study 
exit date if they are in the same month and year
. 


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• Data from unscheduled/re-test visits, excluding lab data, will also be treated the same 
way as scheduled visits, i.e., put in the visit window and decided by the visit day’s 
distance to target day as which one to be used in the analyses. 
• Weight and height will be presented with the metric system units and laboratory data 
will be presented with the Standard International (SI) units.   
• Summary statistics for continuous/ordinal data include sample size (N), mean, 
standard deviation, minimum, median, and maximum and that for categorical data 
include sample size (N), frequency count and percentage.     
• Change from baseline is calculated as follow-up minus baseline, and treatment 
difference will be calculated as BOTOX® minus placebo. 
• The type III sums of squares will be used for all analysis of covariance (ANCOVA) 
and analysis of variance (ANOVA) models. 
• Unless otherwise specified, comparisons on categorical data will be performed using 
Pearson
's Chi-square test.  When 25% or more of the cells have expected counts of 
less 5, Fisher
's exact test will be used. 
• Except for AE and medication onset/stop dates, missing data will not be imputed. 
 
3.  Disposition and Exit Status 
3.1  Screening Log Data 
The number and percent of patients who are screen failures as well as who qualified, along 
with the reasons for failure, will be tabulated.  The demographic information (age, race and 
sex) of the failed and qualified patients will be summarized.  A
 by-site listing of the screen 
failures with failure reasons will be also provided. 
 
3.2  Disposition and Exit Status 
For each analysis population (safety
, mITT and PP), patient disposition (enrolled, completed, 
discontinued, and reasons for discontinuation) will be presented by treatment group.  A
 
cumulative frequency table showing patient disposition (continuing, completed, discontinued 
and reasons for discontinuation) will be provided for the mITT population by visit.   
A
 by-patient data listing presenting exclusions from the PP analyses and the primary 
reason(s) for exclusion will be provided.   
The exit status of the patients is classified as completed or discontinued.  The reason for 
discontinuation include adverse event, lack of efficacy
, lost to follow-up, personal reasons, 
protocol violation and other
.  A
 listing of discontinued patients with exit reasons will be 
provided.  


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 Enrollment by site will be tabulated with the number and percent of patients screened, 
randomized, treated, completed and discontinued. 
The summaries will be provided for both the randomized period and for the open-label period 
of the study
, where applicable. 
 
3.3  Study Duration 
The length of study duration for each subject is defined as the duration between the baseline 
and exit dates.  Summary statistics of study duration by treatment will be provided for the 
randomized period, the open-label period and the whole study period (including the 
randomized period and the open-label period). Duration for the open-label period starts from 
the treatment day (day 1) of the open-label period. 
 
3.4  Protocol Deviations 
Significant protocol deviations will be summarized with incidence by deviation type broken 
further by whether deviation leads to data exclusion from per protocol analysis for both the 
randomized period and the open-label period. 
 
4.  Demographics and Other Baseline Characteristics 
Unless otherwise specified, summaries planned in this section will be presented using the 
mITT population, for patents who participated in the randomized period and for those who 
participated in the open-label period. If a subject participates in the open-label period, the 
demographics and baseline characteristics for the open-label period use the same values as 
those for the randomized period. For summaries for the open-label period, comparisons will 
not be performed. 
 
4.1  Demographics 
Age, race, sex are collected in the demographics Case Report Form (CRF) and height and 
weight are collected as part of the pre-treatment vital signs.  All will be summarized using 
frequency table and/or summary statistics, both by treatment group and overall.  Age will be 
further categorized into <35 and ≥35 years of age groups.  Race will be summarized as 
Caucasian, Black, Asian, Hispanic and other, as well as Caucasian vs. non-Caucasian (Black, 
Asian, Hispanic and other combined). 
Patients
' age, weight and height will be analyzed using a one-way ANOVA
 to evaluate any 
baseline differences among the treatment groups.  The distributions of race (Caucasian and 


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non-Caucasian) will be compared among the treatment groups using Pearson
's Chi-square 
test or Fisher
's exact test.  A
 patient level listing will be provided for all demographic data, 
including height and weight. 
 
4.2  Disease Characteristics 
Baseline disease characteristics include baseline IELT
, 
 
 
  Summary statistics will be provided 
for each variable by treatment group as well as overall.  An one-way ANOVA
 will be used to 
compare these characteristics among treatment groups.  For IELT
, as the eligibility is based 
on the average of the latest four eligible events collected at during screening period, 
arithmetic mean will be used.  
 
4.3  Prior Medications 
Prior medications are medications captured in the CRF that are taken prior to the day 1.  A
 
medication is a prior medication if the (imputed) onset date is before day 1.  
The number and percent of patients who had taken prior medications will be presented for 
each treatment group and overall by the WHO DDE preferred name and the MedDRA
 
preferred term (PT) of the medication
's indication. 
 
4.4  Concomitant Medications/Procedures 
Concomitant medications are medications taken on or after the day of study medication 
administration.  A
 medication is a concomitant medication if the (imputed) onset date is on or 
after day 1, or if the onset date is before day 1 and the stop date is after day 1 (discontinued 
after day 1 or ongoing during the study). 
The number and percent of patients who had taken concomitant medications will be 
presented for each treatment group and overall by the WHO DDE preferred name and the 
MedDRA
 PT of the medication
's indication. 
 
4.5  Past Medical History 
Medical history with onset dates prior to the informed consent date will be tabulated and 
presented for each treatment group and overall.  Medical history will be coded using 
MedDRA
 primary system organ class (SOC).  All medical history will be presented by 


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treatment group and overall.  No statistical comparisons will be performed.  A
 patient-level 
listing of medical and surgical histories will also be provided for each treatment group. 
 
Patients are also asked to fill out a sexual history CRF which will record their PE therapy or 
techniques together with start/stop date information.  The un-coded therapy/technique will be 
tabulated with number and percent of patients using each therapy/technique by treatment 
group and overall.  A
 patient-level listing of the information collected will also be presented. 
 
5.  Efficacy
 Analyses
 
5.1  Collection of Primary Efficacy Measurement(s) and Derivation of 
Primary Efficacy Variable(s) 
The primary efficacy measurement is the patient
's IELT (second) collected from the Sex 
Intercourse Diary (SID).  The SID will be completed by the patient and/or their female 
partner after any vaginal sexual activity during the screening visit and for 12 or 24 weeks 
following study treatment.  Only IELTs from evaluable events recorded in the SID will be 
used for analyses.   
An evaluable event is defined as: 
• An event in which the patient and his partner had vaginal intercourse, and the couple 
have recorded that the ejaculation occurred "intravaginally" and duration of the time 
from penetration to ejaculation has been recorded 
OR 
• An event in which the patient and his partner attempted to have vaginal intercourse.  
However, the couple have recorded that ejaculation occurred "prior to vaginal 
penetration".  In this scenario, the duration of time will be recorded as zero. 
Any other scenarios will not be considered as evaluable and will not be included in deriving 
the primary efficacy variable, although time to withdrawal can be used in exploratory 
analyses.  Number of evaluable events will be summarized by treatment group at baseline, 
weeks 2, 4, 8 and 12 for the randomized period of the study
. 
The primary efficacy variable is the change from baseline in logarithm value of the 
individual patient
's geometric mean IELT for the entire 12 weeks of the randomized period of 
the study
.   
For baseline, the geometric mean IELT is calculated from the most 4 recent evaluable events 
prior to study medication administration.  The geometric mean of the IELTs from all 
postbaseline evaluable events up to week 12 is then calculated and the difference in the 
logarithm of the two geometric mean IELTs (postbaseline - baseline) will be calculated. 


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For IELTs that are zero (events in which ejaculation occurred prior to vaginal penetration), 
0.5 (second) will be added for the calculation of geometric means. 
 
5.2  Primary Efficacy Analyses 
The analyses on the primary efficacy variables will be performed on both the mITT and the 
PP populations.  Comparisons will be made between each of the BOTOX® dose levels and 
placebo without multiplicity adjustment. 
 
5.2.1 Primary Analyses of Primary Efficacy Variable(s) 
The primary null hypothesis is that at week 12 the difference in mean change from baseline 
in logarithm value of the geometric mean IELT between BOTOX
® and placebo is at zero, and 
there is no dose response shown in the change from baseline in logarithm value of the 
geometric mean IELT
.   
To test the primary null hypothesis, the primary efficacy variable in relation to dose levels 
will be analyzed using an ANCOVA
 model with treatment as the fixed effect and baseline 
logarithm value in geometric mean IELT as the covariate to assess the relationship of 
response across the BOTOX
® dose levels.  Comparisons of the LSMEANS from the 
ANCOVA
 model will be made for each of the active BOTOX
® dose levels vs. placebo. 
Coefficient of variation (CV) will be presented for the geometric IELT
, and the LSMEAN 
and its 95% confidence interval (CI) as well as treatment difference in LSMEAN and its 95% 
CI for each active BOTOX® dose level vs. placebo will be back-transformed to original unit 
(seconds) to facilitate review
.  
The same ANCOVA
 model using the PP population will be performed. 
To assess the dose-response of the active treatment, a linear regression model with baseline 
logarithm value in geometric mean IELT and dose level (numeric value) as the independent 
variables and the primary efficacy variable as the dependent variable in the model will be 
conducted at week 12.  The same analysis will also be carried out for the PP population. 
 
5.2.2 Other
 Analyses
 of
 Primary
 Efficacy
 Variable(s)
 
As a sensitivity analysis to the log-normal assumption of the geometric mean IELT
, Wilcoxon 
rank-sum test will be performed on the primary efficacy variable for the treatment difference 
for each of the active BOTOX
® dose level vs. placebo.   
In addition, responder analyses for the primary efficacy variable will also be performed.  As 
treatment responder in PE are defined as 3-8 fold changes in geometric mean IELT
, 
corresponding responders will be defined in the logarithmic value of a 3, 4, 5, 6, 7 and 8 fold 


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change (1.10, 1.39, 1.61, 1.79, 1.95, and 2.08, respectively) for the primary efficacy variable 
and the Pearson
's chi-squared test will be used to compare the proportion of responders 
between each of the active BOTOX® dose group vs. placebo.  
 
5.3  
Secondary Efficacy Analyses 
Secondary efficacy variables include the following:  
• Geometric mean IELT up to weeks 2, 4, 6, 8 and 10 of the randomized period, 
respectively
.   
• Average (arithmetic mean) IELT up to weeks 2, 4, 6, 8, 10 and 12 of the randomized 
period, respectively 
 
Interval-based geometric mean IELT and average IELT for week 4, 8 and 12 (ie, events 
between baseline and week 4, between week 4 and week 8, and between week 8 and week 
12) will also be calculated from the above two as differences between periods. 
 
All analyses on the secondary efficacy variables will not be window-based as indicated in 
Section 2.2.  The target day for each time point, except for week 12, will be used to 
determine to which interval or period a certain event belongs to.  For example, all events on 
or before week 10 target day
, day 70, will be included for analyses with IELTs up to week 10, 
while all events between day 29 (inclusive) and day 56 (inclusive) will be included for 
analyses with IELTs between week 4 and week 8.  Any event data collected on or after the 
week 12 target date of day 84 of the randomized period, and before the day 1 (treatment day) 
of the open-label period, if applicable, will be included in analyses related to week 12. 
 
Comparisons will be made for each active BOTOX® dose level vs. placebo without 
multiplicity adjustment. 
 
5.3.1 Secondary Efficacy Analysis  
Summary statistics will be provided for each of the secondary efficacy variables.  Change 
from baseline in log-transformed geometric mean IELTs and change from baseline in average 
mean IELTs will also be calculated and summarized. 
 
Same ANCOVA
 model used in Section 5.2.1 will be used to the change from baseline in the 
log-transformed geometric mean IELT up to weeks 2, 4, 6, 8, and 10, respectively as well as 
change from baseline in interval-based log-transformed geometric mean IELT for weeks 4, 8 


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and 12, with treatment as the fixed effect, and log-transformed baseline geometric mean 
IELT as the covariate. 
Summary statistics will be provided for average IELT as well as change from baseline in 
average IELT by timepoint.  A
 similar ANCOVA
 model will be used on change from baseline 
in average IELT as well as the interval-based average IELTs:  the model will have treatment 
as the fixed effect and the baseline average IELT as the covariate.  Change from baseline in 
average IELTs up to weeks 2, 4, 6, 8, 10 and 12 and the interval-based change from baseline 
in average IELT for weeks 4, 8 and 12 will not be log-transformed prior to analyses. 
  
5.3.2 Multiplicity Consideration among Secondary Efficacy Analyses  
Not applicable 
 
5.4  Other Analyses of Secondary Efficacy Variables 
Nonparametric analysis using the Wilcoxon rank-sum test will be performed on the 
geometric mean IELT up to weeks 2, 4, 6, 8 and 10 as well as interval-based geometric mean 
IELT for weeks 4, 8 and 12, to compare each active BOTOX
® dose level vs. placebo. 
Responder analyses described in 5.2.2 will also be carried out for geometric mean IELTs up 
to weeks 2, 4, 6, 8 and 10. 
Treatment comparisons of  each active BOTOX® dose level vs. placebo Geometric mean 
IELT up to weeks 4, 8 and 12 will also be performed using methods described in Zhou et al, 
1997: 
1. The likelihood-based Z-score test:  the comparison between an active BOTOX
® dose 
level i and placebo is evaluated by the statistic Z
i: 
)
1
1
(
2
1
)
(
2
1
ˆ
ˆ
0
4
0
4
0
2
0
2
2
0
2
0
−
+
−
+
+
−
+
−
=
n
S
n
S
n
S
n
S
S
S
Z
i
i
i
i
i
i
i
µ
µ
 
Where 
i
µˆ and 0
ˆ
µare the sample mean of the log-transformed geometric mean IELT 
of dose level i and placebo, 2
i
S and 2
0
S are the sample variance of the log-transformed 
geometric mean IELT of dose level i and placebo, and i
n and 0
nare the sample size 
of dose level i and placebo, respectively
. 
Assuming that for each of the active dose level i and placebo, the geometric mean 
IELT are independently log-normally distributed with means M
i and M
0, respectively
, 
then Z
i tests the null hypothesis of M
i=M0, and under the null hypothesis Z
i is 
approximately standard normal. 


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2. Bootstrap approach: 
Let i
T, 0
T and 
)
0
,
(i
T be the sample mean of the geometric mean IELT of the dose level 
i , placebo and the two groups combined, respectively
.  
)
0
,
(
)
(
i
i
ik
i
k
T
T
T
T 
+
−
=
and 
)
0
,
(
0
0
)
0
(
i
j
j
T
T
T
T
+
−
=
form a sample with common mean 
)
0
,
(i
T
, where T
ik and T
0j are 
the geometric mean IELT for the k
th patient in dose level i and the j
th patient in the 
placebo group, for k=1, …, ni and j=1,…, n
0.  Resample from them with replacement 
2000 times, 
)
*(
)
*(
1 ,...,
b
in
b
i
i
Z
Z 
 and 
)
*(
0
)
*(
01
0
,...,
b
n
b
Z
Z 
 for each b=1, …, 2000.  Compute  
0
2
)
*(
0
2
)
*(
)
*(
0
)
*(
*
,
n
n
Z
Z
t
b
i
b
i
b
b
i
i
b
τ
τ
+
−
=
, for b=1,…, 2000. 
Where 
)
*(b
i
Z
,
2
)
*(b
i
τ
 
)
*(
0
b
Z
, and 
2
)
*(
0
b
τ
are the sample mean and variance for the active 
does level i and placebo for the b
th resample, respectively
. 
The test statistic,  
0
2
0
2
0
,
ˆ
ˆ
n
n
T
T
t
i
i
i
i
obs
τ
τ +
−
= 
 
Where 
2
ˆ
i
τand 2
0
ˆ
τare the sample variances of the observed geometric mean IELT of 
active dose level i and placebo, respectively
. 
Then the achieved significance level (ASL) for testing H0: Mi=M0 vs. H
a: Mi≠M0, for 
the dose level i, where M
i and M
0 are the means of the IELTs of dose level i and the 
placebo under the log-normal distribution, respectively
. 
 
2000
|
|
|
|
#
ˆ
,
*
, 
i
obx
i
b
i
t
t
times
of
L
S
A
≥
=
 
 
 
 
 
 
 
 


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5.6  Subgroup Analyses for Efficacy Variables 
No subgroup analysis is planned. 
 
 
 
 
 


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6.1  Study Treatment – Exposure and Administration 
6.1.1 Exposure to Study Treatment(s) 
Patient exposure to the study medication will be characterized by study days.  Study day is 
defined as the number of days from day 1 to exit; if the date of exit is missing, the date of the 
last visit will be used.  Data will be summarized with descriptive statistics for each treatment 
group using safety population. 
 
6.1.2 Administration of Study Treatment(s) 
Patients will receive a single treatment administration during the study
, consisting of 2 
injections (each containing half of the total dose) of the assigned study medication to be 
delivered bilaterally (1 injection per side) to the bulbospongiosus muscle.  Injection of the 
study medication will be performed using ultrasound guidance. 
The following options are permitted either alone or in combination before treatment 
administration: 
• No anesthesia 
• Topical local anesthesia 
o Sterile local anesthetic topical preparation (eg, lidocaine cream) may be 
applied to the skin around the injection site 
• Local anesthetic injections to skin 
o Sterile local anesthetic solution (eg, lidocaine solution) may be injected to the 
skin overlaying the injection site 
• Sedation 
o If it is clinically indicated, may be administered to the patient at the 
investigator
's discretion 
Information on injection of study medication, including date, time of injection, number of 
injection sites, total volume injected and injection location will be provided in a data listing. 
 
6.2  Pre-Treatment Adverse Events  
Adverse Events with an onset date that is before day 1 of the randomized period of the study 
will be counted as pretreatment adverse events. 


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Adverse events will be coded from the verbatim text into MedDRA
 primary SOC and PT
.   
Pretreatment AEs will be presented in descending order of incidence rate by the treatment 
group patient was randomized to for all randomized patients.   
No statistical comparison will be performed. 
A
 patient listing will be generated for pretreatment adverse events. 
 
6.3  Pre-Treatment Serious Adverse Events  
Pre-treatment serious adverse event will be collected and coded the same way as mentioned 
in Section 6.2 and a listing will be generated for pretreatment serious adverse events.  
 
6.4  Adverse Events 
AEs will be coded from the verbatim text into PT and the primary SOC using MedDRA.   
AEs are collected both for the screening/baseline period pretreatment (which are referred to 
as pretreatment AEs) and for the follow-up period after treatment is initiated (which are 
referred to as posttreatment AEs).  A
 treatment-emergent adverse event (TEAE) is an adverse 
event with onset on or after the initiation of study treatment or an adverse event with onset 
prior to study treatment that worsened in severity or became serious after the initiation of 
study treatment. For the randomized period of the study
, TEAEs are those with onset on or 
after the first study treatment, and prior to the study treatment for the open-label period, if 
applicable; for the open-label period, TEAEs are those with onset on or after the study 
treatment for the open-label period. 
 
Three incidence rate tables are standard for summarizing all TEAEs: 
• by descending order of incidence rate 
• by primary SOC and PT 
• by primary SOC, PT and severity 
 
Number and percent of patients with TEAEs will be tabulated by relationship to study drug 
and study procedures.  All treatment-related TEAEs, either study drug-related or study 
procedure-related will also be presented by descending incidence and by primary SOC and 
PT for each treatment group.  Separate tables will be generated for study drug-related and 
study procedure-related TEAEs.  TEAEs leading to study discontinuation will also be 
tabulated by primary SOC and PT for each treatment group. 
 
No statistical comparisons will be made for any adverse event table. 


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Study 191622-133 (final) Analysis Plan 
GDD-BSP-T-001 v2014.6 
19 
 
6.4.1 Potential Distant Spread of Toxin Adverse Events (applicable to 
BOTOX® studies only) 
To assess possible distant spread of toxin (PDSOT), 40 MedDRA
 (version 17.0) preferred 
terms that may be associated with botulinum toxin effects have been identified.  All AEs 
associated with PDSOT will be tabulated by SOC and treatment group; in addition, all 
PDSOT AEs will be listed by subject. The 40 terms are listed below
.   
MedDRA Preferred Terms Evaluated for Possible Distant Spread of Toxin 
 
Cardiac Disorders 
          Bradycardia  
 
Eye Disorders 
          Accommodation disorder  
          Diplopia 
          Extraocular muscle paresis 
          Eyelid function disorder 
          Eyelid ptosis 
          Pupillary reflex impaired 
          Vision blurred 
 
Gastrointestinal Disorders 
          Constipation 
          Dry mouth  
          Dysphagia 
          Ileus paralytic 
 
Infections and Infestations 
          Botulism 
 
Musculoskeletal and Connective Tissue Disorders          
          Muscular weakness 
 
 
 
 
Nervous System Disorders 
          Bulbar palsy  
         Cranial nerve palsies multiple 
         Cranial nerve paralysis 
          Dysarthria 
          VIIth nerve paralysis 
          Facial paresis 
          Hyporeflexia 
          Hypotonia     
          Paralysis 
          Paralysis flaccid 
          Paresis cranial nerve 
          Peripheral nerve palsy 
          Peripheral paralysis 
          Speech disorder 
          Vocal cord paralysis 
          Vocal cord paresis 
  
  
 Renal and Urinary Disorders  
     
          Urinary retention   
 
Respiratory, Thoracic and Mediastinal 
Disorders 
          Aspiration  
          Diaphragmatic paralysis 
          Dysphonia 
          Dyspnoea 
          Pneumonia aspiration 
          Respiratory arrest 
          Respiratory depression 
          Respiratory failure           
  
 
Reproductive System and Breast Disorders         
          Pelvic floor muscle weakness           
 
 
 
Note:  The evaluation of events mapping to these terms will take into consideration the 
known mechanism of action of BOTOX®, the temporal relationship of the event (time to 
onset of the AE), the duration of the event, any re-challenge information if applicable, 
confounding factors that may include co-morbidities, past medical history, concomitant 
medications and other non-specific constitutional symptoms of a subject.  


Allergan Confidential
 191622-133Analysis Plan 
Study 191622-133 (final) Analysis Plan 
GDD-BSP-T-001 v2014.6 
20 
The list may need to be updated before database lock due to version change of the MedDRA. 
6.5  Serious
 Adverse
 Events
 
The number and percent of patients with serious TEAEs will be tabulated by treatment group 
for all serious TEAEs and treatment (study drug- or study procedure-, separately) related 
serious TEAEs by primary SOC and PT
.  Serious TEAEs will leading to study 
discontinuation will also be summarized by Primary SOC. 
All serious adverse events and deaths will also be presented in a listing for each treatment 
group. 
 
6.6  Clinical Laboratory Evaluations 
Hematology and non-fasting clinical chemistry blood samples and urine sample are collected 
and processed by a central laboratory at screening, week 4 and week 12 for both the 
randomized period and the open-label period of the study
.  Measures collected are: 
• Hematology: Hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume (MCV), platelets, 
red blood cell (RBC) count, RBC morphology, total white blood cell (WBC) count 
and differential (eg, neutrophils, bands, lymphocytes, monocytes, basophils, and 
eosinophils). 
• Nonfasting serum chemistry: albumin, alkaline phosphatase, alanine transminase, 
aspartae transminase, bicarbonate, calcium, chloride, creatinine, creatine kinase, 
direct bilirubin, nonfasting glucose, indirect bilirubin, magnesium, phosphorous, 
potassium, sodium, total bilirubin, total cholesterol, total protein, urea nitrogen, and 
uric acid.  
• Urine samples: clarity
, color, bilirubin, blood, glucose, ketones, leukocyte esterase, 
nitrite, pH, protein, specific gravity
, urobilinogen, microscopic sediment (WBCs, 
RBCs, casts, bacteria, crystals, and epithelial cells) 
 
An urine culture and sensitivity will be analyzed by the central lab when the central lab urine 
analysis results are suggestive of a urinary tract infection (eg. Positive leukocyte esterase, 
nitrites, blood, or microscopic sediments such as WBCs, RBCs and/or bacteria) 
All clinical laboratory data analyses and presentations are to be expressed in the SI (Standard 
International) units. 
Hematology
, blood chemistry and urine analysis values will be summarized by visit with 
descriptive statistics.  Change from study baseline (defined as the last assessment prior to 
study medication administration) will be summarized with descriptive statistics. For the 


Allergan Confidential
 191622-133Analysis Plan 
Study 191622-133 (final) Analysis Plan 
GDD-BSP-T-001 v2014.6 
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randomized period, baseline is the last assessment prior to the study medication of the 
randomized period of the study
. For the open-label period, baseline is the last assessment 
prior to the study medication of the open-label period of the study
. Within-group change will 
be evaluated by Wilcoxin Signed-rank test. 
Laboratory values will be categorized as low
, normal, and high according to the reference 
normal range.  For each variable, cross-tabulations (shift tables) of low/normal/high values at 
study baseline will be compared to those at each post-treatment visit.   
Listing of all laboratory data, as well as a patient-level listing of all abnormal (high/low) 
laboratory values will be provided.  
 
6.7  Vital Signs 
Vital signs include pulse rate (bpm) systolic/diastolic blood pressure (mmHg) and body 
temperature (°C) are collected at screening, day 1 (both pre- and post-treatment), week 1 
(sentinel patients only), weeks 2 ,4,8 and 12.  Summary statistics for the raw value as well as 
change from baseline will be provided by treatment group at each time point the data are 
collected.  No statistical comparison will be made for vital signs.  A
 patient-level listing will 
also be provided. Baseline for the randomized period and for the open-label period are 
defined similarly to those for the lab assessments. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
. 








Allergan Confidential
 191622-133Analysis Plan 
Study 191622-133 (final) Analysis Plan 
GDD-BSP-T-001 v2014.6 
25 
12.  Deviations from Protocol  
None. 
 
13.  References 
Zhou XH, Gao S, Hui SL.  Method for comparing the means of two independent log-normal 
samples.  Biometrics.  1997; 53(3): 1129-1135. 
 
14.  
Amendment(s) 
- Section 1.1 amended to include the addition of Cohort 6 based on DRC 
recommendations and also the changes in doses to Cohort 1- 5. 
- Section 2.2 amended to add the Analysis Visit Windows for the open-label period of 
the study
. 
- Section 3.2 – amended to add analyses on disposition and exit status for the open-
label period of the study
. 
- Section 3.3 – amended to add analyses on study duration for the open-label period of 
the study
. 
- Section 3.4 – amended to add analyses on protocol deviations for the open-label 
period of the study
. 
- Section 4 – amended to add analyses on demographics and baseline characteristics for 
the open-label period of the study
. 
- Section 5.1 and 5.3 – amended to limit the efficacy analyses to the randomized period 
only
. 
- Sections 5.5.1 and 5.5.2 – amended to limit the analyses on BSM measurements to 
Cohort 5 only
, and to add exploratory analyses for the open-label period. 
- Sections 6.2, 6.4, 6.5, 6.6, and 6.7 – amended to add analyses on safety for the open-
label period of the study
. 
- Sections 8.1, 8.2, 8.3, and 8.4 – amended to add exploratory analyses and safety 
analyses for the open-label period of the study
. 


Allergan Confidential
 191622-133Analysis Plan 
Study 191622-133 (final) Analysis Plan 
GDD-BSP-T-001 v2014.6 
26 
- Section 9 – Deleted the statements that DRC will perform ongoing unblinded review 
of both safety and efficacy
, to be consistent with the protocol.   
 
 


ALLERGAN
ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) Signed by: 
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Analysis Plan - 191622-133 Amendment 2