Conditions: Premature Ejaculation
Keywords: Sex Sexual Dysfunction IX-01
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 239
Healthy volunteers: no

Brief summary:
A Phase 2b, 8-week, double-blind, placebo-controlled, parallel group study to evaluate the effect of 3 different dose levels of IX-01 on IELT and patient-reported outcome in men with lifelong PE.

Men with self-reported lifelong PE (International Society for Sexual Medicine (ISSM) definition) and in stable heterosexual relationship will undergo a 4-week run-in period during which they will be asked to attempt intercourse at least 4 times. Men with IELT ≤ 1 minute on at least 75% of attempts at intercourse during the no-treatment run-in period will be randomized for the double-blind phase of the study.

In the double-blind phase of the study, men will be asked to take study drug 1 to 6 hours prior to sexual activity. Men and partners will be asked to attempt intercourse a minimum of 8 times during the 8 week double-blind study treatment. The patient or partner will record the IELT on each occasion by use of a stopwatch.

Detailed description:

Arms:
arm 1: 1200 mg dose comprising three 400 mg caplets administered orally at least 1 hour before or after food and 1-6 hours prior to sexual activity arm 2: Three placebo caplets administered orally at least 1 hour before or after food and 1-6 hours prior to sexual activity arm 3: 800 mg dose comprising two 400 mg caplets and one placebo caplet administered orally at least 1 hour before or after food and 1-6 hours prior to sexual activity arm 4: 400 mg dose comprising one 400 mg caplet and two placebo caplets administered orally at least 1 hour before or after food and 1-6 hours prior to sexual activity

Interventions: intervention 1: IX-01 400 mg intervention 2: Placebo intervention 3: IX-01 800 mg intervention 4: IX-01 1200 mg
Intervention descriptions: intervention 1: IX-01 400 mg caplet intervention 2: Placebo caplet(s) intervention 3: IX-01 800 mg (Two 400 mg caplets) intervention 4: IX-01 1200 mg (Three 400 mg caplets)

Protocol document:
Prot_SAP_000.pdf: 
 
IXCHELSIS CONFIDENTIAL 
 
CLINICAL STUDY PROTOCOL 
IND NUMBER 121245 
A Phase 2b, 8-Week, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Effects of 3 Different Dose Levels of IX-01 on 
Intravaginal Ejaculatory Latency Time (IELT), Patient-Reported 
Outcomes, and Safety in Men with Lifelong Premature Ejaculation (PE) 
PROTOCOL NO. IX-0105 
Sponsor: 
Ixchelsis Ltd.  
Discovery Park House 
Discovery Park 
Ramsgate Road, Sandwich 
Kent CT13 9NJ  
United Kingdom 
Sponsor Chief Medical 
Officer: 
Ian Osterloh MSc, MBBS, MRCP 
Chief Medical Officer 
Ixchelsis Ltd. 
Telephone: +44 (0) 7771 971413 
Sponsor Contact and  
Project Manager: 
Katie George BSc Hons, PMP 
Clinical Project Manager 
Ixchelsis Ltd. 
Telephone: +44 (0) 7977 008998 
24-Hour Safety Hotline: 
Telephone: +1 800 201 8725 
Fax: +1 888 488 9697 
Version of Protocol:  
Amendment 1.0 
Original Protocol Version:  
24 October 2016 
Amendment 1.0:  
16 January 2017 
 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Ixchelsis Ltd. The 
concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Ixchelsis Ltd. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice. 


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IXCHELSIS CONFIDENTIAL 
 
Protocol Approval – Sponsor Signatory 
Study Title 
A Phase 2b, 8-Week, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Effects of 3 Different Dose Levels of IX-01 on 
Intravaginal Ejaculatory Latency Time (IELT), Patient-Reported 
Outcomes, and Safety in Men with Lifelong Premature Ejaculation (PE) 
Protocol Number IX-0105 
Amendment 1.0 
16 January 2017 
 
Protocol accepted and approved by: 
Chief Medical Officer 
Ian Osterloh MSc, MBBS, MRCP  
Ixchelsis Ltd.  
Discovery Park House 
Discovery Park 
Ramsgate Road, Sandwich 
Kent CT13 9NJ  
United Kingdom  
 
 
 
Signature 
 
Date 
 


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IXCHELSIS CONFIDENTIAL 
 
Protocol Approval – Principal Investigator 
Study Title 
A Phase 2b, 8-Week, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Effects of 3 Different Dose Levels of IX-01 on 
Intravaginal Ejaculatory Latency Time (IELT), Patient-Reported 
Outcomes, and Safety in Men with Lifelong Premature Ejaculation (PE) 
Protocol Number IX-0105 
Amendment 1.0 
16 January 2017 
 
Protocol accepted and approved by: 
Principal Investigator 
Dr Stanley Althof 
Center for Marital and Sexual Health of South Florida 
1515 North Flagler Drive 
Suite 540 
West Palm Beach 
FL 33401 
United States 
 
 
 
Signature 
 
Date 
 


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IXCHELSIS CONFIDENTIAL 
 
Protocol Approval – Biostatistician 
Study Title 
A Phase 2b, 8-Week, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Effects of 3 Different Dose Levels of IX-01 on 
Intravaginal Ejaculatory Latency Time (IELT), Patient-Reported 
Outcomes, and Safety in Men with Lifelong Premature Ejaculation (PE) 
Protocol Number IX-0105 
Amendment 1.0 
16 January 2017 
 
Protocol accepted and approved by: 
Senior Biostatistician 
Nicolas Girard 
PPD Development Ltd.  
19, rue Docteur Freysz, 67000 Strasbourg 
France 
Telephone: +33 980 757 587 
 
 
 
Signature 
 
Date 
 


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IXCHELSIS CONFIDENTIAL 
 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 2b, 8-Week, 
Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effects of 
3 Different Dose Levels of IX-01 on Intravaginal Ejaculatory Latency Time (IELT), 
Patient-Reported Outcomes, and Safety in Men with Lifelong Premature Ejaculation (PE)” 
and the accompanying  Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 1.0, dated 24 October 2016, the International 
Council for Harmonisation harmonised tripartite guideline E6(R1): Good Clinical Practice 
and all applicable government regulations. I will not make changes to the protocol before 
consulting with Ixchelsis Ltd or implement protocol changes without institutional review 
board approval except to eliminate an immediate risk to patients. I agree to administer study 
treatment only to patients under my personal supervision or the supervision of a 
subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Ixchelsis Ltd. 
 
 
 
Signature of Principal Investigator 
 
Date 
Stanley Althof 
 
 
Printed Name of Principal Investigator 
 
 
 
 


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Table of Contents 
Table of Contents ....................................................................................................................... 6 
List of Tables .............................................................................................................................. 9 
List of Figures ............................................................................................................................ 9 
Protocol Synopsis..................................................................................................................... 10 
List of Abbreviations................................................................................................................ 16 
1 
Introduction ...................................................................................................................... 18 
1.1 
Disease Under Treatment ........................................................................................ 18 
1.2 
Study Drug .............................................................................................................. 19 
1.3 
Preclinical Experience ............................................................................................ 20 
1.3.1 
Nonclinical Pharmacology ....................................................................... 20 
1.3.2 
Safety Pharmacology ............................................................................... 21 
1.3.3 
Toxicology ............................................................................................... 21 
1.3.4 
Pharmacokinetics and Product Metabolism in Animals .......................... 22 
1.3.5 
Clinical Data ............................................................................................ 22 
1.4 
Study Rationale ....................................................................................................... 28 
1.4.1 
Rationale for Dose Selection ................................................................... 28 
1.5 
Potential Risks and Benefits ................................................................................... 29 
2 
Study Objectives............................................................................................................... 31 
2.1 
Primary Objective ................................................................................................... 31 
2.2 
Secondary Objectives.............................................................................................. 31 
3 
Investigational Plan .......................................................................................................... 32 
3.1 
Study Design ........................................................................................................... 32 
4 
Patient Selection and Withdrawal Criteria ....................................................................... 35 
4.1 
Selection of Study Population ................................................................................. 35 
4.1.1 
Inclusion Criteria ..................................................................................... 35 
4.1.2 
Exclusion Criteria .................................................................................... 35 
4.2 
Withdrawal of Patients From the Study .................................................................. 37 
5 
Study Treatments .............................................................................................................. 39 


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5.1 
Method of Assigning Patients to Treatment Groups ............................................... 39 
5.2 
Treatments Administered ........................................................................................ 39 
5.3 
Management of Clinical Supplies ........................................................................... 39 
5.3.1 
Study Drug Packaging and Storage ......................................................... 39 
5.3.2 
Test Article Accountability ...................................................................... 40 
5.3.3 
Product Complaints and Medication Errors............................................. 40 
5.4 
Blinding................................................................................................................... 41 
5.4.1 
Breaking the Blind ................................................................................... 41 
5.5 
Treatment Compliance ............................................................................................ 41 
5.6 
Prior and Concomitant Therapy .............................................................................. 41 
6 
Study Assessments and Procedures .................................................................................. 43 
6.1 
Study Visits ............................................................................................................. 43 
6.2 
Efficacy Assessments .............................................................................................. 49 
6.3 
Safety Assessments ................................................................................................. 51 
6.3.1 
Adverse Events ........................................................................................ 53 
6.3.1.1 
Definitions of Adverse Events ................................................................. 53 
6.3.1.2 
Eliciting and Documenting Adverse Events ............................................ 54 
6.3.1.3 
Reporting Adverse Events ....................................................................... 54 
6.3.1.4 
Assessment of Severity ............................................................................ 55 
6.3.1.5 
Assessment of Causality .......................................................................... 55 
6.3.1.6 
Follow-Up of Patients Reporting Adverse Events ................................... 56 
6.4 
Pregnancy ................................................................................................................ 56 
6.5 
Laboratory Analyses ............................................................................................... 57 
7 
Statistical and Analytical Plan .......................................................................................... 58 
7.1 
Primary Efficacy Endpoint ..................................................................................... 58 
7.2 
Secondary Efficacy Endpoints ................................................................................ 58 
7.2.1 
Key Secondary Efficacy Endpoints ......................................................... 58 
7.2.2 
Other Secondary Efficacy Endpoints ....................................................... 59 
7.3 
Sample Size Calculations ........................................................................................ 60 
7.4 
Analysis Sets ........................................................................................................... 61 
7.5 
Description of Subgroups to be Analyzed .............................................................. 61 


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7.6 
Statistical Analysis Methodology ........................................................................... 62 
7.6.1 
Analysis of Primary Efficacy Endpoint ................................................... 62 
7.6.2 
Analysis of Secondary Efficacy Endpoint ............................................... 63 
7.6.2.1 
Change From Baseline Endpoints ........................................................... 63 
7.6.2.2 
Proportion Endpoints ............................................................................... 64 
7.6.2.3 
Percentage Endpoints ............................................................................... 64 
7.6.2.4 
Missing Data ............................................................................................ 64 
7.6.3 
Safety Analyses ........................................................................................ 64 
7.6.4 
Other Analyses ......................................................................................... 66 
7.6.5 
Interim Analyses ...................................................................................... 67 
8 
Data Quality Assurance .................................................................................................... 68 
8.1 
Case Report Forms and Source Documents............................................................ 68 
9 
Ethics ................................................................................................................................ 70 
9.1 
Institutional Review Board ..................................................................................... 70 
9.2 
Ethical Conduct of the Study .................................................................................. 70 
9.3 
Patient Information and Consent ............................................................................ 70 
10 Investigator’s Obligations ................................................................................................ 72 
10.1 Confidentiality ........................................................................................................ 72 
10.2 Study Conduct ......................................................................................................... 72 
10.3 Records Retention ................................................................................................... 72 
10.4 Publications ............................................................................................................. 73 
11 Study Management ........................................................................................................... 74 
11.1 Monitoring .............................................................................................................. 74 
11.2 Study Termination ................................................................................................... 74 
12 Reference List................................................................................................................... 75 
13 Appendices ....................................................................................................................... 77 
13.1 Appendix 1: Schedule of Events ............................................................................. 77 
13.2 Appendix 2: Evaluation Instruments ...................................................................... 80 
13.2.1 
Clinical Global Impression of Change (CGIC) ....................................... 80 
13.2.2 
Premature Ejaculation Profile (PEP) ....................................................... 80 


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13.2.3 
International Index of Erectile Function (IIEF) ....................................... 81 
13.2.4 
Patient Health Questionnaire 9 (PHQ-9) ................................................. 88 
13.2.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................ 89 
13.3 Appendix 3: Laboratory Safety Tests ...................................................................... 93 
13.4   Appendix 4: Amendment 1.0……………………………...……………………...95 
 
 
List of Tables 
Table 13-1 
Schedule of Events .......................................................................................... 78 
 
List of Figures 
Figure 3-1 
Study Design ................................................................................................... 32 
Figure 7-1 
Overview of the Multiplicity Control ............................................................. 62 
 


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Protocol Synopsis 
Protocol Number: 
IX-0105 
Title: 
A Phase 2b, 8-Week, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Effects of 3 Different Dose 
Levels of IX-01 on Intravaginal Ejaculatory Latency Time 
(IELT), Patient-Reported Outcomes, and Safety in Men with 
Lifelong Premature Ejaculation (PE) 
Sponsor: 
Ixchelsis Ltd. 
Discovery Park House, Discovery Park 
Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom 
Study Phase: 
Phase 2b 
Study Sites: 
Approximately 30 sites in the United States 
Indication: 
Premature Ejaculation 
Rationale: 
In a previous clinical study, the selective oxytocin-receptor 
antagonist, IX-01 has been shown to prolong intravaginal 
ejaculatory latency time (IELT) and improve patient-reported 
outcomes in men with lifelong premature ejaculation (PE). This 
study is designed to explore the relationship between efficacy 
and dose. 
Objectives: 
• 
To determine the efficacy of 3 different dose levels of IX-01 
to prolong IELT in men with PE. 
• 
To determine the efficacy of 3 different dose levels of IX-01 
on Clinical Global Impression of Change (CGIC), control of 
ejaculation, ejaculation-related distress and interpersonal 
difficulty, and satisfaction with sexual intercourse in men 
with PE. 
• 
To determine the toleration and safety of 3 different dose 
levels of IX-01 taken as required in men with PE. 
Patient Population: 
• 
Men aged ≥18 years and ≤60 years in stable (≥6 months) 
heterosexual relationship and who have lifelong PE.  
• 
PE confirmed by IELT ≤1 minute on at least 75% of 
attempts at sexual intercourse during the run-in period.  
• 
Men meeting other aspects of International Society for 
Sexual Medicine (ISSM) definition including inability to 
delay ejaculation on all or nearly all vaginal penetrations 
and negative personal consequences such as distress, bother 
and frustration. 


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• 
Patient and partner willing to attempt intercourse at least 
4 times during the run-in period and at least 8 additional 
times during the double-blind part of the study. 
• 
Partner not planning pregnancy and willing to use 
contraception (unless not of childbearing potential, eg, 
surgically sterilized).  
• 
Patient willing to limit use of alcohol on days in which he 
takes study drug (not more than 3 standard drinks as defined 
in the Informed Consent Form). 
• 
Patient capable of giving written informed consent. 
• 
Key exclusion criteria include any IELT value >2 minutes 
during the run-in period;, any patient making <4 attempts at 
sexual intercourse during the run-in period; any patient who 
rates their control of ejaculation as fair, good, or very good 
(Premature Ejaculation Profile [PEP] question administered 
at the end of the run-in period); any patient who rates their 
ejaculation-related “personal distress” as “not at all” or “a 
little bit” (PEP question administered at the end of the run-in 
period); 
coexisting 
International 
Index 
of 
Erectile 
Dysfunction (IIEF; Erectile Function domain <22 during the 
run-in period); concomitant use of phosphodiesterase type 5 
inhibitors, 
selective 
serotonin 
reuptake 
inhibitor 
(SSRIs)/selective 
serotonin 
norepinephrine 
reuptake 
inhibitor (SSNRIs), monoamine oxidase inhibitors, alpha 
blockers, 5-alpha reductase inhibitors, topical anesthetics, 
and/or tramadol; any history (last 6 months) of use of Botox 
or similar product to treat PE; any other sexual disorder of 
patient or partner that could interfere with the results; any 
current sexually transmitted disease; and being unwilling to 
stop other treatments including psychotherapy and sex 
therapy for PE; PHQ-9 total score >9 and/or score of >0 on 
Question 9 of PHQ-9. 
Study Design: 
A 
Phase 
2b, 
8-week, 
double-blind, 
placebo-controlled, 
parallel-group study to evaluate the effect of 3 different dose 
levels of IX-01 on IELT and patient-reported outcome in men 
with lifelong PE. 
Men with self-reported lifelong PE (ISSM definition) and in 
stable heterosexual relationship will undergo a 4-week run-in 
period during which they will be asked to attempt intercourse at 
least 4 times. Men with IELT ≤ 1 minute on at least 75% of 


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attempts at intercourse during the no-treatment run-in period will 
be randomized for the double-blind phase of the study. 
In the double-blind phase of the study, men will be asked to take 
study drug 1 to 6 hours prior to sexual activity. Men and partners 
will be asked to attempt intercourse a minimum of 8 times 
during the 8-week double-blind study treatment. The patient or 
partner will record the IELT on each occasion by use of a 
stopwatch. 
Estimated Study 
Duration: 
Each patient will require a minimum of 6 visits if they do not 
terminate the study early. The duration of the study for each 
patient is approximately 4 months (including the 8-week double-
blind treatment period). 
Efficacy Assessments: 
Electronic diary (eDiary) (LogPad) will capture the following: 
Sexual activity (date and time) 
• IELT 
• Level of control of timing of ejaculation and level of 
ejaculation-related personal distress associated with 
each event. 
Patient Questionnaires/Instruments: 
Questionnaires administered at the end of the run-in period 
and after 4 and 8 weeks of double-blind treatment  
• Premature Ejaculation Profile (PEP) including 
additional question on bother 
• Patient Global Impression of Severity (PGIS) 
Questionnaire to be administered at end of double-blind 
treatment only 
• Clinical Global Impression of Change (CGIC) 
Pharmacokinetic or 
Pharmacodynamic 
Assessments: 
This protocol does not require sampling for pharmacokinetics. 
Safety Assessments: 
• 
Physical examination and vital signs 
• 
Weight and body mass index 
• 
Electrocardiograms 
• 
Laboratory safety tests 
• 
Concomitant medications  
• 
Adverse events 
• 
IIEF 


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• 
Patient Health Questionnaire 9 (PHQ-9) 
• 
Columbia-Suicide Severity Rating Scale 
Study Drug, Dosage, 
and Route of 
Administration: 
Study drug will be supplied as 400 mg caplets (IX-01 or 
matching placebo). One dose is 3 caplets to be taken orally 1 to 
6 hours before sexual activity, but not more than once per day. 
There will be 4 dosage groups (placebo, IX-01 400 mg, IX-01 
800 mg, and IX-01 1200 mg). In order to preserve the blind, 
each dose will be supplied in a blister pack containing 3 caplets 
(which will comprise placebo and/or IX-01, depending on the 
treatment group assigned). 
Sample Size: 
The target total is for 220 patients to be randomized in the study. 
The randomization ratio will be 2:2:3:3 (placebo, IX-01 400 mg, 
IX-01 800 mg, and IX-01 1200 mg dose groups, respectively). 
Thus, 44 patients each will be randomized to the placebo and 
IX-01 400 mg dose groups, and 66 patients each will be 
randomized to the IX-01 800 mg and IX-01 1200 mg dose 
groups. The 2:3 ratio results in only slight loss of statistical 
power from 1:1 randomization while increasing the chances that 
a patient will be randomized to an effective dose of study drug. 
Assuming an alpha (2-sided) of 0.05 and an SD of 70 seconds, a 
sample size of 220 patients randomized in total (44 to the 
placebo and IX-01 400 mg dose groups and 66 to the IX-01 
800 mg 
and 
IX-01 
1200 
mg 
dose 
groups) 
provides 
approximately 85%, 90%, and 90% power to detect a mean 
difference of 45 seconds between change from baseline in 
geometric mean (GM) of IELT for the IX-01 400 mg, IX-01 
800 mg, and IX-01 1200 mg dose groups, respectively, 
compared with the placebo group.  
Sequential multiplicity control testing of IX-01 1200 mg dose 
versus placebo, followed by IX-01 800 mg dose versus placebo 
and then IX-01 400 mg dose versus placebo will be done in 
order to control for multiplicity.  
Additional patients may be recruited if some patients discontinue 
from the study with less than 2 postbaseline IELT assessments. 
Statistical Methods: 
The primary efficacy endpoint of this study is the change in GM 
IELT over the treatment assessment period compared with 
baseline, ie, [GM(IELTtreatment period) – GM(IELTbaseline)]. 
Change from baseline in GM IELT over the treatment 
assessment period will be analyzed using a mixed linear model, 
including treatment and baseline IELT as fixed factors and site 


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as a random factor.  
The primary comparison of interest is IX-01 1200 mg versus 
placebo. If it is statistically significant at α=0.05, then the 
following comparisons will be tested in the following order: 
• 
IX-01 800 mg vs placebo group 
• 
IX-01 400 mg vs placebo group 
If at any point in the sequence statistical significance is not met, 
then subsequent analyses in the sequence cannot be deemed 
statistically significant. In such cases, nominal P values and 
95% CI will be reported and interpreted in an exploratory 
manner. Irrespective of whether there are any statistically 
significant differences between treatment groups, IELT data 
from all treatment groups will also be used to model a possible 
dose response relationship. 
The same approach to control for multiple comparisons as 
proposed for the primary endpoint will be used for each 
secondary endpoint analysis. 
The following key secondary efficacy endpoints will be 
analyzed: 
1. Fold change in GM IELT over the treatment assessment 
period compared with baseline. 
2. Proportion of patients with ≥2.5-fold increase in GM IELT 
over the treatment assessment period compared with 
baseline, 
ie, 
[proportion 
of 
subjects 
with 
GM(IELTtreatment period)/GM(IELTbaseline) ≥2.5]. 
3. Proportion of patients rating their PE as improved per the 
CGIC questionnaire. 
4. Proportion of patients achieving mean change in category of 
≥1 or ≥2 on control of timing of ejaculation (PEP), ie, 
improving control from “very poor” or “poor” to “fair,” 
“good,” or “very good” at end of treatment. 
5. Proportion of patients achieving mean change in category of 
≥1 or ≥2 in ejaculation-related personal distress (PEP), ie, 
improving 
rating 
of 
ejaculation-related 
distress 
to 
“moderate,” “a bit,” or “not at all” at end of treatment. 
6. Proportions of patients achieving change in category of ≥2 
on control of timing of ejaculation (PEP) and achieving 
change in category of ≥1 in ejaculation-related personal 
distress (PEP) at end of treatment.  


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7. Mean change from baseline in score on control of 
ejaculation (e-diary) over the treatment assessment period. 
8. Mean change from baseline in score on ejaculation-related 
personal distress (e-diary) over the treatment assessment 
period. 
Analyses of e-diary data expressed in change from baseline over 
the treatment assessment period will be carried out using a 
mixed linear model. All analyses should include treatment, 
baseline IELT, and the baseline score of the analyzed endpoint as 
fixed effects and the site as a random effect. 
For each analysis on proportion endpoints, difference in the 
proportions between each test group and placebo group will be 
tested using a logistic model. All analyses should include 
treatment, baseline IELT and the site as factors. P values and 
adjusted odds ratios will be presented. 
Amendment 1.0: 
16 January 2017 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CGIC 
Clinical Global Impression of Change 
CNS 
Central nervous system 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP3A4 
Cytochrome P450 3A4  
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyltransferase 
GM 
Geometric mean 
GMP 
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IELT 
Intravaginal ejaculatory latency time 
IIEF 
International Index of Erectile Function 
IRB 
Institutional review board 
ISSM 
International Society for Sexual Medicine 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
NOAEL 
No observed adverse effect level 
PDE5 
Phosphodiesterase type 5  
PE 
Premature ejaculation 


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Abbreviation 
Definition 
PEP 
PGIS 
Premature Ejaculation Profile 
Patient Global Impression of Severity 
PHQ-9 
Patient Health Questionnaire 9 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SSNRI 
Selective Serotonin Norepinephrine Reuptake Inhibitor 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WHO-DD 
WHO Drug Dictionary 


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1 
Introduction 
1.1 
Disease Under Treatment 
Premature ejaculation (PE) is a common male sexual dysfunction, but the etiology is not well 
understood. Although historically considered to be predominantly a condition of 
psychological origin, over the last decade, it has been increasingly recognized that men with 
PE starting and continuing from their earliest sexual experiences may have a genetic 
predisposition to ejaculate rapidly and that men who acquire PE later in life may have a 
variety of psychosocial and physical factors that bring on the condition.1 Thus, PE is 
subclassified as “lifelong” or “acquired”.2 Patients with lifelong PE give a history of rapid 
ejaculation from the first sexual experience and persistence of rapid ejaculation (before or 
within 1 to 2 minutes after vaginal penetration) throughout life. Acquired PE is characterized 
by a gradual or sudden onset following normal ejaculation experiences before onset of the 
condition, when time to ejaculation becomes short (but often not as short as in lifelong PE). 
Until recently, there has been no universally accepted definition of PE. Generally, definitions 
of PE acknowledge certain core components: short ejaculatory latency, lack of control over 
ejaculation, and ejaculation-related personal bother or distress. The Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5), published in 2013, defines the condition 
as persistent or recurrent pattern of ejaculation occurring during partnered sexual activity 
within approximately one minute following vaginal penetration and before the individual 
wishes it, and is associated with clinically significant distress in the individual. The 
International Consultation on Sexual Dysfunctions suggests that men with an intravaginal 
ejaculatory latency time (IELT) less than 2 minutes qualify as having PE.3 Over the last few 
years, there has been a new evidence-based definition that has gained widespread acceptance. 
It is the definition adopted by the International Society for Sexual Medicine (ISSM), and 
defines PE as a male sexual dysfunction characterized by ejaculation which always or nearly 
always occurs prior to or within about one minute of vaginal penetration (lifelong PE) OR a 
clinically significant reduction in latency time, often to about 3 minutes or less (acquired PE), 
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.4 The definition applies to both lifelong and acquired PE but is limited to 
intravaginal sexual activity. The ISSM definition is similar to the DSM-5. 


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Premature Ejaculation can have a profoundly negative effect on quality of life, and men with 
PE are more likely to report low satisfaction with their sexual relationship, low satisfaction 
with sexual intercourse, difficulty relaxing during intercourse, and less frequent intercourse 
than men without PE.5,6 PE also diminishes self-confidence and damages the relationship 
with the partner and may cause mental distress, anxiety, embarrassment, and depression.7 
Rosen and Althof confirmed a high level of psychological distress associated with PE that 
can be as impactful as erectile dysfunction on the couple.8 They also found that women were 
impacted as much and possibly more than their partners by PE and were an important reason 
for men to seek treatment. Another study9 confirmed that the partner’s satisfaction with the 
sexual relationship decreased with increasing severity of the man’s condition, and a more 
recent study reported that the detrimental effects of PE often resulted in the termination of the 
relationship.10 
At present, the only approved prescription oral medication specifically for the management 
of PE is dapoxetine (Priligy®), which has approval in over 60 countries in Europe, Asia, and 
Latin America.11 Dapoxetine is a selective serotonin reuptake inhibitor (SSRI) taken on 
demand. When SSRIs are used for the management of depression, they have been associated 
with the side effect of anorgasmia and hence have been prescribed off-label (often as 
continuous daily dosing regimens but sometimes on demand) for the treatment of PE. 
Patients are often reluctant to begin off-label treatment of PE with SSRIs for reasons of not 
wanting to take an antidepressant, treatment effects below expectations, and cost. Recently, 
the European Medicines Agency approved a topical prescription-only treatment (PSD502®), 
a local anesthetic containing lidocaine and prilocaine.12 
In view of the paucity of available treatment options for men with PE, new oral treatments 
with different modes of action and different benefit/risk profiles are needed. 
1.2 
Study Drug 
IX-01 is a small molecule being developed for the treatment of PE. 
IX-01 is a potent, competitive antagonist, which is highly selective for the oxytocin receptor, 
and exhibits little interaction with the vasopressin receptor family. The chemical name is 
5-{3-[3-(2-chloro-4-fluorophenoxy)azetidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-
yl}-2-methoxypyridine. IX-01 is a white-to-pale colored solid. 


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A caplet dosage form of IX-01 has been developed for oral dosing and use in clinical studies. 
The caplet strength is 400 mg, and the caplet is formulated per Good Manufacturing Practice 
(GMP) guidelines. Further information on the formulation is provided in the Investigator’s 
Brochure. 
1.3 
Preclinical Experience 
Detailed information regarding the nonclinical pharmacology and toxicology of IX-01 may 
be found in the Investigator’s Brochure. 
1.3.1 
Nonclinical Pharmacology 
In Vitro Pharmacology 
IX-01 is a potent, competitive antagonist, which is highly selective for the oxytocin receptor, 
and exhibits little interaction with the vasopressin receptor family. Its potency is similar for 
human and rat oxytocin receptors. The functional inhibition constants (KB) for the human and 
rat native uterine smooth muscle oxytocin receptors are 5.7 nM and 8.9 nM, respectively. 
IX-01 has little activity against the human recombinant V1B receptor, with an IC50 >10 µM 
for the receptor-binding assay. It is equally inactive against the V2 receptor in the V2 receptor 
β-lactamase reporting assay (agonist format: EC50 >10 µM; antagonist format: IC50 >1 µM). 
The compound is more than 100-fold selective against the V1A receptor in either native or 
recombinant human oxytocin receptor assays and > 85-fold selective over the V1A receptor in 
rat native assays. 
In Vivo Pharmacology 
IX-01 has been evaluated in 2 in vivo pharmacological models. In the anesthetized rat 
electromyography model of ejaculation, IX-01 interrupted the expulsion phase of ejaculation. 
In the anesthetized rat central nervous system (CNS) neuronal firing model, IX-01 
demonstrated CNS penetration and modulation of an oxytocin-mediated response in the 
nucleus tractus solitarius. 


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1.3.2 
Safety Pharmacology 
The biochemical activity of IX-01 was screened in different assays for enzymes, receptors, 
and transporters. Activities were observed in 3 of 60 for the receptors, channels, and 
transporters tested. There was no activity detected in enzyme assays. 
In isolated dog Purkinje fibers, dose-dependent reductions in action potential duration at 50% 
and 90% repolarization occurred at IX-01 concentrations of 10 and 30 µM. IX-01 also 
reduced peak hERG potassium current amplitude at high concentration. It was devoid of any 
biologically relevant hemodynamic or electrocardiogram (ECG) effects in conscious dogs up 
to the dose of 20 mg/kg (total Cmax of 9007 nM). 
IX-01 does not affect respiratory function in male rats up to doses of 150 mg/kg. The only 
effects were a small reduction in respiratory rate and a nonstatistically significant decrease in 
minute volume at 450 mg/kg. 
IX-01 had no adverse effects on neurofunctional assessment in male rats. 
IX-01 at dose levels up to 20 mg/kg (Cmax 9007.5 nM, 3780 ng/mL) does not adversely affect 
cardiovascular function in conscious male dogs. 
1.3.3 
Toxicology 
Administration of IX-01 to male rats and male dogs were performed per Good Laboratory 
Practice. 
In the toxicology program, IX-01 was orally administered to male rats and dogs for up to 
90 days. Adaptive changes related to liver enzyme induction were noted in the liver as well 
as in the thyroid and pituitary. Deaths observed at doses ≥750 mg/kg in the 1-month studies 
and exploratory rat studies were likely due to hypothermia. In addition to low core body 
temperature, these deaths were preceded by clinical signs such as decreased blood pressure, 
decreased respiration rate, and neurological signs in the animals. At 200 mg/kg of IX-01, 
dogs exhibited potential neurological signs consisting of titubation, prostration, whining, 
partially closed eyes, tremors, and occasional diarrhea. The no observed adverse effect levels 
(NOAELs) with repeated administration were 450 mg/kg in rats and 120 mg/kg in dogs. The 
corresponding Cmax and AUC values in rats were 10 100 ng/mL (525 ng/mL free) and 


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140 000 ng × h/mL (7280 ng × h/mL free), respectively, and in dogs were 52 900 ng/mL 
(5660 ng/mL free) and 778 000 ng × h/mL (83 246 ng × h/mL free), respectively. The 
NOAEL is based on adverse clinical effects apparently associated with the CNS observed at 
higher doses.  
IX-01 was negative in genetic toxicology testing and presented no phototoxic potential in 
vitro. 
1.3.4 
Pharmacokinetics and Product Metabolism in Animals 
Pharmacokinetic studies were done in rats and dogs, and in vitro. It was found that 87.4% to 
94.8% of IX-01 was bound to rat, dog, and human and dog plasma proteins in vitro. IX-01 
penetrated the CNS. Clearance predominantly occurred through cytochrome P450 (CYP) 
3A4 metabolism, with minor contributions from CYP2C19, CYP2D6, and glucuronidation. 
The overall potency of IX-01 as an inhibitor of CYP metabolism is weak; however, CYP3A4 
inhibitors or inducers may alter the pharmacokinetics of IX-01. 
1.3.5 
Clinical Data 
To date, 162 male subjects have received one or more doses of IX-01. Clinical safety and 
pharmacokinetic data are available from four completed Phase 1 studies (A8651001, 
IX-0101, IX-0102, and IX-0104). Also, preliminary clinical safety and kinetic data are 
available from recently completed study IX-0106. A Phase 2a proof-of-concept study (IX-
0103) has also been completed and demonstrated the efficacy of IX-01 (doses 400 to 800 mg 
as needed) to prolong 
IELT, improve ejaculation-related control, and reduce 
ejaculation-related distress in men with lifelong PE. 
Single-Ascending Dose Study 
The first-in-human study (A8651001) recruited 30 healthy male volunteers in 3 sequential 
cohorts and evaluated 11 different dose levels of IX-01 ranging from 0.3 mg to 2400 mg. The 
overall incidence of adverse events (AEs) was similar across all treatment groups, including 
placebo. The most common treatment-emergent adverse events (TEAEs) were 
nasopharyngitis, headache, insomnia, and nightmares. The most frequent treatment-related 
AE was headache. All of the AEs were considered mild to moderate in severity. Three 
subjects who had received IX-01 and one subject who had received placebo reported events 


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of nightmare after dosing. These events were single episodes with the exception of one 
subject who reported 3 episodes of nightmare after 2 different doses of IX-01 (one episode 
while receiving 400 mg and 2 episodes while receiving 800 mg). All events of nightmare 
were mild in intensity. 
There was no evidence of a drug- or dose-related effect on laboratory test results, and there 
were no clinically significant changes in vital signs or ECGs. One subject in Cohort 2 
discontinued from the study due to mild, asymptomatic, non-sustained ventricular 
tachycardia (IX-01, 400 mg) that appeared approximately 7 hours post-dose and lasted only 3 
seconds. Although it is impossible to completely exclude a relationship to the study drug, the 
short episode resolved without requiring any treatment and was not accompanied by 
symptoms or hemodynamic changes. 
There was no effect of IX-01 on core body temperature at any dose studied. The mean 
maximum exposure reached (1.9 μg/mL total, 452 nM total) was similar to that which 
resulted in mild hypothermia in rats (1-10 μg/mL; 238-2380 nM total). 
Peak plasma concentrations (Tmax) of IX-01 occurred approximately 1 to 2 hours after oral 
dosing. Overall, exposure (AUC) increased subproportionally with dose. The terminal 
half-life was approximately 12 hours. Under fed conditions (800 mg), both peak 
concentration and overall exposure were increased (1.8-fold and 1.3-fold, respectively). 
Urinary excretion of intact drug was negligible, with < 0.05% of the dose excreted over 24 
hours after dosing. 
Multiple-Ascending Dose Study (1) 
The multiple-ascending dose study (IX-0101) recruited 48 volunteers in 4 cohorts of 
12 subjects each. Within each cohort, subjects were randomized (1:3) to receive placebo or 
IX-01 in the fasted state once daily for 10 consecutive days. The final cohort received the 
maximum dose (1200 mg daily) permitted by the protocol. The protocol required monitoring 
of vital signs and the recording of 12-lead ECGs at frequent intervals postdose on Days 1 and 
10 and predose on Days 1, 5, 8, and 10. Continuous Holter ECG monitoring was performed 
on all subjects from 2 hours predose to 8 hours postdose on Days 1 and 10. In addition, aural 
temperature was recorded at frequent intervals postdose on Days 1 and 10, and predose and 
12 hours postdose on Days 2 to 9. 


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All 48 subjects completed the study, and there were no serious adverse events (SAEs) and no 
severe AEs. There was no evidence of any treatment-related changes in aural temperature at 
any of the doses administered. The mean maximum plasma concentration of IX-01 reached 
in this study (2.2 μg/mL total at Cmax on Day 10 in the 1200 mg dose group) was higher than 
the mean maximum exposure achieved with a single 2400 mg dose of IX-01 in 
Study A8651001, and thus, the clinical safety data provide further evidence that hypothermia 
observed in some rat studies does not translate to a similar finding in human. 
The overall number of AEs reports was low with no clear evidence of a dose-related increase 
in incidence. No particular AE occurred in more than one subject per treatment group apart 
from headache (2 of 9 subjects receiving 1200 mg IX-01). Two subjects (one receiving 
placebo and one receiving 800 mg IX-01) reported intermittent vivid dreams (coded as 
abnormal dreams) throughout most of the dosing phase of the study. There were no reports of 
nightmares. 
There were no clinically significant changes in vital signs, 12-lead ECGs, or ECG monitoring 
by telemetry reported by the investigator for any of the subjects in any of the dose groups. 
The Day 10 pharmacokinetic profiles were similar to those observed on Day 1. IX-01 was 
rapidly absorbed, reaching Cmax at approximately 1.5 hours (Tmax) postdose (range 
0.5-4 hours) across the dose range. Post-Cmax, plasma concentrations declined in a biphasic 
manner. The terminal half-life (t1/2) was similar across all dose groups, with mean estimates 
of 11.6 to 12.3 hours. The geometric mean (GM) steady-state Cmax values increased 
subproportionally compared with dose, with a 6.2-fold increase over a 12-fold dose range. 
Accumulation ratios (Cmax and AUC0-24h values on Day 10/Day 1) were 1.24 and 1.34, 
respectively, for the 1200 mg dose. 
Semen samples were collected from all subjects at 2 to 4 hours postdose on Day 9, and the 
concentrations of drug were subsequently measured. The mean amount of IX-01 in the 
ejaculate (2 μg or less) constituted <0.0003% of the administered dose, and as such, the 
intravaginal dose to the partner of a subject taking IX-01 is negligible. 


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Multiple-Ascending Dose Study (2) 
A maximally tolerated dose was not identified in Study IX-0101, and therefore, a second 
multiple-ascending doses study (IX-0104) was performed. This study recruited 24 volunteers 
in 2 cohorts of 12 subjects each. Within each cohort, subjects were randomized (1:2) to 
receive placebo or IX-01 in the fasted state once daily for 10 consecutive days. The final 
cohort received the maximum dose (2400 mg daily) permitted by the protocol. The protocol 
required monitoring of vital signs and the recording of 12-lead ECGs at frequent intervals 
postdose on Days 1 and 10 and predose on Days, 1, 5, 8, and 10. Continuous Holter ECG 
monitoring was performed on subjects from 2 hours predose to 8 hours postdose on Days 1 
and 10. In addition, aural temperature was recorded at frequent intervals postdose on Days 1 
and 10, and predose and 12 hours postdose on Days 2 to 9. 
Both cohorts of Study IX-0104 completed with no SAEs and no severe AEs reported. In 
Cohort 1, there were 2 AEs that were considered possibly related to treatment by the 
investigator. One subject in the placebo group reported headache of moderate severity on 
Day 1. It lasted for 4 hours and required treatment with paracetamol but fully resolved. 
Another subject who received 1600 mg IX-01 reported pruritic rash of moderate severity on 
Day 8. Dosing with study drug was discontinued, and the subject was given one application 
of antihistamine ointment. The AE was fully resolved at follow-up. In Cohort 2, there was 
only one AE reported and was for a subject who received 2400 mg IX-01 and was noted to 
have urticaria of moderate severity starting approximately one hour after dosing on Day 1. 
Dosing was discontinued in this subject as a precaution, but the urticaria had fully resolved 
without treatment less than 3 hours after first being noted. There were no clinically 
significant changes in vital signs, 12-lead ECGs, or ECG monitoring by telemetry reported 
by the investigator for any of the subjects in any of the dose groups.  
IX-01 was rapidly absorbed, reaching Cmax at approximately 2 hours (Tmax) postdose. The 
GM Cmax values on Day 1 were 1883 and 2622 ng/mL for the 1600 mg and 2400 mg 
treatment groups, respectively. The GM AUCtau values on Day 1 were 14 953 and 
25 926 h × ng/mL for the 1600 mg and 2400 mg treatment groups, respectively.  
The Day 10 pharmacokinetic profiles were similar to those observed on Day 1. IX-01 was 
rapidly absorbed, reaching Cmax at approximately 2 hours (Tmax) postdose (range 1.5 to 


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4 hours) across the dose range. The GM Cmax values on Day 10 were 2552 and 2516 ng/mL 
for the 1600 mg and 2400 mg treatment groups, respectively. The GM AUCtau values on 
Day 10 were 28 623 and 27 862 h × ng/mL for the 1600 mg and 2400 mg treatment groups, 
respectively.  
The terminal half-life (t1/2) was similar in both dose groups, with mean estimates of 11.6 to 
11.7 hours. This study confirmed subproportional increases in the absorption of IX-01 when 
administered as a dispersion in the fasted state.  
Relative Bioavailability Study (200mg capsules) 
In Study IX-0102, 12 subjects were randomized to receive IX-01 800 mg dispersion in the 
fasted state, IX-01 800 mg (4 × 200 mg capsules) in the fasted state, and IX-01 800 mg 
(4 × 200 mg capsules) administered after a high-fat meal. 
The bioavailability of the capsule formulation was similar to that of the dispersion 
formulation when both are administered in the fasted state. Administration of a high-fat meal 
immediately prior to the capsules increased the bioavailability of IX-01. 
In this study, the subjects also underwent lumbar puncture 1 to 6 hours after receiving the 
dispersion formulation. The results confirmed that IX-01 is present in the cerebrospinal fluid; 
CNS penetration of IX-01 is important for the potential to treat PE. 
Relative Bioavailability Study (400mg caplets) 
In Study IX-0106, 12 subjects were randomized to receive IX-01 1600 mg dispersion in the 
fasted state, IX-01 1600 mg (4 × 400 mg caplets) in the fasted state, and IX-01 1600 mg 
(4 × 400 mg caplets) administered after a high-fat meal. 
The preliminary results indicate that the GM Cmax values were 2152 ng/ml for the caplet 
formulation administered in the fasted state, and that the caplet has an improved 
bioavailability compared to the dispersion, with GM Cmax and AUC 1.8 fold those of the 
dispersion. In addition, food increased the bioavailability (AUC) of the caplet (1.5 fold), 
which is comparable to the effect of food seen with the capsule and dispersion formulations 
previously. However, unlike the capsule and dispersion formulations, the rate of absorption 
was not significantly delayed for the caplet formulation with Cmax increasing 2.7 fold in the 


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presence of food. There were no treatment-related adverse events or safety issues reported in 
this study. 
Proof-of-Concept Study 
IX-0103 was an 8-week, double-blind, placebo-controlled, Phase 2a clinical study that 
recruited 88 men with lifelong PE at 10 study centers in the United States and Australia. 
Eligible patients (men fulfilling the ISSM definition of lifelong PE with ≥75% of 
intercourses lasting ≤60 seconds during a 4-week run-in period without treatment) were 
randomized (2:1 ratio) to an 8-week treatment period with IX-01, 400  mg (2 capsules), or 
equivalent double-blind placebo, with the medication being taken as required, 1 to 6 hours 
prior to sexual activity. If treatment was poorly tolerated, the dose could be reduced to 200 
mg or equivalent placebo. From Week 2 onwards, the investigator could increase the dose to 
800 mg or equivalent placebo (4 capsules) if toleration was acceptable and optimal efficacy 
had not been obtained.  
During the treatment period, patients were required to return to the study site at Weeks 2, 4, 
and 8 and use their electronic diary (LogPad) to complete the Premature Ejaculation Profile 
(PEP) and other patient-reported outcomes. A follow-up visit was to be performed 2 weeks 
after the end of treatment. 
The mean age of men in this study was 43 years, and the baseline GM IELT was <30 seconds 
in both treatment groups. Patients randomized to IX-01 took a mean of 14.6 (range 1-59) 
doses during the study. Patients randomized to placebo took a mean of 13.0 (range 1-51) 
doses. Fifty (89.3%) and 23 (76.7%) patients (IX-01 and placebo, respectively) took the 
permitted maximum dose of 4 capsules at least once during the study. 
Mean IELT values increased 3.6-fold from baseline for IX-01, compared with 1.8-fold for 
placebo. Mean IELT values increased by over 1 minute (61.0 seconds) for IX-01 compared 
with 16.4 seconds for placebo. The results also showed clinically and statistically significant 
improvements in perceived control of ejaculation and ejaculation-related personal distress at 
end of treatment for IX-01 compared with placebo. Twenty-one (44%) patients randomized 
to IX-01 rated their PE as improved at the end of treatment compared with 3 (13%) of 
patients randomized to placebo. There were also clinically and statistically significant 


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improvements for some of the results of the 4-week recall PEP, with 17 (33%) patients 
randomized to IX-01 improving their control of ejaculation to “fair,” “good,” or “very good” 
compared with one (3%) patient randomized to placebo. There was also a clinically and 
statistically significant difference in favor of IX-01 for the proportion of patients whose level 
of ejaculation-related distress improved to “moderate,” “a bit,” or “not at all,” 24 (46%) for 
patients randomized to IX-01 versus 4 (16%) for patients randomized to for placebo. 
There were no serious and no severe AEs reported during this study. The proportions of 
patients reporting AEs were similar for IX-01 and placebo, with no AE reported by more than 
2 patients in any treatment group. Two patients were discontinued from IX-01 for possibly 
treatment-related AEs: one for AE of increased transaminases that normalized during 
treatment and one for AE of nausea. There were no safety signals arising from review of vital 
signs, laboratory function test results, 12-lead ECGs, and other safety assessments. 
This study has demonstrated the ability of IX-01 (taken as required prior to sexual activity) to 
improve all the 3 key features (short ejaculation time, lack of control, and ejaculation-related 
distress) of the condition in men with most severe form of lifelong PE. IX-01 was effective 
while maintaining a toleration and safety profile indistinguishable from placebo in this study. 
Post hoc exploratory analyses indicated that the 800 mg dose was more effective than the 
initial 400 mg dose, and thus, there is likely to be potential for increased efficacy when larger 
doses are administered in future studies. 
1.4 
Study Rationale 
IX-01 is a CNS-penetrant, selective oxytocin receptor antagonist that has shown to be 
effective in treating men with lifelong PE when doses of 400 to 800 mg have been 
administered prior to intercourse. The present study is to determine the efficacy and safety of 
3 different dose levels (administered as required prior to intercourse) of IX-01 to prolong 
IELT in patients with lifelong PE. The design of the study including the choice of efficacy 
instruments is consistent with the latest recommendations by experts in PE.13 
1.4.1 
Rationale for Dose Selection 
The results of study IX-0103 indicated that single doses of IX-01 (400 to 800 mg 
administered as capsules), taken 1 to 6 hours prior to intercourse in the fasted state, prolong 


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IELT and improve ejaculation-related control and distress. A post hoc analysis indicated that 
400 mg is less effective than the 800 mg dose. However, even at 800 mg, less than half of the 
patients reported benefit, and therefore, the objective of this study is to explore the efficacy 
and safety of 1200 mg (3 x 400 mg caplets) and to compare the response at this dose with 
placebo, 400 mg, and 800 mg doses. In the previous efficacy study, doses of 400 to 800 mg 
were taken one hour before or after food and 1 to 6 hours prior to sexual activity. In this 
study, it is also recommended to take the study drug at least one hour before or after food, 
and 1 to 6 hours prior to sexual activity. A 400 mg caplet formulation has been developed to 
improve bioavailability and to allow a reduced number of caplets to be taken per dose of IX-
01. 
1.5 
Potential Risks and Benefits 
The nonclinical toxicology, pharmacology, and pharmacokinetic data generated to date and 
the clinical safety, pharmacokinetic, and pharmacodynamic data generated in studies 
A8651001 and IX-0101 to IX-0104 support an acceptable risk-benefit profile to evaluate the 
efficacy and toleration of single doses of orally administered IX-01 (taken as required but not 
more than once per day) in adult males, aged 18 to 60 years, inclusive, with PE. The 
maximum dose to be administered in this study is 1200 mg (3 x 400 mg caplets) taken prior 
to sexual activity but not more than once per day. Doses up to and including 2400 mg 
administered as a dispersion and taken in the fasted state once daily for 10 consecutive days 
have been well tolerated by healthy volunteers. Small reductions in mean systolic and 
diastolic blood pressure between active and placebo groups were not of clinical significance. 
Two subjects have been discontinued from IX-01 because of skin AEs: a subject who had a 
pruritic skin rash after 8 days of consecutive dosing with 1600 mg, and a subject with 
transient urticaria after a single dose of 2400 mg. In Study IX-0106 twelve subjects have 
received 1600mg administered as 4 x 400 caplets in fasted state and 11 subjects also received 
4 x 400 mg caplets after a high fat meal.  No treatment-related adverse events were observed. 
As in the previous Phase 2 study, the safety of the patients will be assessed at frequent 
intervals by physical examination and laboratory safety tests. Although preclinical and 
clinical data generated to date with IX-01 provide no evidence of adverse effects on mood, 
this protocol includes questionnaires and interviews to screen for depression and suicidality, 
which is in accordance with other clinical studies of new treatments for PE. 


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Formal teratology and reproductive studies have not been performed with IX-01. The amount 
of IX-01 in human ejaculate has been measured and is <0.0003% of the administered dose. 
This study will only recruit patients who are not attempting to father a child. 


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2 
Study Objectives 
2.1 
Primary Objective 
The primary objective of this study is to determine the efficacy of three different dose levels 
of IX-01 to prolong IELT in men with lifelong PE. 
2.2 
Secondary Objectives 
• To determine the efficacy of three different dose levels of IX-01 on Clinical Global 
Impression of Change (CGIC), control of ejaculation, ejaculation-related distress and 
interpersonal difficulty, and satisfaction with sexual intercourse in men with PE. 
• To determine the toleration and safety of three different dose levels of IX-01 taken as 
required in men with PE. 


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3 
Investigational Plan 
3.1 
Study Design 
The design of this study is illustrated in Figure 3-1. This will be a randomized, double-blind, 
placebo-controlled study in men with lifelong PE to determine the efficacy, safety, and 
tolerability of three different dose levels of IX-01 compared with placebo. The study will be 
performed in multiple centers in the United States. The patient population will consist of 
male adults aged 18 to 60 years in stable heterosexual relationship and who have lifelong PE. 
A target of 220 patients with IELT ≤1 minute on ≥ 75% of attempts at intercourse during the 
no-treatment run-in period will be randomized. 
Figure 3-1 
Study Design 
For patients who are receiving regular selective serotonin reuptake inhibitors only 
 
 
 
 
 
 
 
 
 
 
Screening (Visit 1) will occur approximately 4 weeks before dosing (Visit 2). During 
screening, patients will undergo the measurements and examinations detailed in the Schedule 
of Events (Table 13-1). Eligible patients will be provided with a LogPad (electronic diary) 
and stopwatch. Patients will be asked to attempt sexual intercourse at least 4 times during the 
4-week run-in period. 
Washout 
IX-01 400 mg 
Week 10 
Visit 6 
Follow-Up 
Week 8 
Visit 5 or 
Early Termination 
Week 4 
Visit 4 
Week 2 
Visit 3 
Week 0 
Visit 2 
Baseline 
Week -4 
Visit 1 
Screening 
Week -8 
Prescreening  
Optional 
Screening 
Placebo 
Follow-Up 
IX-01 1200 mg 
IX-01 800 mg 


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Note: Patients taking chronic SSRIs for the treatment of PE must have an additional 4-week 
washout prior to the 4-week run in period. Patients taking CYP3A4 inducers or moderate and 
potent CYP3A4 inhibitors must be excluded from the study or stop and refrain from their use 
at Visit 1. 
At the end of the run-in period, patients will undergo their baseline measurements and 
examinations detailed in the Schedule of Events (Table 13-1), which includes a PEP, 
International Index of Erectile Function (IIEF), Patient Health Questionnaire 9 (PHQ-9), and 
mandatory Columbia-Suicide Severity Rating Scale (C-SSRS) assessment. The patient’s 
LogPad is used for completing the questionnaires and providing results to the Investigator 
regarding the eligibility of the patient, based on IELT and patient-reported outcome criteria. 
The C-SSRS is a face-to-face interview that must be administered by the Investigator or 
his/her designate. If the patient does not meet eligibility to remain in the study, the 
Investigator must not randomize the patient and may suggest alternate treatment. 
Eligible patients will undergo one 8-week treatment period, during which time they are 
randomized to take IX-01, 400, 800, or 1200 mg or matching placebo. In order to maintain 
the double-blind, each dose will be presented as 3 caplets in blisters in single-dose units. 
Thus, for example, a patient randomized to 400 mg IX-01 will receive blister cards with each 
dose comprising one IX-01 400 mg caplet and two matching placebo caplets. Patients will 
complete an e-diary (LogPad) on all days during the treatment period that sexual activity is 
performed with or without the use of the study drug. 
During the treatment period, patients will be expected to return to the study site and use their 
LogPad to complete the following questionnaires according to the study schedule: 
• Premature Ejaculation Profile (PEP) 
• International Index of Erectile Function (IIEF) 
• Patient Health Questionnaire (PHQ-9) 
• Patient Global Impression of Severity (PGIS) 
• Clinical  Global Impression of Change (CGIC) – Early Termination/Visit 5 only 


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The LogPad will provide results to the Investigator regarding whether or not the patient is 
required to complete the C-SSRS. The C-SSRS is mandatory at baseline, and is only 
mandatory at all other visits if the PHQ-9 total score is >9, and/or the PHQ-9 Question 9 
score is > 0; it may also be administered at any time if clinically indicated, in the opinion of 
the Investigator. A final follow-up visit is conducted 2 weeks after the end of double-blind 
treatment. For more details of the procedures at each study visit, please refer to Section 6. 


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4 
Patient Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
4.1.1 
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Men aged ≥18 years and ≤60 years in stable (≥6 months) heterosexual relationship and 
who have lifelong PE. 
2. Premature ejaculation confirmed by IELT ≤1 minute on ≥75% attempts at sexual 
intercourse during the run-in period. 
3. Patient meets other aspects of ISSM definition including inability to delay ejaculation on 
all or nearly all vaginal penetrations and negative personal consequences such as distress, 
bother, and frustration. 
4. Patient and partner willing to attempt intercourse at least 4 times during the run-in period 
and at least 8 additional times during the double-blind part of the study. 
5. Partner not planning pregnancy and willing to use contraception (unless not of 
childbearing potential, eg, surgically sterilized). 
6. Patient willing to limit use of alcohol on days in which he takes study drug (not more 
than 3 standard drinks as defined in the Informed Consent Form). 
7. Patient capable of giving written informed consent. 
4.1.2 
Exclusion Criteria 
1. Any IELT value >2 minutes during the run-in period. 
2. Any patient making <4 attempts at sexual intercourse during the run-in period (screening 
may be extended or patient may be rescreened if there are extenuating circumstances). 
3. Any patient who rates his control of ejaculation as fair, good, or very good (PEP question 
administered at the end of the run-in period). 
4. Any patient who rates his ejaculation-related “personal distress” as “not at all” or “a little 
bit” (PEP question administered at the end of run-in period).  


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5. Coexisting Erectile Dysfunction (IIEF Erectile Function domain <22 during the run-in 
period). 
6. Concomitant use of phosphodiesterase type 5 (PDE5) inhibitors, SSRIs/selective 
serotonin norepinephrine reuptake inhibitor (SSNRIs), monoamine oxidase inhibitors, 
alpha blockers, 5-alpha reductase inhibitors, topical anesthetics, and/or tramadol. 
7. Any history (last 6 months) of use of Botox or similar product to treat PE. 
8. Any patient who has received IX-01 in a previous clinical study. 
9. Any patient who is unwilling to stop other treatments for PE (including but not limited to 
pharmacological, sex therapy, psychotherapy multiple condoms, and prior masturbation). 
10. Any other sexual disorder of patient or partner that could interfere with results. 
11. Any current sexually transmitted disease. 
12. Any major medical condition of patient that could interfere with ability to have sexual 
activity and/or require hospital treatment. 
13. Body mass index (BMI) >40 kg/m2 or weight <60 kg. 
14. Participation in a clinical drug study anytime during the 30 days prior to screening. 
15. History of or positive test results for Human immunodeficiency virus (HIV), hepatitis B. 
16. History of prostate disease or clinically significant prostate disease. 
17. History of myocardial infarction, coronary bypass surgery, coronary artery angioplasty, 
unstable angina, clinically evident congestive heart failure, cardiac pacemaker, or 
cerebrovascular accident. 
18. Cardiac arrhythmia: significant cardiac arrhythmia shown on screening ECG, or a known 
or suspected history of significant cardiac arrhythmias. 
19. History of drug-induced allergic reactions including skin reactions. 
20. History of congenital QT prolongation and/or corrected QT interval >450 msec at 
screening visit using the Bazett formula. 
21. Mean systolic cuff blood pressure >140 mm Hg, as assessed by 3 measurements taken in 
sequence within 5 to 10 minutes of last measure.  


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22. Mean diastolic cuff blood pressure >90 mm Hg, as assessed by 3 measurements taken in 
sequence within 5 to 10 minutes of the last measure.  
23. Significant psychiatric disease and/or risk of suicidal tendency as assessed by clinical 
evaluation and PHQ-9 and C-SSRS. 
• 
PHQ-9 total score >9 and/or score of >0 on Question 9 of PHQ-9 would be 
exclusion criterion. 
24. Any other major medical or psychological or psychiatric condition that could cause the 
patient to be unsuitable for the study or could interfere with interpretation of the study 
results. 
25. Clinically significant abnormal laboratory function test results (including liver enzymes 
>2 × the upper limit of normal [ULN] or bilirubin >1.5 × ULN). 
26. Patients taking CYP3A4 inducers, or moderate and potent CYP3A4 inhibitors. 
27. History of or other evidence of recent alcohol or drug abuse. 
4.2 
Withdrawal of Patients From the Study 
Patients will be discontinued from the investigational product and/or from the study in the 
following circumstances: 
1. Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study. 
2. The patient requests to be discontinued from the study. 
3. Sponsor decision to stop the study or to stop the patient’s participation in the study for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and Good Clinical Practice (GCP). 
4. If a clinically significant event occurs that is considered related to the study drug, then the 
investigational product is to be discontinued and appropriate measures taken. A clinically 
significant event will be defined as a moderate to severe AE (eg, rash), abnormal clinical 
sign, or clinical laboratory finding that may pose a risk to the well-being of the patient. 


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5. The results of the PHQ-9 and C-SSRS indicate a change in mental condition and a risk to 
the patient by continuing in the study. (see Section 13.2) 
6. Certain laboratory test criteria are fulfilled: 
a. Discontinuation of the investigational product for abnormal liver tests must occur 
when a patient meets one of the following conditions after consultation with the 
designated medical monitor:  
i. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × 
ULN 
ii. ALT or AST >5 × ULN for more than 2 weeks 
iii. ALT or AST >3 × ULN and total bilirubin level >2 × ULN or prothrombin 
time >1.5 × ULN 
iv. ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%) 
1. Liver function tests should be repeated if ALT and or AST 
>3 × ULN and/or bilirubin >1.5 × ULN (or 1.5 × baseline value if 
baseline value was >ULN) 
The nature of any conditions, clinical signs or symptoms, or abnormal laboratory values 
present at the time of discontinuation and any applicable follow-up procedures will be 
documented. Patients who are discontinued early from the study should complete the Early 
Termination visit (see Section 6.1). Every effort will be made to follow up all patients for 
safety. 
Study site participation may be discontinued if the sponsor or its designee, the Investigator, 
or the Institutional Review Board (IRB) of the study site judges it necessary for any reason 
consistent with applicable laws, regulations, and GCP. 


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5 
Study Treatments 
5.1 
Method of Assigning Patients to Treatment Groups 
The study will be conducted in a double-blind manner using a placebo matching the active 
drug in appearance, labelling, and packaging. Randomization numbers will be assigned 
according to the randomization schedule that contains patient identification numbers with a 
corresponding assignment of active drug or placebo. Assignment of study medication as well 
as site investigational product inventory control and emergency unblinding will be managed 
by an automated system (Interactive Web Response System). 
The randomization ratio of the target 220 patients is 2:2:3:3 (0, 400, 800, 1200 mg dose 
groups). Thus, 44 patients will each to be randomized to placebo and IX-01 400 mg dose 
groups, and 66 patients will each to be randomized to IX-01 800 mg and 1200 mg dose 
groups. The sponsor retains the option to replace any patients who drop out without any 
postbaseline efficacy data. 
5.2 
Treatments Administered 
Study drug will be supplied as 400 mg caplets (IX-01 or matching placebo), and treatment 
allocation will be composed of 4 dosage groups (placebo, IX-01 400 mg, IX-01 800 mg, and 
IX-01 1200 mg). One dose is 3 caplets (placebo and/or IX-01, depending on the dosage) to 
be taken orally at least one hour before or after food, 1 to 6 hours before sexual activity, but 
not more than once per day. 
5.3 
Management of Clinical Supplies 
5.3.1 
Study Drug Packaging and Storage 
In order to preserve the blind, each dose will be supplied in a blister card containing 3 caplets 
(which will comprise placebo and/or IX-01, depending on the treatment group assigned). 
Seven single-dose cards will then be packed into a tamper sealed carton, in line with the visit 
schedules. Supplies will be shipped at ambient temperature with temperature-monitoring 
devices (TempTale®). On arrival, the site will check if the temperature-monitoring device has 
alarmed; if not, the supplies are approved for use. If the alarm has been triggered following a 
temperature excursion, supplies will be placed in quarantine while the TempTale® data are 


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returned and reviewed by Ixchelsis or delegate. The site will then be informed if the 
excursion warrants the supplies being destroyed and/or replaced or if they are cleared for use. 
All supplies will be packed, labelled, and released in accordance with GMP and GCP 
guidelines. The investigator, or an approved representative (eg, pharmacist), will ensure that 
all investigational product is stored in a secure area, under recommended storage conditions 
59°F-86°F (15°C-30°C) and in accordance with applicable regulatory requirements. Any 
excursions from the recommended storage conditions should be reported to the sponsor 
within 24 hours of the finding. 
5.3.2 
Test Article Accountability 
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product. 
Unless otherwise notified, all investigational product both used and unused must be saved for 
study treatment accountability. The investigational product accountability records must be 
available for verification by the study monitor at each monitoring visit. At the completion of 
the study, a final reconciliation of all investigational product will be performed and Ixchelsis 
will provide instructions regarding the disposition of any unused investigational product. If 
Ixchelsis authorizes destruction at the study site, the investigator must ensure that the 
materials are destroyed in compliance with applicable environmental regulations, 
institutional policies, and any special instructions provided by Ixchelsis including written 
confirmation that the supplies can be destroyed. Destruction must be adequately documented 
and the documentation provided to Ixchelsis. 
5.3.3 
Product Complaints and Medication Errors 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify or suspect a potential product complaint should immediately contact Ixchelsis or 
designee and report the event. Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from an 
Ixchelsis or a designated quality representative. 


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The Investigator or his/her designee is responsible for handling the product complaint 
process in accordance with the instructions provided for this study in the Study Training 
Manual. 
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or medication error results in an SAE, an SAE form should be completed and sent 
to Ixchelsis or designee. 
5.4 
Blinding 
5.4.1 
Breaking the Blind 
All study medication will be administered in a double-blind manner. Only in the case of an 
emergency, when knowledge of the investigational product is essential for the clinical 
management or welfare of the patient, the Investigator may unblind a patient’s treatment 
assignment. If the blind is broken for any reason, the Investigator must notify the Sponsor or 
designee immediately after the unblinding incident without revealing the patient’s study 
treatment assignment. In addition, the Investigator will record the date and reason for 
revealing the blinded treatment assignment for that patient in the electronic case report form 
(eCRF). 
5.5 
Treatment Compliance 
There is no requirement for the patient to take medication every day. However, he should 
only take a maximum of one dose (3 caplets) per day and record this in the LogPad. The 
Investigator should record the amounts of study drug dispensed and returned at each visit 
during the treatment period. The patient should always take the 3 caplets from the same 
blister card with each dose. He should never take more or less than these 3 caplets per dose.  
5.6 
Prior and Concomitant Therapy 
Use of SSRIs must be stopped, and patients who were previously taking SSRIs regularly 
require an additional 4-week washout prior to the 4-week run-in period. Patients who require 
SSRI treatment for depression or other illnesses (not PE) should not be included in the study.  


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Concomitant treatment with PDE5 inhibitor (eg, sildenafil, tadalafil, vardenafil), topical 
anesthetics, and/or tramadol is prohibited. Additionally, any history (current or last 6 months) 
of use of Botox or similar product to treat PE is not allowed. 
The following treatments are also prohibited during the study: monoamine oxidase inhibitors, 
alpha blockers, 5-alpha reductase inhibitors (including finasteride [Propecia] for hair loss). 
Herbal supplements are also prohibited. 
Concomitant use of potent or moderate CYP3A4 inhibitors (eg, ketoconazole, itraconazole, 
ritonavir) and inducers (eg, bosentan, carbamazepine, phenytoin, phenobarbital, St John’s 
Wort, and rifamipicin) is not allowed from at least 4 weeks before the start of dosing until the 
end of the study. 


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6 
Study Assessments and Procedures 
6.1 
Study Visits 
A complete listing of study measurements and evaluations may be found in the Schedule of 
Events (Table 13-1). 
Screening Visit 1 
Approximately 28 days (±3 days) prior to the first dosing, patients will attend the center for 
assessment of eligibility for the study. Written informed consent must be obtained from each 
potentially eligible patient by study site personnel prior to the initiation of screening 
procedures as outlined in this protocol. 
Note: Patients taking chronic SSRIs for the treatment of PE must have an additional 4-week 
washout prior to the 4-week run-in period. 
After providing signed written informed consent, patients will complete screening 
assessments. Each patient who undergoes screening for study enrollment will be assigned an 
identification number, which will provide a means of identifying each patient. Information 
and data collected will include the following: 
• Assessment of patient eligibility according to the entry criteria, including clinical 
interview by the Investigator or his/her qualified designee to indicate that the patient 
meets the ISSM definition of PE. In particular, the investigator should ask the patient 
about the duration of the symptoms of PE, since lifelong PE can only be diagnosed if 
ejaculation always or nearly always occurred prior to or within about 1 minute of vaginal 
penetration from the earliest sexual experience. 
• Medical history and assessment of concomitant medication. 
• Year and month of birth, gender at birth, and race (ethnicity). 
• Height, weight and physical examination. A physical examination will be conducted by 
the Investigator or other licensed study site personnel to establish an overall profile of the 


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patient’s health and to identify and document any abnormal physical findings prior to the 
patient’s participation in the study. 
• Recording of vital sign data (heart rate and blood pressure measurements). 
• 12-lead ECG. 
• Blood sampling for laboratory safety tests (including hematology and clinical chemistry 
analyses) and serology for HBsAg, HCV Ab, HIV 1, and HIV 2. 
• Urinalysis. 
• Urine drug screen. 
Patients willing to take part in the study and who are eligible according to the criteria already 
assessed during the screening visit will be provided with a LogPad and stopwatch. They will 
complete training on how to use the LogPad during this visit. Once the training is completed, 
patients will be asked to attempt intercourse with their partners at least 4 times during the 
4-week run-in period, to use the stopwatch to time the attempt, and to record the relevant 
details in the LogPad including whether alcoholic drinks were taken prior to intercourse. At 
the next study visit (Visit 2), the patient must bring the LogPad to the study site. Further 
details for LogPad use and instructions are found in the Study Training Manual. 
Baseline Visit 2 
On Visit 2 (Day 0, Week 0 ±7 days from screening), patients will attend the study center, and 
information and data collected will include the following: 
• Assessment of patient eligibility according to the IELT entry criteria. The patient will 
return the LogPad to the investigator. The LogPad will provide a summary of the IELT 
data collected during the run-in period and will indicate whether the patient is eligible to 
continue in the study based on the IELT criteria. (Note: Refer to the Study Training 
Manual for instructions if a patient does not remember to return the LogPad.) 
• The investigator will provide the LogPad back to the patient for completion of the PEP, 
PGIS, IIEF, and PHQ-9. After completion of these questionnaires, the patient will return 


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the LogPad to the investigator. The LogPad will provide a further summary that will 
indicate whether the patient is eligible to continue in the study based on the results of the 
PEP, IIEF, and PHQ-9. If the patient is not eligible based on these assessments, then he 
should not be randomized or continued in the study, and the investigator may discuss 
alternate treatment options. 
• Weight. 
• Physical examination. 
• Recording of vital sign data (heart rate, blood pressure, and oral temperature 
measurements) and 12-lead ECG. 
• Blood sampling for laboratory safety tests (including hematology, clinical chemistry, and 
coagulation analyses). 
• Urinalysis. 
• Urine drug screen. 
• C-SSRS. 
• Adverse events and concomitant medication update. 
• The patients who meet all of the eligibility criteria will be randomized and assigned a 
treatment number. Eligible patients will be provided with at least 7 doses of study drug 
(IX-01 or placebo). Further supplies can be dispensed at this visit based on a discussion 
between the Investigator and patient but the maximum allowed dose is 1 dose (3 caplets) 
per day. Each dose of study drug comprises 3 caplets contained within a discrete blister 
card. Patients must be informed that 1 dose is all 3 caplets, and the dose should be taken 
with water at least one hour before or after food. Patients should attempt sexual 
intercourse approximately 1 to 6 hours after taking the dose. The patients will also be 
provided with a LogPad. Patients should be reminded on the instructions for using the 
stopwatch and also the LogPad to record their usage of the study medication, as well as 
all occasions that they attempt sexual intercourse and whether alcoholic drinks were 


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taken. Patients will be asked if they are willing to try intercourse with their partner 
approximately 8 times or more between Visit 2 and Visit 5 although less than 8 attempts 
will not be classified as a protocol deviation. Patients should be reminded to bring their 
LogPad and any unused study medication back to the study site for Visit 3. 
Visit 3 
• Patients will return to the study center on Day 14 ± 3 days (Week 2). The patients will be 
asked for information on any AEs that have occurred or are occurring and concomitant 
medication usage since Visit 2. The remaining study medication will be collected, and a 
check of the quantity remaining will be performed. After completion of all assessments, 
the patient will receive enough medication to take at least 7 doses of study drug (IX-01 or 
placebo). Further supplies can be dispensed at this visit based on a discussion between 
the Investigator and patient but the maximum allowed dose is 1 dose (3 caplets) per day. 
(Note: Refer to the Study Training Manual for instructions if a patient does not remember 
to return the LogPad.) 
• The patient will return the LogPad. 
• The investigator will provide the LogPad back to the patient for completion of the 
PHQ-9. Once complete, the patient will return the LogPad to the investigator. 
• If the results of the PHQ-9 indicate a change in mental condition and/or if the investigator 
suspects a deleterious change in mood (see Section 13.2), the investigator must 
administer the C-SSRS. 
• Physical examination. Any changes in physical findings that meet the definition for an 
AE and that occur after the patient initiates investigational product will be recorded as 
AEs in the eCRF. 
• Blood sampling for laboratory safety tests (including hematology and clinical chemistry 
analyses). 
• Adverse events and concomitant medication update. 


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Visit 4 
• Patients will return to the study center on Day 28 ± 7 days (Week 4). The patients will be 
asked for information on any AEs that have occurred or are occurring and concomitant 
medication usage since Visit 3. The remaining study medication will be collected, and a 
check of the quantity remaining will be performed. After completion of all assessments, 
the patient will receive enough medication to take at least another 14 doses of study drug 
(IX-01 or placebo). Further supplies can be dispensed at this visit based on a discussion 
between the Investigator and patient but the maximum allowed dose is 1 dose (3 caplets) 
per day. (Note: Refer to the Study Training Manual for instructions if a patient does not 
remember to return the LogPad.) 
• The patient will return the LogPad. 
• The investigator will provide the LogPad back to the patient for completion of the PEP, 
PGIS, IIEF, and PHQ-9. Once complete, the patient will return the LogPad to the 
investigator. 
• If the results of the PHQ-9 indicate a change in mental condition (or the investigator 
suspects an adverse change), the investigator should administer the C-SSRS and 
determine if the patient may remain in the study. 
• Physical examination. 
• Recording of vital signs data (heart rate and blood pressure measurements). 
• Blood sampling for laboratory safety tests (including hematology and clinical chemistry 
analyses). 
• Urinalysis. 
• Adverse events and concomitant medication update. 


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Visit 5 (End of Treatment or Early Termination) 
Note that if a patient is discontinued from the study at any time during the treatment period 
earlier than expected, then he must return to the study site and complete an early termination 
visit (Visit 5). 
• Patients will return to the study center on Day 56 ± 7 days (Week 8). The patients will be 
asked for information on any AEs that occurred or are occurring and concomitant 
medication usage since Visit 4. The patient must return the LogPad. The remaining study 
medication will be collected. The LogPad will be checked and retained at the study 
center. (Note: Refer to the Study Training Manual for instructions if a patient does not 
remember to return the LogPad.) 
• The investigator will provide the LogPad back to the patient for completion of the PEP, 
IIEF, PHQ-9, PGIS and CGIC. After completion, the patient will return the LogPad to the 
investigator. 
• If the results of the PHQ-9 indicate a change in mental condition (or the investigator 
suspects an adverse change), the investigator should administer the C-SSRS. 
• Weight. 
• Physical examination. 
• Recording of vital sign data (heart rate and blood pressure measurements) and 12-lead 
ECG. 
• Blood sampling for laboratory safety tests (including hematology and clinical chemistry 
analyses). 
• Urinalysis. 
• Urine drug screen. 
• Adverse events and concomitant medication update. 


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End of Study Visit 6 (Follow Up) 
Patients will return to the study center for a follow-up visit on Day 70 ± 7 days (Week 10), 
and the following assessments will be performed approximately 2 weeks after the last visit: 
• Weight. 
• Physical examination. 
• Recording of vital sign data (heart rate and blood pressure measurements) and 12-lead 
ECG. 
• Blood sampling for laboratory safety tests (including hematology and clinical chemistry 
analyses). 
• Urinalysis. 
• Adverse events and concomitant medication update. 
• C-SSRS, only if clinically indicated per the protocol. 
6.2 
Efficacy Assessments 
Outcome measures included during treatment include results from the use of the following: 
• Stopwatch to measure IELT. 
• LogPad (e-diary) to record summary of study drug intake and details of sexual 
intercourse attempts (including IELT and two PEP questions (control and ejaculation-
related personal distress). 
• Responses to the PEP questionnaire. 
• Responses to PGIS questionnaire. 
• Responses to the CGIC questionnaire.   
 


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IELT  
The IELT is the time from the start of intercourse (penetration) until ejaculation and is 
recorded by the patient or partner using the stopwatch provided. At the start of the run-in 
phase, the patient and partner should decide who will activate the stopwatch and 
subsequently stop the stopwatch to record the timing of intercourse. The same person should 
start and stop the stopwatch with every intercourse attempt throughout the study until Visit 5. 
LogPad 
The LogPad has been specifically designed to enable patients to record details of sexual 
intercourse attempts and study drug use throughout the study. The key data to be recorded by 
the patients are date and time of study drug caplets taken, date and time of any intercourse 
attempt, IELT, level of control of timing of ejaculation; and level of ejaculation-related 
personal distress. The patient also will use the LogPad at each study visit to complete the 
PEP, PGIS, IIEF, and PHQ-9 (PEP, PGIS and IIEF are not completed at Visit 3/Week 2). At 
the final treatment visit (Visit 5 or Early Termination), the CGIC is also collected via the 
LogPad. For further details of the LogPad design and function, refer to the Study Training 
Manual. 
PEP 
The PEP is a widely used self-administered tool that includes measures of perceived control 
over ejaculation, ejaculation-related personal distress, ejaculation-related interpersonal 
difficulty, and satisfaction with intercourse. It has been used in many previous studies of PE 
and is considered validated for this purpose. All of the domains are relevant to a patient with 
PE, and the instrument has the advantage of being simple and quick to use.14.  In this study an 
additional exploratory question on bother will be included in the 4-week recall version used 
at baseline, week 4 and week 8. 
 
PGIS 
The Patient Global Impression of Severity is a questionnaire that asks the patient to assess 
the severity of their condition (categories of response are no PE, mild, moderate, severe). 


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CGIC 
The Clinical Global Impression of Change (CGIC) (also referred to as PGIC) is a simple and 
validated instrument that allows the patient to rate the change in his condition (PE) at the end 
of treatment on a 7-point scale ranging from “much worse” to “much better.”15  In this study 
the CGIC will be administered after the PEP at the final visit and will include two additional 
questions.  See Appendix 2.   
6.3 
Safety Assessments 
Adverse Events 
The Investigator and study personnel will monitor each patient for AEs occurring throughout 
the study treatment period. The process of collection and reporting of AEs is described in 
Section 6.3.1. 
Vital Signs 
Vital sign measurements will be taken after the patient has been resting in the sitting position 
for at least 5 minutes and will include diastolic and systolic blood pressure and heart rate. 
Vital signs may be repeated if clinically significant values are measured. Out-of-range blood 
pressure or heart rate measurements will be repeated at the Investigator’s discretion 
especially if the investigator believes that the initial measurements are due to insufficient 
relaxation or error. Any confirmed, clinically significant vital sign measurements must be 
recorded as AEs. 
Electrocardiogram (ECG) 
A single 12-lead ECG will be collected after a 5-minute period of rest and should be 
completed before any blood collection. If any clinically significant changes in findings are 
observed versus the predose or baseline visits, they must be documented. If a clinically 
significant abnormal finding occurs after the patient initiates use of the study drug, then it 
will be recorded as an AE in the eCRF. 


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IIEF 
The IIEF is a validated 15-item questionnaire that was designed to evaluate sexual function 
in men with possible erectile dysfunction. The main purpose of including this instrument in 
this study is to exclude men with coexisting erectile dysfunction at baseline and to check 
whether erectile dysfunction occurs during the study.16 As this instrument was designed for 
use in men with possible erectile dysfunction, the investigator should clarify the meaning of 
Questions 4, 5, and 15 before the patient completes the questionnaire. The patient should be 
told that he is being asked to assess whether he can maintain his erection until ejaculation 
occurs (Questions 4 and 5) and about his confidence to get and keep an erection until 
ejaculation occurs (Question 15). 
Psychological Assessments 
The following questionnaire will be self-completed by each patient using the LogPad 
(e-diary). 
• Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a reliable and valid screening tool for depression severity. The module scores 
each of the 9 Diagnostic and Statistical Manual of Mental Disorders, fourth edition 
(DSM-IV) criteria as “0” (not at all) to “3” (nearly every day). A PHQ-9 score ≥10 had a 
sensitivity of 88% and a specificity of 88% for major depression. PHQ-9 scores of 5, 10, 15, 
and 20 represented mild, moderate, moderately severe, and severe depression, respectively.17 
The questionnaire will be completed at each study visit during the treatment period. 
The Investigator will administer the following instrument at baseline and at other times 
thereafter throughout the study as required by the protocol. 
• C-SSRS 
The C-SSRS is a structured clinical interview used to assess an individual’s behavior to 
exhibit thoughts or intent to commit suicide.18 Investigators and other designated staff 
performing the interview must be trained in its use. 


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6.3.1 
Adverse Events 
6.3.1.1 Definitions of Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical 
product and that does not necessarily have a causal relationship with this treatment. An AE 
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. 
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is 
to establish drug effect. After the informed consent form (ICF) is signed, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs. 
An SAE or serious adverse drug reaction is any untoward medical occurrence at any dose 
that: 
• results in death; 
• is life threatening (immediate risk of death); 
• requires inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability/incapacity; 
• results in a congenital anomaly/birth defect. 
An SAE may also be any other medically important event that, in the opinion of the 
Investigator, may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. (Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or convulsions 
occurring at home that do not require an inpatient hospitalization). 
Serious adverse event collection begins after the patient has signed informed consent and has 
received investigational product through to 28 calendar days after last administration of the 
investigational product. 


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Planned surgeries should not be reported as SAEs unless the underlying medical condition 
has worsened during the course of the study. 
The investigator does not need to actively monitor patients for AEs once the study has ended 
(after follow-up visit), unless stipulated otherwise in the protocol. However, if an investigator 
becomes aware of any SAEs occurring after the patient’s participation in the study has ended, 
the investigator should report the SAEs to Ixchelsis or designated representative regardless of 
the investigator’s opinion of causation. In order to adhere to all applicable laws and 
regulations for reporting an SAE, the study site must notify Ixchelsis or designated 
representative within 24 hours of the study site staff becoming aware of the SAE. 
6.3.1.2 Eliciting and Documenting Adverse Events 
For all AEs, the investigator must pursue and obtain information adequate to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Ixchelsis or designated representative. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE. 
6.3.1.3 Reporting Adverse Events 
All observed AEs and their suspected causal relationship to the study product will be 
reported. Adverse events and SAEs should be reported using concise medical terminology as 
appropriate in the eCRF. 
For all AEs, the Investigator must obtain information adequate both to determine the outcome 
of the AE and to assess whether it meets criteria for classification as an SAE requiring 
immediate notification to Ixchelsis or designated representative. 


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If an SAE occurs, expedited reporting to regulatory authorities will follow local regulations, 
as appropriate. The Investigator must report all SAEs to Ixchelsis or designated 
representative within 24 hours of the Investigator’s awareness of the event. This timeframe 
also applies to additional new information on previously reported SAEs. The contact details 
for reporting SAEs by telephone and fax are as follows: 
PPD 24-Hour Safety Hotline: 
+1 800 201 8725 
PPD 24-Hour Safety Hotline Fax: 
+1 888 488 9697 
6.3.1.4 Assessment of Severity 
Severity describes the intensity of a specific event: 
• Mild – Symptom(s) barely noticeable to the patient or does not make the patient 
uncomfortable. The AE does not influence performance or functioning. Prescription 
drugs are not ordinarily needed for relief of symptom(s). 
• Moderate – Symptom(s) of a sufficient severity/intensity to make the patient 
uncomfortable. Performance of daily activities is influenced. Treatment of symptom(s) 
may be needed. 
• Severe – Symptom(s) of a sufficient severity to cause the patient severe discomfort. 
Severity may cause cessation of treatment with the investigational product. Treatment for 
symptom(s) may be given. 
• Life-threatening – Symptom(s) of a sufficient severity/intensity to cause the patient to be 
at immediate risk of death. Treatment for symptom(s) may be given. 
6.3.1.5 Assessment of Causality 
For all AEs, sufficient information should be obtained by the Investigator to determine the 
causality of the AE (serious and nonserious). An Investigator’s causality assessment is the 


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determination of whether there exists a reasonable possibility that the study product caused 
or contributed to an AE. If the Investigator’s final determination of causality is unknown 
because the Investigator does not know whether or not the study product caused the AE, then 
the AE will be handled as “related to investigational product” for reporting purposes and 
reporting expedited according to local regulations. If the Investigator’s final determination of 
causality is “unknown but not related to investigational product,” this information should be 
clearly documented in the study records. 
In addition, if the Investigator determines that an SAE is associated with study procedures, 
the Investigator must record this causal relationship in the source documents and eCRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
6.3.1.6 Follow-Up of Patients Reporting Adverse Events 
For all AEs, follow up by the Investigator is required until the event or its sequelae resolve or 
stabilize at a level acceptable to the Investigator. The medical monitor will monitor safety 
data throughout the course of the study. 
6.4 
Pregnancy 
If the partner of a patient is of childbearing potential, then at least one reliable form of 
contraception must be used. 
If a patient used condoms during the run-in period when engaging in sexual intercourse, then 
he must continue to use the same brand and type of condom for every sexual intercourse 
attempt. If the condom is the main method of contraception, then it should be used with 
spermicide (or similar product according to availability). If the patient did not use a condom 
during the run-in period, then his partner must use a form of contraception such as 
intrauterine device, diaphragm with spermicide (or similar product according to availability), 
oral contraceptives, injectable progesterone, subdermal implants, or tubal ligation when 
engaging in sexual intercourse, unless the patient has had a documented vasectomy or 
confirmed azoospermia. 
This criterion must be followed from the time of the run-in period until 30 days after the last 
dose of study medication. 


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If a patient reports that his partner is pregnant, the patient must be withdrawn from the study 
and the Investigator will inform Ixchelsis or designee, who will endeavor to collect any 
relevant information on the outcome of the pregnancy unless there is confirmation that the 
patient was not exposed to study drug prior to or during the pregnancy. Cases of pregnancy 
that occur after a patient has been consented should be reported. Data on fetal outcome and 
breastfeeding will be collected for regulatory reporting and drug safety evaluation. 
The Investigator must report the pregnancy to Ixchelsis or designee with 24 hours of the 
study site staff becoming aware of the pregnancy. 
6.5 
Laboratory Analyses 
The central laboratory will process all samples collected for laboratory safety function tests. 
Section 13.3 provides a full list of tests, and the details regarding the laboratory safety tests 
and sampling can be found in the Study Training Manual. 
Collection of blood and urine samples for clinical laboratory analysis will occur per the 
Schedule of Events (Table 13-1). Whole blood samples will be collected at each of these time 
points for hematology and clinical chemistry with coagulation testing being performed at 
baseline. An additional collection of blood sample for serology testing (hepatitis B surface 
antigen, hepatitis C virus antibody, HIV 1, HIV 2) will be performed at screening only. 
Urine samples will be collected for urinalysis (Screening, Visit 2, Visits 4-6) and urine drug 
screen (Screening, Visit 2 and Visit 5 only).  


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7 
Statistical and Analytical Plan 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the change in GM IELT over the treatment 
assessment period compared with baseline, ie, [GM(IELTtreatment period) – GM(IELTbaseline)]. 
7.2 
Secondary Efficacy Endpoints 
7.2.1 
Key Secondary Efficacy Endpoints 
The following key secondary efficacy endpoints will be analyzed: 
1. Fold change in GM IELT over the treatment assessment period compared with baseline. 
2. Proportion of patients with ≥2.5-fold increase in GM IELT over the treatment assessment 
period 
compared 
with 
baseline, 
ie, 
[proportion 
of 
subjects 
with 
GM(IELTtreatment period)/GM(IELTbaseline) ≥2.5]. 
3. Proportion of patients rating their PE as improved per the CGIC questionnaire. 
4. Proportion of patients achieving mean change in category of ≥1 or ≥2 on control of 
timing of ejaculation (PEP), ie, improving control from “very poor” or “poor” to “fair,” 
“good,” or “very good” at end of treatment. 
5. Proportion of patients achieving mean change in category of ≥1 or ≥2 in 
ejaculation-related personal distress (PEP), ie, improving rating of ejaculation-related 
distress to “moderate,” “a bit,” or “not at all” at end of treatment. 
6. Proportions of patients achieving change in category of ≥2 on control of timing of 
ejaculation (PEP) and achieving change in category of ≥1 in ejaculation-related personal 
distress (PEP) at end of treatment 
7. Mean change from baseline in score on control of ejaculation (e-diary) over the treatment 
assessment period. 
8. Mean change from baseline in score on ejaculation-related personal distress (e-diary) 
over the treatment assessment period. 


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7.2.2 
Other Secondary Efficacy Endpoints 
The following other secondary efficacy endpoints will be analyzed: 
1. Fold change from baseline in (arithmetic) mean IELT over the treatment assessment 
period. 
2. Change from baseline in (arithmetic) mean IELT over the treatment assessment period. 
3. Proportion of patients with GM IELT of ≥1 minute over the treatment assessment period. 
4. Proportion of patients with GM IELT of ≥2 minutes over the treatment assessment period. 
5. Proportion of patients with GM IELT of ≥3 minutes over the treatment assessment period. 
6. Proportion of patients with GM IELT of ≥4 minutes over the treatment assessment period. 
7. Proportion of patients with GM IELT of ≥5 minutes over the treatment assessment period. 
8. Proportion of patients with GM IELT increase over the treatment assessment period of 
≥45 seconds compared with baseline. 
9. Proportion of patients with GM IELT increase over the treatment assessment period of 
≥1 minute compared with baseline. 
10. Percentage of intercourse attempts lasting >1 minute over the treatment assessment 
period. 
11. Percentage of intercourse attempts lasting >2 minutes over the treatment assessment 
period. 
12. Percentage of intercourse attempts lasting >3 minutes over the treatment assessment 
period. 
13. Percentage of intercourse attempts lasting >4 minutes over the treatment assessment 
period. 
14. Percentage of intercourse attempts lasting >5 minutes over the treatment assessment 
period. 
15. Proportion of patients improving on PGIS 
16. Proportion of patients achieving ≥1 category of improvement from baseline to end of 
treatment in each of the following (from 4-weekly PEP questionnaire): 


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a. Satisfaction with sexual intercourse 
b. Control over ejaculation during sexual intercourse 
c. Ejaculation-related distress 
d. Ejaculation-related interpersonal difficulty 
e. Ejaculation-related bother 
17. Change in score from baseline in each of the following (from 4-weekly PEP 
questionnaire): 
a. Satisfaction with sexual intercourse 
b. Control over ejaculation during sexual intercourse 
c. Ejaculation-related distress 
d. Ejaculation-related interpersonal difficulty 
e. Ejaculation-related bother 
7.3 
Sample Size Calculations 
The target total is for 220 patients to be randomized in the study. 
The randomization ratio will be 2:2:3:3 (placebo, IX-01 400 mg, IX-01 800 mg, and IX-01 
1200 mg dose groups, respectively). 
Thus, 44 patients each will be randomized to placebo and IX-01 400 mg dose groups, and 
66 patients each will be randomized to IX-01 800 mg and IX-01 1200 mg dose groups. The 
2:3 ratio results in only slight loss of statistical power from 1:1 randomization, while 
increasing the chances that a patient will be randomized to an effective dose of study drug. 
Assuming an alpha (2-sided) of 0.05 and an SD of 70 seconds, a sample size of 220 patients 
randomized in total (44 to the placebo and IX-01 400 mg dose groups and 66 to the IX-01 
800 mg and IX-01 1200 mg dose groups) provides approximately 85%, 90%, and 90% power 
to detect a mean difference of 45 seconds between change from baseline in GM of IELT for 
the IX-01 400 mg, IX-01 800 mg, and IX-01 1200 mg dose groups, respectively, compared 
with the placebo group.  


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Sequential multiplicity control testing of IX-01 1200 mg dose versus placebo, followed by 
IX-01 800 mg dose versus placebo and then IX-01 400 mg dose versus placebo will be done 
in order to control for multiplicity. See details below. 
Additional patients may be recruited if some patients discontinue from the study with less 
than 2 postbaseline IELT assessments. 
7.4 
Analysis Sets 
The following 4 populations, defined as below, will be used in the analyses: 
Intent-to-Treat (ITT) Set: The ITT Set is defined as all randomized patients who have taken 
at least 1 dose of study medication. Patients will be analyzed according to the treatment arm 
to which they were randomized. 
Modified Intent-to-Treat (mITT) Set: The mITT Set is defined as all randomized patients 
who have taken at least 1 dose of study medication and with at least 2 postbaseline 
analyzable IELT assessments. Patients will be analyzed according to the treatment arm to 
which they were randomized. 
Safety Set: The Safety Set consists of all randomized patients who have taken at least 1 dose 
of study medication. Patients will be analyzed according to the treatment arm for the study 
drug that  they actually received. 
Per-Protocol Set: The Per-Protocol Set is defined as all patients from the mITT without any 
major protocol deviation that could affect the evaluability of the primary efficacy parameter. 
Patients will be analyzed according to the treatment arm to which they were randomized. 
The allocation of patients to analysis sets will be done in a blinded way prior to database 
lock. 
7.5 
Description of Subgroups to be Analyzed 
Details will be provided in the Statistical Analysis Plan (SAP) for any proposed subgroup 
analyses (e.g. patients with all baseline IELTs were <= 60 seconds).  


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7.6 
Statistical Analysis Methodology 
Summary statistics will be provided for all study endpoints. For continuous endpoints n 
(number of patients included in the analysis), mean, SD, median, minimum, maximum, 
Quartile 1, and Quartile 3 will be provided. For categorical endpoints, the number and 
frequency in each category will be provided. Adjusted effect size and 95% CI will be 
displayed for all treatment comparisons. 
For the purpose of e-diary data analyses, the treatment assessment period will include all 
assessments done between end of treatment and end of treatment minus 28 days, if patients 
have a sufficient amount of assessments within this time window. The time window may be 
extended back for patients without a sufficient amount of assessments within the predefined 
time window. Additional details will be provided in the SAP regarding the derivation of the 
treatment assessment period. 
7.6.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy analysis of the primary endpoint will be performed on the mITT 
population. Change from baseline in GM IELT over the treatment assessment period will be 
analyzed using a mixed linear model, including treatment and baseline IELT as fixed factors 
and type of site as a random factor. 
The primary comparison of interest is IX-01 1200 mg versus placebo. If it is statistically 
significant at α=0.05, then the following comparisons will be tested in the following order: 
• IX-01 800 mg vs placebo group 
• IX-01 400 mg vs placebo group 
An overview of the approach to control for multiple comparisons is provided in Figure 7-1. 
Figure 7-1 
Overview of the Multiplicity Control 
 
IX-01 1200 mg 
vs placebo 
IX-01 800 mg 
vs placebo 
p≤0.05 
IX-01 400 mg 
vs placebo 
p≤0.05 


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If at any point in the sequence statistical significance is not met, then subsequent analyses in 
the sequence cannot be deemed statistically significant. In such cases, nominal P values and 
95% CI will be reported and interpreted in an exploratory manner. Irrespective of whether 
there are any statistically significant differences between treatment groups, IELT data from 
all treatment groups will also be used to model a possible dose response relationship. Further 
details on dose response analysis will be provided in the SAP. 
The analyses above will be repeated using the Per-Protocol and ITT populations to examine 
the robustness of the primary results. 
As a sensitivity analysis of the primary endpoint, a nonparametric approach will be carried 
out on the mITT population in order to obtain the median treatment effect and 95% CI. 
7.6.2 
Analysis of Secondary Efficacy Endpoint 
All secondary analyses will be carried out testing each dose group versus the placebo group 
on for the ITT population. 
The same approach to control for multiple comparisons as proposed for the primary endpoint 
will be used for each secondary endpoint analysis. 
7.6.2.1 Change From Baseline Endpoints 
Analyses of e-diary data expressed in change from baseline over the treatment assessment 
period will be carried out using a mixed linear model. All analyses should include treatment, 
baseline IELT, and the baseline score of the analyzed endpoint as fixed effects and the site as 
a random effect. In addition to the mixed linear model, a nonparametric approach may be 
carried out for specific secondary endpoints. Further details will be provided in the SAP. 
Change in score from baseline in each of the PEP questions (ie, Endpoint 17 of Section 7.2.2) 
will be carried out using a mixed-effect model repeated measure model. All analyses should 
include treatment, baseline IELT, the baseline score of the analyzed endpoint, the visit, and 
the interaction between visit and treatment as fixed effects and the site as a random effect. 
Visit will be considered as the repeated measurement. 


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7.6.2.2 Proportion Endpoints 
For each analysis on proportion endpoint, difference in the proportions between each test 
group and placebo group will be tested using a logistic model. All analyses should include 
treatment, baseline IELT, and the type of site as factors. P values and adjusted odds ratios 
will be presented. 
7.6.2.3 Percentage Endpoints 
The percentage of intercourse attempts lasting longer than a predefined threshold during the 
treatment assessment period will be analyzed by treatment as continuous data. 
Analyses will be carried out using a mixed linear model. All analyses should include 
treatment and baseline IELT as fixed effects and the type of site as a random effect. 
7.6.2.4 Missing Data 
Sensitivity analyses for the primary endpoint with methods of handling missing data will be 
specified in the SAP. 
7.6.3 
Safety Analyses 
Safety analyses will be based on all patients included in the safety population. 
Changes from baseline will be the absolute changes from baseline:  
Change from baseline = raw value – baseline value 
Study Drug Administration and Exposure: Study drug administration and exposure will be 
summarized and listed. Further details on study drug administration and exposure calculation 
will be given in the SAP. 
Medical History: Medical history details recorded at screening will be summarized and 
listed according to the coded Medical Dictionary for Regulatory Activities (MedDRA) (latest 
version) by system organ class, preferred term, and treatment group. 


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Concomitant Medications: Previous and concomitant medications will be summarized 
according to the WHO Drug Dictionary (WHO-DD). The number and percentage of patients 
for each treatment group will be presented for previous and concomitant medications. 
The patient will record in the LogPad whether he had any alcoholic drinks within 4 hours 
prior to sexual intercourse.  
Adverse Events: Adverse events will be coded according to the coded MedDRA (latest 
version). Treatment-emergent AEs will be tabulated by system organ class, preferred term, 
and treatment group. Further details will be given in the SAP on the definition of TEAEs. 
The following summary tables will be produced: 
• TEAEs 
• Serious TEAEs 
• TEAEs leading to study drug discontinuation 
• Treatment-related TEAEs leading to study drug discontinuation 
• Treatment-related TEAEs 
• Treatment-related serious TEAEs 
All AEs recorded during the study (including non-treatment-emergent AEs) will be listed. 
Physical Examination and Vital Signs: Abnormal physical examinations will be listed. 
Descriptive by-visit summaries of vital signs data will be presented by treatment group 
(including raw values and change from baseline). Vital signs will include blood pressure, 
heart rate, and temperature. 
Height, Weight, and BMI: Baseline height, weight, and BMI will be summarized and listed. 
Weight and BMI as well as mean change from baseline will be summarized for Week 8 and 
end-of-study visits. 


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ECGs: Descriptive summaries of change in overall assessment of ECG data from baseline to 
Week 8 and end of study will be presented in a shift table (normal, abnormal [not clinically 
significant], and abnormal [clinically significant]) by treatment group. 
Laboratory Safety Tests: Hematology and clinical chemistry safety tests will be 
summarized by treatment and visit. Postbaseline visit will include change from baseline. 
Shift tables displaying baseline versus worst postbaseline results will be provided by 
treatment group. 
PHQ-9: The PHQ-9 is comprised of 9 questions and is used to monitor depression 
symptoms. All questions elicit responses on an ordered 4-point scale (0-3), which are added 
together to generate a single summary score. Higher summary scores indicate an increase in 
depression severity. The questionnaire is administered at baseline, Week 2, Week 4, and 
Week 8 visits. Total PHQ-9 scores will be summarized by treatment and visit, with the 
postbaseline visit displaying raw values as well as change from baseline. In addition, 
responses to the final question “If you checked off any problems, how difficult have these 
problems made it for you to do your work, take care of things at home, or get along with 
other people?” will be summarized by visit as frequency data. 
Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a structured clinical 
interview used to assess an individual’s behavior to exhibit thoughts or intent to commit 
suicide. The questionnaire will be completed at baseline and may be administered at other 
visits thereafter if clinically indicated. Baseline results will be summarized and listed. 
Postbaseline results will be listed. 
International Index of Erectile Function (IIEF): The IIEF is a questionnaire that 
comprises 15 questions assessing the effect that erection problems have had on the patient’s 
sex life over the previous 4 weeks. It is administered at baseline, Week 4, and Week 8. 
Summary statistics will be provided by visit, and questionnaires will be listed in detail. 
7.6.4 
Other Analyses 
Not applicable. 


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7.6.5 
Interim Analyses 
No formal interim analyses of unblinded data are planned. 


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8 
Data Quality Assurance 
The study will be conducted in accordance with the International Council for Harmonisation 
(ICH) GCP and the appropriate regulatory requirement(s). The investigator will receive 
training regarding the appropriate use of the investigational product as described in the 
protocol and the Investigator’s Brochure. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient. Study data will be entered on a electronic case report form (eCRF) by site personnel 
using a secure, validated, web-based electronic data capture (EDC) application. Ixchelsis and 
Ixchelsis-authorized representatives will have access to all data upon entry in the EDC 
application. 
Study monitors will discuss instances of missing or uninterpretable data with the investigator 
so these can be resolved. Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF. 
8.1 
Case Report Forms and Source Documents 
The term CRF should be understood to refer to either a paper form or electronic data record 
or both, depending on the data collection method used in this study. This study is expected to 
use a web-based EDC application. Ixchelsis or designee will supply eCRFs for each patient 
screened. Historical information and study data, specified in the protocol, will be recorded on 
the eCRFs by the investigator or designee. All patient data from each study visit must be 
collected on source documents and must be promptly entered on the eCRFs in accordance 
with the specific instructions given. Case report form entries will be performed by an 
investigator or designee and the study coordinator, who are authorized to complete such 
documentation. It is the investigator’s responsibility to ensure completion and to review and 
approve all eCRFs. Case report forms must be signed by the investigator or by an authorized 
staff member. These signatures serve to attest that the information contained on the CRFs is 
true. At all times, the investigator has final personal responsibility for the accuracy and 
authenticity of all clinical and laboratory data entered on the eCRFs.  
Patient source documents are the physician’s patient records maintained at the study site.  


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In some cases, the eCRF may also serve as the source document. In these cases, Ixchelsis (or 
designee) and the investigator must prospectively document which items will be recorded in 
the source documents and for which items the eCRF will stand as the source document. 
If queries are generated by Ixchelsis or designee to the participating medical institutions for 
resolution, the eCRF data will be changed or a response will be recorded in accordance with 
the specific instructions given. 
The investigator must maintain source documents, such as all original signed ICFs, 
laboratory reports, and complete medical history. All source documents should be accessible 
for verification by the site monitor, auditor, IRB, or for inspections by regulatory authorities. 
Direct access to these documents must be guaranteed by the investigator or designee. If 
electronic records are maintained at the medical institution, the method of verification must 
be specified in documents within that medical institution. 


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9 
Ethics 
9.1 
Institutional Review Board 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent, and other relevant documents, eg, recruitment 
advertisements, if applicable from the IRB. The study will commence only after the IRB has 
given full approval and the investigator has received the approval documents. All 
correspondence with the IRB should be retained in the investigator file. Copies of IRB 
approvals will be forwarded to Ixchelsis Ltd. Documentation of the IRB compliance with 
ICH GCP will be maintained by the site and will be available for review by Ixchelsis Ltd or 
its designee. 
9.2 
Ethical Conduct of the Study 
The study will be conducted in accordance with all appropriate regulatory requirements, local 
laws, and under the IRB-approved protocol. The study will be conducted in accordance with 
current ICH GCP, all appropriate patient privacy requirements, and the ethical principles 
outlined in the Declaration of Helsinki. 
9.3 
Patient Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
Part 50 shall be obtained from each patient before entering the study or performing any 
unusual or nonroutine procedure that involves risk to the patient. The investigator or 
subinvestigator (designated by the investigator) will fully explain the nature of the study to 
each patient using the IRB-approved informed consent document prior to each patient 
entering the study. The investigator or subinvestigator will explain the nature, purpose and 
methods, reasonably anticipated benefits, and potential hazards of the study to each patient in 
simple terms using the IRB-approved consent document. The investigator or subinvestigator 
will obtain written informed consent from each patient before any study specific activity is 
performed. The investigator will retain the original of each patient’s signed consent form. 
The ICF must be in compliance with ICH GCP, local regulatory requirements, and legal 
requirements.  


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The ICF and any changes made during the course of the study must be prospectively 
approved by both the IRB and Ixchelsis before use. 


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10 Investigator’s Obligations 
10.1 Confidentiality 
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number. The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the US Food and Drug Administration and 
applicable laws. 
10.2 Study Conduct 
The investigator will conduct the study in compliance with the protocol provided by Ixchelsis 
and given approval/favorable opinion by the IRB and the appropriate regulatory authority. 
Modifications to the protocol are not to be made without agreement of both the investigator 
and Ixchelsis. Changes to the protocol will require written IRB approval/favorable opinion 
before implementation, except when the modification is needed to eliminate an immediate 
hazard or hazards to patients. Ixchelsis or a designee will submit all protocol modifications to 
the appropriate regulatory authority(ies) in accordance with the governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard or 
hazards to patients, the investigator will contact Ixchelsis or a designee, if circumstances 
permit, to discuss the planned course of action. Any departures from the protocol must be 
documented. 
10.3 Records Retention 
To enable evaluations and/or audits from regulatory authorities or Ixchelsis, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs, hospital records), all original signed ICFs, source 
documents, and detailed records of treatment disposition. The study 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 requirements or by an agreement 


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with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution 
as to when these documents no longer need to be retained. The investigator and institution 
should take measures to prevent accidental or premature destruction of these documents. 
If the investigator relocates, retires, or for any reason withdraws from the study, Ixchelsis 
should be prospectively notified. The study documents must be transferred to an acceptable 
designee, such as another investigator, another institution, or to Ixchelsis. The investigator 
must obtain Ixchelsis’s written permission before disposing of any records, even if the 
retention requirements have been met. 
10.4 Publications 
All information regarding IX-01 supplied by Ixchelsis to the Investigator is privileged and 
confidential information and Ixchelsis retains ownership of all data.  
Following completion of the study, the data from the entire study may be considered for 
reporting at a scientific meeting or for publication in a scientific journal, in which case 
Ixchelsis will be responsible for these activities and will work with the Investigator to 
determine how the manuscript is written and edited, the number and order of authors, the 
publication to which it will be submitted, and other related issues. Authorship will be based 
on criteria stipulated by leading clinical journals (eg, contribution to 1 or more areas of study 
design, data analysis and interpretation, and manuscript preparation and review). 


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11 Study Management 
11.1 Monitoring 
Monitoring and auditing procedures will be followed to comply with ICH GCP guidelines. 
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation. During the course of the study, the study monitor will make study site 
visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained. The investigator and institution will allow 
Ixchelsis monitors or designee and appropriate regulatory authorities direct access to source 
documents to perform this verification. 
It is important that the investigator(s) and relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11.2 Study Termination 
Premature termination of this clinical study may occur because of a regulatory authority 
decision, change in opinion of the IRB, drug safety problems, or at the discretion of 
Ixchelsis. 
If the study is prematurely terminated or suspended, Ixchelsis will promptly inform all of the 
investigators. The relevant regulatory authorities and IRBs will be informed in accordance 
with local regulations. The investigator or designee should promptly inform the participating 
patients. As directed by Ixchelsis, all study materials must be collected and all CRFs 
completed to the greatest extent possible. 


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12 Reference List 
1. McMahon CG. Ejaculatory dysfunction—the evolution of a new understanding. Transl 
Androl Urol. 2016;5(4):402-8. 
2. Godpodinoff ML. Premature ejaculation: clinical subgroups and etiology. J Sex Marital 
Ther. 1989;15(2):130-4. 
3. McMahon CG, Abdo C, Incrocci L, et al. Disorders of orgasm and ejaculation in men. 
J Sex Med. 2004;1(1):58-65. 
4. Serefoglu EC, McMahon CG, Waldinger MD, et al. An evidence-based unified definition 
of lifelong and acquired premature ejaculation: report of the second International Society 
for Sexual Medicine ad hoc committee for the definition of premature ejaculation. J Sex 
Med. 2014;11(6):1423-41. 
5. Rowland D, Perelman M, Althof S, et al. Self-reported premature ejaculation and aspects 
of sexual functioning and satisfaction. J Sex Med. 2004;1(2):225-32. 
6. Rowland DL, Patrick DL, Rothman M, et al. The psychological burden of premature 
ejaculation. J Urol. 2007;177(3):1065-70. 
7. Symonds T, Roblin D, Hart K, et al. How does premature ejaculation impact a man’s life? 
J Sex Marital Ther. 2003;29(5):361-70. 
8. 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. 
9. Byers ES, Grenier G. Premature or rapid ejaculation: heterosexual couples’ perceptions of 
men’s ejaculatory behavior. Arch Sex Behav. 2003;32(3):261-70. 
10. Burri A, Giuliano F, McMahon C, et al. Female partner’s perception of premature 
ejaculation and its impact on relationship breakups, relationship quality, and sexual 
satisfaction. J Sex Med. 2014;11(9):2243-55. 
11. European Medicines Agency (EMA). Assessment report for Priligy and associated names. 
London, 20 January 2012. EMA/73530/2012 [cited 2016 Oct 14] [19 screens]. Available 
from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Priligy_2
9/WC500124578.pdf. 


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12. Fortacin (lidocaine/prilocaine) [summary of product characteristics]. Plethora Solutions 
Limited. Chalgrove, UK; 2016 [cited 2016 Oct 14] [10 screens]. Available from: 
http://www.plethorasolutions.co.uk/uploads/SPC_12_and_20_dose_17may16.pdf. 
13. McMahon CG. The design and methodology of premature ejaculation interventional 
studies. Transl Androl Urol. 2016;5(4):508-25. 
14. Patrick DL, Giuliano F, Ho KF, et al. The Premature Ejection Profile: validation of 
self-reported outcome measures for research and practice. BJU Int. 2009;103(3):358-64. 
15. Althof SE, Brock GB, Rosen RC, et al. Validity of the patient-reported Clinical Global 
Impression of Change as a measure of treatment response in men with premature 
ejaculation. J Sex Med. 2010;7(6):2243-52. 
16. Rosen RC, Riley A, Wagner G, et al. The International Index of Erectile Function (IIEF): 
a 
multidimensional 
scale 
for 
assessment 
of 
erectile 
dysfunction. 
Urology. 
1997;49(6):822-30. 
17. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
measure. J Gen Intern Med. 2001;16(9):606-13. 
18. Posner K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale (C-SSRS): 
Baseline [Internet]. New York (NY): The Research Foundation for Mental Hygiene, Inc. 
Version 
2009 Jan 14 
[cited 
2016 Oct 14]. 
Available 
from: 
http://cssrs.columbia.edu/docs/C-SSRS_1_14_09_Baseline.pdf. 
 


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13 Appendices 
13.1 Appendix 1: Schedule of Events  
 


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Table 13-1 
Schedule of Events 
IX-0105 
Study Schedule and Events 
 
For Patients on 
Chronic SSRIs only 
Prescreening Visit1 
(Week -8) 
Visit 11 
Screening 
 
(Week -4) 
Visit 22 
Baseline 
 
(Week 0) 
Visit 32 
 
 
(Week 2) 
Visit 42 
 
 
(Week 4) 
Visit 5 or  
Early Termination2 
 
(Week 8) 
Visit 6  
Follow Up 
 
(Week 10) 
Days Post First Dose (Window) 
-56 
-28 (±3) 
0 (±7) 
14 (±3) 
28 (±7) 
56 (±7) 
70 (±7) 
Informed Consent 
X 
X1 
 
 
 
 
 
Medical History and Demography 
X 
X1 
 
 
 
 
 
Inclusion/Exclusion Criteria and 
Eligibility Review 
X 
X 
X3 
 
 
 
 
Physical Examination 
 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Weight 
 
X 
X 
 
 
X 
X 
Blood Pressure and Heart Rate  
 
X 
X 
 
X 
X 
X 
Oral Temperature 
 
 
X 
 
 
 
 
12-lead ECG (single) 
 
X 
X  
 
 
X  
X 
Safety Laboratory Tests (Clinical 
Chemistry, Hematology, and 
Coagulation4)  
 
X 
X 
X 
X 
X 
X 
Urinalysis  
 
X 
X 
 
X 
X 
X 
Serology (HBsAg, HCV Ab, 
HIV 1, HIV 2) 
 
X 
 
 
 
 
 
Urine Drug Screen 
 
X 
X 
 
 
X 
 
Randomization  
 
 
X 
 
 
 
 
e-Diary Supply5 
 
X 
X 
X 
X 
 
 
Diary Evaluation5 
 
 
X 
X 
X 
X 
 
Study Drug Supply 
 
 
X 
X 
X 
 
 
Study Drug Compliance 
 
 
 
X 
X 
X 
 
IIEF6 
 
 
X 
 
X 
X 
 
PEP6 (with additional question) 
 
 
X 
 
X 
X 
 


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IX-0105 
Study Schedule and Events 
 
For Patients on 
Chronic SSRIs only 
Prescreening Visit1 
(Week -8) 
Visit 11 
Screening 
 
(Week -4) 
Visit 22 
Baseline 
 
(Week 0) 
Visit 32 
 
 
(Week 2) 
Visit 42 
 
 
(Week 4) 
Visit 5 or  
Early Termination2 
 
(Week 8) 
Visit 6  
Follow Up 
 
(Week 10) 
Days Post First Dose (Window) 
-56 
-28 (±3) 
0 (±7) 
14 (±3) 
28 (±7) 
56 (±7) 
70 (±7) 
PGIS 
 
 
X 
 
X 
X 
 
CGIC 
 
 
 
 
 
X 
 
PHQ-9 
 
 
X 
X 
X 
X 
 
Columbia-Suicide Severity Rating 
Scale7 
 
 
X 
(X) 
(X) 
(X) 
(X) 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: CGIC, Clinical Global Impression of Change; ECG, electrocardiogram; HBsAg, hepatitis B surface antigen; HCV Ab, hepatitis C virus 
antibody; HIV, human immunodeficiency virus; IELT, intravaginal ejaculatory latency time; IIEF, International Index of Erectile Function; PEP, 
Premature Ejaculation Profile; PHQ-9, Patient Health Questionnaire 9; SSRI, selective serotonin reuptake inhibitor. 
1. 
Only patients taking chronic SSRIs will have an additional 4-week washout prior to the 4-week run-in period. They will attend a Prescreening 
Visit and will return to the site for a complete screening (Visit 1) once their washout period is complete. Informed consent and medical history 
will be obtained at the Prescreening Visit for patients who are receiving chronic SSRIs. 
2. 
Refer to the Study Training Manual for instructions if a patient does not remember to return the LogPad. 
3. 
The patient will return the LogPad to the investigator. The LogPad will provide a summary of the IELT data collected during the run-in period, 
and will indicate whether the patient is eligible to continue in the study based on the IELT criteria 
4. 
Coagulation (prothrombin time and activated partial thromboplastin time) will be tested at baseline (Visit 2). Only prothrombin time will be taken 
at other time points if certain laboratory test criteria defined in Section 4.2 are fulfilled. 
5. 
Medication use, IELT, ejaculation control, and ejaculation-related distress and alcohol intake are collected after each event via e-diary. 
6. 
IIEF and PEP have 4-week recall periods, and so these questionnaires are completed by the patients at study visits as above. 
7. 
Columbia-Suicide Severity Rating Scale is only mandatory at baseline but may be administered at other visits if clinically indicated. 
 


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13.2 Appendix 2: Evaluation Instruments 
13.2.1 Clinical Global Impression of Change (CGIC) 
This patient-completed questionnaire is often referred to as PGIC (Patient Global Impression 
of Change). The following questions will be asked after the patient has completed the PEP at 
the final visit: 
Compared to the start of the study, would you describe your premature ejaculation problem 
as: 
3 = Much worse 
2 = Worse 
1 = Slightly worse 
 0 = No change 
 1 = Slightly better 
 2 = Better 
 3 = Much better 
 
Compared to the start of the study did you experience a meaningful change in the time you 
took to ejaculate (cum)?   (Yes/No) 
Compared to the start of the study did you experience a meaningful change in your level of 
distress related to your premature ejaculation?  (Yes/No) 
13.2.2 Premature Ejaculation Profile (PEP) 
1. Over the past month, was your control over ejaculation during sexual intercourse: 
1 – Very Poor 
2 – Poor 
3 – Fair 
4 – Good 
5 – Very Good 
2. Over the past month, was your satisfaction with sexual intercourse: 
1 – Very Poor 
2 – Poor 
3 – Fair 
4 – Good 
5 – Very Good 
3. Over the past month, how distressed were you by how fast you ejaculated during sexual 
intercourse: 


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1 – Extremely 
2 – Quite a bit     3 – Moderately      4 – A little bit 5 – Not at all 
4. Over the past month, to what extent did how fast you ejaculated during sexual intercourse 
cause difficulty in your relationship with your partner: 
1 – Extremely 
2 – Quite a bit     3 – Moderately      4 – A little bit 5 – Not at all 
Additional Question 
5. Over the past month, how bothered were you by how fast you ejaculated during 
sexual intercourse: 
1 – Extremely 
2 – Quite a bit     3 – Moderately      4 – A little bit 5 – Not at all 
Patient Global Impression of Severity (PGIS) 
This questionnaire will be completed after the patient has completed the PEP.   
How would you rate your premature ejaculation (PE) now?  1 No PE (none), 2 Mild 3 
Moderate 4 Severe 
13.2.3 International Index of Erectile Function (IIEF) 
These questions ask about the effect your erection problems have had on your sex life over 
the past 4 weeks. Please answer these questions as honestly and as clearly as possible. 
Please answer every question by checking the appropriate box. If you are unsure about how 
to answer, please give the best answer you can. 
In answering these questions, the following definitions apply: 
* 
Sexual intercourse 
 
Is defined as sexual penetration of the partner. 
** 
Sexual Activity 
 
Includes intercourse, caressing, foreplay and masturbation. 


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*** 
Ejaculate 
 
Is defined as the ejection of semen from the penis (or the sensation of this). 
**** Sexual stimulation 
 
Includes situations such as loveplay with a partner, looking at erotic pictures, etc. 
1. Over the past 4 weeks how often were you able to get an erection during sexual 
activity**? 
 
Please check one box only. 
No sexual activity 
 
Almost always or always 
 
Most times (much more than half the time) 
 
Sometimes (about half the time) 
 
A few times (much less than half the time)  
Almost never or never 
 
 
2. Over the past 4 weeks when you had erections with sexual stimulation****, how often 
were your erections hard enough for penetration? 
 
Please check one box only. 
No sexual stimulation 
 
Almost always or always 
 
Most times (much more than half the time) 
 
Sometimes (about half the time) 
 
A few times (much less than half the time)  
Almost never or never 
 
 
 


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The next 3 questions will ask about the erections you may have had during sexual 
intercourse*. 
3. Over the past 4 weeks when you attempted sexual intercourse* how often were you able 
to penetrate (enter) your partner? 
 
Please check one box only. 
Did not attempt intercourse  
Almost always or always 
 
Most times (much more than half the time) 
 
Sometimes (about half the time) 
 
A few times (much less than half the time)  
Almost never or never 
 
 
4. Over the past 4 weeks during sexual intercourse* how often were you able to maintain 
your erection after you had penetrated (entered) your partner? 
 
Please check one box only. 
Did not attempt intercourse  
Almost always or always 
 
Most times (much more than half the time) 
 
Sometimes (about half the time) 
 
A few times (much less than half the time)  
Almost never or never 
 
 


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5. Over the past 4 weeks during sexual intercourse* how difficult was it to maintain your 
erection to completion of intercourse? 
 
Please check one box only. 
Did not attempt intercourse  
Extremely difficult  
Very difficult 
 
Difficult 
 
Slightly difficult 
 
Not difficult 
 
 
6. Over the past 4 weeks how many times have you attempted sexual intercourse*? 
 
Please check one box only. 
No attempts 
 
1-2 attempts  
3-4 attempts  
5-6 attempts  
7-10 attempts 
 
11 + attempts 
 
 
7. Over the past 4 weeks when you attempted sexual intercourse* how often was it 
satisfactory for you? 
 
Please check one box only. 
Did not attempt intercourse  
Almost always or always 
 
Most times (much more than half the time) 
 
Sometimes (about half the time) 
 
A few times (much less than half the time)  
Almost never or never 
 
 


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8. Over the past 4 weeks how much have you enjoyed sexual intercourse*? 
 
Please check one box only. 
No intercourse 
 
Very highly enjoyable  
Highly enjoyable  
Fairly enjoyable  
Not very enjoyable  
Not enjoyable 
 
 
9. Over the past 4 weeks when you had sexual stimulation**** or intercourse* how often 
did you ejaculate***? 
 
Please check one box only. 
No sexual stimulation or intercourse 
 
Almost always or always 
 
Most times (much more than half the time) 
 
Sometimes (about half the time) 
 
A few times (much less than half the time)  
Almost never or never 
 
 
10. Over the past 4 weeks when you had sexual stimulation**** or intercourse* how often 
did you have the feeling of orgasm with or without ejaculation***? 
 
Please check one box only. 
No sexual stimulation or intercourse 
 
Almost always or always 
 
Most times (much more than half the time) 
 
Sometimes (about half the time) 
 
A few times (much less than half the time)  
Almost never or never 
 
 


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The next 2 questions ask about sexual desire. Let’s define sexual desire as a feeling that 
may include wanting to have a sexual experience (e.g. masturbation or intercourse*), 
thinking about sex, or feeling frustrated due to lack of sex. 
11. Over the past 4 weeks how often have you felt sexual desire? 
 
Please check one box only. 
No sexual stimulation or intercourse 
 
Almost always or always 
 
Most times (much more than half the time) 
 
Sometimes (about half the time) 
 
A few times (much less than half the time)  
Almost never or never 
 
 
12. Over the past 4 weeks how would you rate your level of sexual desire? 
 
Please check one box only. 
Very high  
High  
Moderate  
Low 
 
Very Low 
 
None at all 
 
 
13. Over the past 4 weeks how satisfied have you been with your overall sex life? 
 
Please check one box only. 
Very satisfied  
Moderately satisfied 
 
About equally satisfied and dissatisfied 
 
Moderately dissatisfied 
 
Very dissatisfied 
 
 


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14. Over the past 4 weeks how satisfied have you been with your sexual relationship  
with your partner? 
 
Please check one box only. 
Very satisfied  
Moderately satisfied 
 
About equally satisfied and dissatisfied 
 
Moderately dissatisfied 
 
Very dissatisfied 
 
 
15. Over the past 4 weeks how would you rate your confidence that you could get and keep 
an erection? 
 
Please check one box only. 
Very high  
High  
Moderate  
Low 
 
Very Low 
 
 


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13.2.4 Patient Health Questionnaire 9 (PHQ-9) 
PATIENT HEALTH QUESTIONNAIRE – 9 
Over the last 2 weeks, how often have you been 
bothered by any of the following problems? 
(Use “✔” to indicate your answer) 
Not at all 
Several 
days 
More 
than half 
the days 
Nearly 
every 
day 
1. Little interest or pleasure in doing things 
0 
1 
2 
3 
2. Feeling down, depressed, or hopeless 
0 
1 
2 
3 
3. Trouble falling or staying asleep, or sleeping too 
much 
0 
1 
2 
3 
4. Feeling tired or having little energy 
0 
1 
2 
3 
5. Poor appetite or overeating 
0 
1 
2 
3 
6. Feeling bad about yourself – or that you are a 
failure or have let yourself or your family down 
0 
1 
2 
3 
7. Trouble concentrating on things, such as reading 
the newspaper or watching television 
0 
1 
2 
3 
8. Moving or speaking so slowly that other people 
could have noticed?  Or the opposite – being so 
fidgety or restless that you have been moving 
around a lot more than usual 
0 
1 
2 
3 
9. Thoughts that you would be better off dead or of 
hurting yourself in some way 
0 
1 
2 
3 
 
For OFFICE CODING        0       +          +           +          + 
 
 
Total Score:           + 
If you checked off any problems, how difficult have these problems made it for you to do your 
work, take care of things at home, or get along with other people? 
Not difficult 
at all 
 
Somewhat 
difficult 
 
Very 
difficult 
 
Extremely 
difficult 
 
 
Developed by Drs. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke, and colleagues, with an educational grant 
from Pfizer Inc. No permission required to reproduce, translate, display, or distribute. 
 


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13.2.5 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS18 is intended to be used by individuals who have received training in its 
administration. The questions contained in the C-SSRS are suggested probes. Ultimately, the 
determination of the presence of suicidal ideation or behavior depends on the judgment of the 
individual administering the scale. 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” 
section.  If the answer to question 2 is “yes”, ask questions 3, 4 and 5.  
If the answer to question 1 and/or 2 is “yes”, complete “Intensity of 
Ideation” section below. 
Lifetime: Time 
He Felt Most 
Suicidal 
Past ____ 
Months 
1. 
Wish to be Dead 
Patient endorses thoughts about a wish to be dead or not alive anymore, or wish to 
fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe: 
Yes 
 No 
 
Yes 
 No 
 
2. 
Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve 
thought about killing myself”) without thoughts of ways to kill oneself/associated 
methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
Yes 
 No 
 
Yes 
 No 
 
3. 
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Patient endorses thoughts of suicide and has thought of at least one method during the 
assessment period. This is different than a specific plan with time, place or method 
details worked out (e.g. thought of method to kill self but not a specific plan). 
Includes a person who would say, “I thought about taking an overdose but I never 
made a specific plan as to when, where or how I would actually do it…and I would 
never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
Yes 
 No 
 
Yes 
 No 
 
4. 
Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and patient reports having some intent to 
act on such thoughts, as opposed to “I have the thoughts but I definitely will not do 
anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
Yes 
 No 
 
Yes 
 No 
 
5. 
Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and 
patient has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do 
you intend to carry out this plan? 
If yes, describe: 
Yes 
 No 
 
Yes 
 No 
 


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INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of 
ideation (i.e., 1-5 from above, with 1 being the least severe and 5 being the most 
severe). Ask about time he was feeling the most suicidal. 
Lifetime 
Most Severe Ideation: 
 __________ 
__________________ 
 
 
Type # (1-5) 
Description of Ideation 
Past X Months  Most Severe Ideation: __________ 
__________________ 
 
 
Type # (1-5) 
Description of Ideation 
Most Severe 
Most Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week (2) Once a week (3) 2-5 times (4) Daily or almost daily (5) Many 
times each day 
_____ 
_____ 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting – a few seconds or minutes 
(4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time 
(5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
_____ 
_____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some difficulty (0) Does not attempt to control thoughts 
_____ 
_____ 
Deterrents 
Are there things-anyone or anything (e.g., family, religion, pain of death) – that 
stopped you from wanting to die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from committing suicide (4) Deterrents most likely did 
 
 
not stop you 
(2) Deterrents probably stopped you 
 
(5) Deterrents definitely did not 
 
 
stop you 
(3) Uncertain that deterrents stopped you 
(0) Does not apply 
_____ 
_____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing 
yourself? Was it to end the pain or stop the way you were feeling (in other words 
you couldn’t go on living with this pain or how you were feeling) or was it to get 
attention, revenge or a reaction from others? Or both? 
(1)Completely to get attention, revenge or a 
(4) Mostly to end or stop the pain (you 
 
reaction from others 
couldn’t go on living with the pain or how 
 
you were feeling) 
(2) Mostly to get attention, revenge or a 
(5) Completely to end or stop the pain (you 
 
reaction from others 
couldn’t go on living with the pain or how 
 
you were feeling) 
(3) Equally to get attention, revenge or a 
(0) Does not apply 
 
reaction from others and to end/stop the pain 
_____ 
 


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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate event; must ask about all types) 
Lifetime 
Past ____ 
Years 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result 
of act. Behavior was in part thought of as method to kill oneself. Intent does not have 
to be 100%. If there is any intent/desire to die associated with the act, then it can be 
considered an actual suicide attempt. There does not have to be any injury or harm, 
just the potential for injury or harm. If person pulls trigger while gun is in mouth but 
gun is broken so no injury results, this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred 
clinically from the behavior or circumstances. For example, a highly lethal act that is 
clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to 
head, jumping from window of a high floor/story). Also, if someone denies intent to 
die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
 
What did you do? 
 
Did you ____as a way to end your life? 
 
Were you trying to end your life when you ____? 
 
Or Did you think it was possible you could have died from ____? 
Or did you do it purely for other reasons/without ANY intention of killing yourself 
(like to relieve stress, feel better, get sympathy, or get something else to happen)? 
(Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Yes 
 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
_____ 
Yes 
 No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
_____ 
Has patient engaged in Non-Suicidal Self-Injurious Behavior? 
Yes 
 No 
 
Yes 
 No 
 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-
injurious act (if not for that, actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this 
becomes an attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward 
self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to 
jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck but has 
not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but 
someone or something stopped you before you actually did anything? 
If yes, describe: 
 
Yes 
 No 
 
 
 
 
 
 
 
 
Total # of 
interrupted 
 
_____ 
Yes 
 No 
 
 
 
 
 
 
 
 
Total # of 
interrupted 
 
_____ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before 
they actually have engaged in any self-destructive behavior. Examples are similar to interrupted 
attempts, except that the individual stops him/herself, instead of being stopped by something 
else. 
Has there been a time when you started to do something to try to end your life but 
you stopped yourself before you actually did anything? 
If yes, describe: 
 
Yes 
 No 
 
 
 
 
Total # of 
aborted 
 
_____ 
Yes 
 No 
 
 
 
 
Total # of 
aborted 
 
_____ 


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Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything 
beyond a verbalization or thought, such as assembling a specific method (e.g., buying pills, 
purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill 
yourself (such as collecting pills, getting a gun, giving valuables away or writing a 
suicide note)? 
If yes, describe:  
 
Yes 
 No 
 
Yes 
 No 
 
Suicidal Behavior 
Suicidal behavior was present during the assessment period? 
Yes 
 No 
 
Yes 
 No 
 
Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Most Lethal 
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
0.  No physical damage or very minor physical damage (e.g., surface scratches. 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; 
sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, 
somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive 
care required (e.g., comatose with reflexes intact; third-degree burns less than 20% 
of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required 
(e.g., comatose without reflexes; third-degree burns over 20% of body; extensive 
blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
_____ 
 
Enter Code 
 
_____ 
 
Enter Code 
 
_____ 
Potential Lethality: Only Answer if Actual Lethality = 0 
Likely lethality of actual attempt if no medical damage (the following examples, 
while having no actual medical damage, had potential for very serious lethality: put 
gun in mouth and pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away before run over). 
 
0.  Behavior not likely to result in injury 
1.  Behavior likely to result in injury but not likely to cause death 
2.  Behavior likely to result in death despite available medical care  
 
Enter Code 
 
_____ 
 
 
Enter Code 
 
_____ 
 
Enter Code 
 
_____ 
 


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13.3 Appendix 3: Laboratory Safety Tests 
Hematology Profile 
Hemoglobin 
Hematocrit 
Platelets 
Neutrophils 
Lymphocytes 
Monocytes 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Eosinophils 
Basophils 
Red blood cell count 
White blood cell count 
Other Blood Screens and Coagulation 
Hepatitis B surface antigen. Screening Only 
Hepatitis C virus antibody. Screening Only  
HIV 1 and HIV 2 EIA antibody.  Screening Only 
Prothrombin time (international normalized ratio value). Baseline Only 
Activated partial thromboplastin time. Baseline Only 
Clinical Chemistry Profile 
Sodium 
Potassium 
Magnesium 
Chloride 
Calcium 
Alkaline phosphate 
Glucose, random, serum 
Bicarbonate 
Creatinine, enzymatic 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Gamma glutamyl transpeptidase (GGT) 
Cholesterol 
High-density lipoprotein cholesterol 


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Low-density lipoprotein cholesterol (CALC) 
Triglycerides 
Urea (blood urea nitrogen) 
Urine Drug Screen 
Amphetamines  
Barbiturates  
Benzodiazepines  
Cannabinoids  
Cocaine metabolite  
Ethanol  
Opiates  
Phencyclidine  
Propoxyphene  
 
 
 


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13.4 Appendix 4 Amendment 1.0 
Reasons for Amendment 
• Inclusion of new data from recently complete caplet bioavailability study IX-0106 
• 1600 mg dose changed to 1200 mg dose thus number of caplets required per single 
dose reduced from four caplets to three caplets  
• Inclusion of additional information to be collected in LogPad as suggested by FDA 
Protocol Sections Amended 
The amended protocol sections are detailed below. The format is as follows: 
• The “change from” section represents the current text in the protocol 
• The “change to” section represents the revised text. Bolded text is used to indicate the 
addition of information to the current text, and strike-out text (e.g. text) is used to 
show the deletion of information from the current text 
Summary of Changes 
All references to 1600 mg dose have been changed to 1200 mg throughout the protocol with 
the exception of pages 25 and 26 which refer to the 1600 mg dose in the Multiple-Ascending 
Dose Study (2) 
All references to 4 caplets have been changed to 3 caplets throughout the protocol 
All references to ‘type of site’ have been replaced with ‘site’ throughout the protocol 
Protocol Synopsis 
Efficacy Assessments 
 
Change From 
 
Patient Questionnaires/Instruments: 
Questionnaires administered at the end of the run-in period 
and after 4 and 8 weeks of double-blind treatment  
• Premature Ejaculation Profile (PEP)  
Questionnaire to be administered at end of double-blind 
treatment only 
• Clinical Global Impression of Change (CGIC) 


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Change To 
 
Patient Questionnaires/Instruments: 
Questionnaires administered at the end of the run-in period 
and after 4 and 8 weeks of double-blind treatment  
• Premature Ejaculation Profile (PEP) including 
additional question on bother 
• Patient Global Impression of Severity (PGIS) 
Questionnaire to be administered at end of double-blind 
treatment only 
• Clinical Global Impression of Change (CGIC) 
List of Abbreviations 
Add Text 
PGIS Patient Global Impression of Severity 
1.3.5 Clinical Data 
Change From 
To date, 150 male subjects have received one or more doses of IX-01. Clinical safety and 
pharmacokinetic data are available from four completed Phase 1 studies (A8651001, 
IX-0101, IX-0102, and IX-0104). A Phase 2a proof-of-concept study (IX-0103) has also been 
completed and demonstrated the efficacy of IX-01 (doses 400 to 800 mg as needed) to 
prolong IELT, improve ejaculation-related control, and reduce ejaculation-related distress in 
men with lifelong PE. 
Change To 
To date, 150 162 male subjects have received one or more doses of IX-01. Clinical safety and 
pharmacokinetic data are available from four completed Phase 1 studies (A8651001, 
IX-0101, IX-0102, and IX-0104). Also, preliminary clinical safety and kinetic data are 
available from recently completed study IX-0106. A Phase 2a proof-of-concept study (IX-
0103) has also been completed and demonstrated the efficacy of IX-01 (doses 400 to 800 mg 


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as needed) to 
prolong 
IELT, improve ejaculation-related control, 
and reduce 
ejaculation-related distress in men with lifelong PE. 
1.3.5 Clinical Data 
Change From 
Relative Bioavailability Study 
Change To 
Relative Bioavailability Study (200 mg capsules) 
1.3.5 Clinical Data 
Add Text 
Relative Bioavailability Study (400mg caplets) 
In Study IX-0106, 12 subjects were randomized to receive IX-01 1600 mg dispersion in 
the fasted state, IX-01 1600 mg (4 × 400 mg caplets) in the fasted state, and IX-01 1600 
mg (4 × 400 mg caplets) administered after a high-fat meal. 
The preliminary results indicate that the GM Cmax values were 2152 ng/ml for the caplet 
formulation administered in the fasted state, and that the caplet has an improved 
bioavailability compared to the dispersion, with GM Cmax and AUC 1.8 fold those of 
the dispersion. In addition, food increased the bioavailability (AUC) of the caplet (1.5 
fold), which is comparable to the effect of food seen with the capsule and dispersion 
formulations previously. However, unlike the capsule and dispersion formulations, the 
rate of absorption was not significantly delayed for the caplet formulation with Cmax 
increasing 2.7 fold in the presence of food. There were no treatment-related adverse 
events or safety issues reported in this study. 
1.4.1 Rationale for Dose Selection 
Change From 


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The results of study IX-0103 indicated that single doses of IX-01 (400 to 800 mg), taken 1 to 
6 hours prior to intercourse in the fasted state, prolong IELT and improve ejaculation-related 
control and distress. A post hoc analysis indicated that 400 mg is less effective than the 
800 mg dose. However, even at 800 mg, less than half of the patients reported benefit, and 
therefore, the objective of this study is to explore the efficacy and safety of 1600 mg and to 
compare the response at this dose with placebo, 400 mg, and 800 mg doses. In the previous 
efficacy study, doses of 400 to 800 mg were taken one hour before or after food and 1 to 
6 hours prior to sexual activity. In this study, it is also recommended to take the study drug 
one hour before or after food and 1 to 6 hours prior to sexual activity. A 400 mg caplet 
formulation has been developed to allow a reduced number of caplets to be taken per dose of 
IX-01. 
Change To 
The results of study IX-0103 indicated that single doses of IX-01 (400 to 800 mg 
administered as capsules), taken 1 to 6 hours prior to intercourse in the fasted state, prolong 
IELT and improve ejaculation-related control and distress. A post hoc analysis indicated that 
400 mg is less effective than the 800 mg dose. However, even at 800 mg, less than half of the 
patients reported benefit, and therefore, the objective of this study is to explore the efficacy 
and safety of 16200 mg (3 x 400 mg caplets) and to compare the response at this dose with 
placebo, 400 mg, and 800 mg doses. In the previous efficacy study, doses of 400 to 800 mg 
were taken one hour before or after food and 1 to 6 hours prior to sexual activity. In this 
study, it is also recommended to take the study drug at least one hour before or after food 
and 1 to 6 hours prior to sexual activity. A 400 mg caplet formulation has been developed to 
improve bioavailability and to allow a reduced number of caplets to be taken per dose of 
IX-01. 
1.5 Potential Risks and Benefits 
Change From 
The nonclinical toxicology, pharmacology, and pharmacokinetic data generated to date and 
the clinical safety, pharmacokinetic, and pharmacodynamic data generated in studies 
A8651001 and IX-0101 to IX-0104 support an acceptable risk-benefit profile to evaluate the 
efficacy and toleration of single doses of orally administered IX-01 (taken as required but not 


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more than once per day) in adult males, aged 18 to 60 years, inclusive, with PE. The 
maximum dose to be administered in this study is 1600 mg taken prior to sexual activity but 
not more than once per day. Doses up to and including 2400 mg administered as a dispersion 
and taken in the fasted state once daily for 10 consecutive days have been well tolerated by 
healthy volunteers. Small reductions in mean systolic and diastolic blood pressure between 
active and placebo groups were not of clinical significance. Two subjects have been 
discontinued from IX-01 because of skin AEs: a subject who had a pruritic skin rash after 
8 days of consecutive dosing with 1600 mg, and a subject with transient urticaria after a 
single dose of 2400 mg. As in the previous Phase 2 study, the safety of the patients will be 
assessed at frequent intervals by physical examination and laboratory safety tests. Although 
preclinical and clinical data generated to date with IX-01 provide no evidence of adverse 
effects on mood, this protocol includes questionnaires and interviews to screen for depression 
and suicidality, which is in accordance with other clinical studies of new treatments for PE. 
Change To 
The nonclinical toxicology, pharmacology, and pharmacokinetic data generated to date and 
the clinical safety, pharmacokinetic, and pharmacodynamic data generated in studies 
A8651001 and IX-0101 to IX-0104 support an acceptable risk-benefit profile to evaluate the 
efficacy and toleration of single doses of orally administered IX-01 (taken as required but not 
more than once per day) in adult males, aged 18 to 60 years, inclusive, with PE. The 
maximum dose to be administered in this study is 16200 mg (3 x 400 mg caplets) taken prior 
to sexual activity but not more than once per day. Doses up to and including 2400 mg 
administered as a dispersion and taken in the fasted state once daily for 10 consecutive days 
have been well tolerated by healthy volunteers. Small reductions in mean systolic and 
diastolic blood pressure between active and placebo groups were not of clinical significance. 
Two subjects have been discontinued from IX-01 because of skin AEs: a subject who had a 
pruritic skin rash after 8 days of consecutive dosing with 1600 mg, and a subject with 
transient urticaria after a single dose of 2400 mg. In Study IX-0106 twelve subjects have 
received 1600mg administered as 4 x 400 caplets in fasted state and 11 subjects also 
received 4 x 400 mg caplets after a high fat meal.  No treatment-related adverse events 
were observed. As in the previous Phase 2 study, the safety of the patients will be assessed at 
frequent intervals by physical examination and laboratory safety tests. Although preclinical 
and clinical data generated to date with IX-01 provide no evidence of adverse effects on 


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mood, this protocol includes questionnaires and interviews to screen for depression and 
suicidality, which is in accordance with other clinical studies of new treatments for PE. 
 3.1 Study Design 
Change From 
Figure 13-1 
Study Design 
For patients who are receiving regular selective serotonin reuptake inhibitors only 
 
 
 
 
 
 
 
 
 
 
Change To 
Figure 13-2 
Study Design 
For patients who are receiving regular selective serotonin reuptake inhibitors only 
 
 
 
 
 
 
Washout 
IX-01 400 mg 
Screening 
Placebo 
Follow-Up 
IX-01 16200 mg 
IX-01 800 mg 
Washout 
IX-01 400 mg 
Week 10 
Visit 6 
Follow-Up 
Week 8 
Visit 5 or 
Early Termination 
Week 4 
Visit 4 
Week 2 
Visit 3 
Week 0 
Visit 2 
Baseline 
Week -4 
Visit 1 
Screening 
Week -8 
Prescreening  
Optional 
Screening 
Placebo 
Follow-Up 
IX-01 1600 mg 
IX-01 800 mg 


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3.1 Study Design 
Change From 
Eligible patients will undergo one 8-week treatment period, during which time they are 
randomized to take IX-01, 400, 800, or 1600 mg or matching placebo. In order to maintain 
the double-blind, each dose will be presented as 4 caplets in blisters in single-dose units. 
Thus, for example, a patient randomized to 400 mg IX-01 will receive blister cards with each 
dose comprising one IX-01 400 mg caplet and three matching placebo caplets. Patients will 
complete an e-diary (LogPad) on all days during the treatment period that sexual activity is 
performed with or without the use of the study drug. 
Change To 
Eligible patients will undergo one 8-week treatment period, during which time they are 
randomized to take IX-01, 400, 800, or 16200 mg or matching placebo. In order to maintain 
the double-blind, each dose will be presented as 34 caplets in blisters in single-dose units. 
Thus, for example, a patient randomized to 400 mg IX-01 will receive blister cards with each 
dose comprising one IX-01 400 mg caplet and two three matching placebo caplets. Patients 
will complete an e-diary (LogPad) on all days during the treatment period that sexual activity 
is performed with or without the use of the study drug. 
3.1 Study Design 
Change From 
During the treatment period, patients will be expected to return to the study site and use their 
LogPad to complete the following questionnaires according to the study schedule: 
• Premature Ejaculation Profile (PEP) 
• International Index of Erectile Function (IIEF) 
• Patient Health Questionnaire (PHQ-9) 
Week 10 
Visit 6 
Follow-Up 
Week 8 
Visit 5 or 
Early Termination 
Week 4 
Visit 4 
Week 2 
Visit 3 
Week 0 
Visit 2 
Baseline 
Week -4 
Visit 1 
Screening 
Week -8 
Prescreening  
Optional 


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• Clinical Global Impression of Change (CGIC) – Early Termination/Visit 5 only 
Change To 
During the treatment period, patients will be expected to return to the study site and use their 
LogPad to complete the following questionnaires according to the study schedule: 
• Premature Ejaculation Profile (PEP) 
• International Index of Erectile Function (IIEF) 
• Patient Health Questionnaire (PHQ-9) 
• Patient Global Impression of Severity (PGIS) 
• Clinical Global Impression of Change (CGIC) – Early Termination/Visit 5 only 
5.3.1 Study Drug Packaging and Storage 
Change From 
All supplies will be packed, labelled, and released in accordance with GMP and GCP 
guidelines. The investigator, or an approved representative (eg, pharmacist), will ensure that 
all investigational product is stored in a secure area, under recommended storage conditions 
(15°C-30°C) and in accordance with applicable regulatory requirements. Any excursions 
from the recommended storage conditions should be reported to the sponsor within 24 hours 
of the finding. 
Change To 
All supplies will be packed, labelled, and released in accordance with GMP and GCP 
guidelines. The investigator, or an approved representative (eg, pharmacist), will ensure that 
all investigational product is stored in a secure area, under recommended storage conditions 
59°F-86°F (15°C-30°C) and in accordance with applicable regulatory requirements. Any 
excursions from the recommended storage conditions should be reported to the sponsor 
within 24 hours of the finding. 
Section 6.1 Study Visits 


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Screening Visit 1 
Change From 
Patients willing to take part in the study and who are eligible according to the criteria already 
assessed during the screening visit will be provided with a LogPad and stopwatch. They will 
complete training on how to use the LogPad during this visit. Once the training is completed, 
patients will be asked to attempt intercourse with their partners at least 4 times during the 
4-week run-in period, to use the stopwatch to time the attempt, and to record the relevant 
details in the LogPad. At the next study visit (Visit 2), the patient must bring the LogPad to 
the study site. Further details for LogPad use and instructions are found in the Study Training 
Manual. 
Change To 
Patients willing to take part in the study and who are eligible according to the criteria already 
assessed during the screening visit will be provided with a LogPad and stopwatch. They will 
complete training on how to use the LogPad during this visit. Once the training is completed, 
patients will be asked to attempt intercourse with their partners at least 4 times during the 
4-week run-in period, to use the stopwatch to time the attempt, and to record the relevant 
details in the LogPad including whether alcoholic drinks were taken prior to intercourse. 
At the next study visit (Visit 2), the patient must bring the LogPad to the study site. Further 
details for LogPad use and instructions are found in the Study Training Manual. 
Baseline Visit 2 
Change From 
• The investigator will provide the LogPad back to the patient for completion of the PEP, 
IIEF, and PHQ-9. After completion of these questionnaires, the patient will return the 
LogPad to the investigator. The LogPad will provide a further summary that will indicate 
whether the patient is eligible to continue in the study based on the results of the PEP, 
IIEF, and PHQ-9. If the patient is not eligible based on these assessments, then he should 
not be randomized or continued in the study, and the investigator may discuss alternate 
treatment options. 


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• The patients who meet all of the eligibility criteria will be randomized and assigned a 
treatment number. Eligible patients will be provided with at least 7 doses of study drug 
(IX-01 or placebo). Further supplies can be dispensed at this visit based on a discussion 
between the Investigator and patient but the maximum allowed dose is 1 dose (3 caplets) 
per day. Each dose of study drug comprises 3 caplets contained within a discrete blister 
card. Patients must be informed that 1 dose is all 3 caplets, and the dose should be taken 
with water at least one hour before or after food. Patients should attempt sexual 
intercourse approximately 1 to 6 hours after taking the dose. The patients will also be 
provided with a LogPad. Patients should be reminded on the instructions for using the 
stopwatch and also the LogPad to record their usage of the study medication, as well as 
all occasions that they attempt sexual intercourse. Patients will be asked if they are 
willing to try intercourse with their partner approximately 8 times or more between Visit 
2 and Visit 5 although less than 8 attempts will not be classified as a protocol deviation. 
Patients should be reminded to bring their LogPad and any unused study medication back 
to the study site for Visit 3. 
Change To 
• The investigator will provide the LogPad back to the patient for completion of the PEP, 
PGIS, IIEF, and PHQ-9. After completion of these questionnaires, the patient will return 
the LogPad to the investigator. The LogPad will provide a further summary that will 
indicate whether the patient is eligible to continue in the study based on the results of the 
PEP, IIEF, and PHQ-9. If the patient is not eligible based on these assessments, then he 
should not be randomized or continued in the study, and the investigator may discuss 
alternate treatment options. 
• The patients who meet all of the eligibility criteria will be randomized and assigned a 
treatment number. Eligible patients will be provided with at least 7 doses of study drug 
(IX-01 or placebo). Further supplies can be dispensed at this visit based on a discussion 
between the Investigator and patient but the maximum allowed dose is 1 dose (3 caplets) 
per day. Each dose of study drug comprises 3 caplets contained within a discrete blister 
card. Patients must be informed that 1 dose is all 3 caplets, and the dose should be taken 
with water at least one hour before or after food. Patients should attempt sexual 
intercourse approximately 1 to 6 hours after taking the dose. The patients will also be 


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provided with a LogPad. Patients should be reminded on the instructions for using the 
stopwatch and also the LogPad to record their usage of the study medication, as well as 
all occasions that they attempt sexual intercourse and whether alcoholic drinks were 
taken. Patients will be asked if they are willing to try intercourse with their partner 
approximately 8 times or more between Visit 2 and Visit 5 although less than 8 attempts 
will not be classified as a protocol deviation. Patients should be reminded to bring their 
LogPad and any unused study medication back to the study site for Visit 3. 
Section 6.1 Study Visits 
Visit 4 
Change From 
• The investigator will provide the LogPad back to the patient for completion of the PEP, 
IIEF, and PHQ-9. Once complete, the patient will return the LogPad to the investigator. 
Change To 
• The investigator will provide the LogPad back to the patient for completion of the PEP, 
PGIS, IIEF, and PHQ-9. Once complete, the patient will return the LogPad to the 
investigator. 
 
Section 6.1 Study Visits 
Visit 5 (End of Treatment or Early Termination) 
Change From 
• The investigator will provide the LogPad back to the patient for completion of the PEP, 
IIEF, PHQ-9, and CGIC. After completion, the patient will return the LogPad to the 
investigator. 
Change To 


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• The investigator will provide the LogPad back to the patient for completion of the PEP, 
IIEF, PHQ-9, PGIS and CGIC. After completion, the patient will return the LogPad to 
the investigator. 
6.2 Efficacy Assessments 
Change From 
Outcome measures included during treatment include results from the use of the following: 
• Stopwatch to measure IELT. 
• LogPad (e-diary) to record summary of study drug intake and details of sexual 
intercourse attempts (including IELT). 
• Responses to the PEP questionnaire. 
• Responses to the CGIC questionnaire. 
Change To 
Outcome measures included during treatment include results from the use of the following: 
• Stopwatch to measure IELT. 
• LogPad (e-diary) to record summary of study drug intake and details of sexual 
intercourse attempts (including IELT and two PEP questions (control and ejaculation-
related personal distress)). 
• Responses to the PEP questionnaire. 
• Responses to PGIS questionnaire. 
• Responses to the CGIC questionnaire. 
Change From 


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LogPad 
The LogPad has been specifically designed to enable patients to record details of sexual 
intercourse attempts and study drug use throughout the study. The key data to be recorded by 
the patients are date and time of study drug caplets taken, date and time of any intercourse 
attempt, IELT, level of control of timing of ejaculation; and level of ejaculation-related 
personal distress. The patient also will use the LogPad at each study visit to complete the 
PEP, IIEF, and PHQ-9 (PEP, and IIEF are not completed at Visit 3/Week 2). At the final 
treatment visit (Visit 5 or Early Termination), the CGIC is also collected via the LogPad. For 
further details of the LogPad design and function, refer to the Study Training Manual. 
PEP 
The PEP is a widely used self-administered tool that includes measures of perceived control 
over ejaculation, ejaculation-related personal distress, ejaculation-related interpersonal 
difficulty, and satisfaction with intercourse. It has been used in many previous studies of PE 
and is considered validated for this purpose. All of the domains are relevant to a patient with 
PE, and the instrument has the advantage of being simple and quick to use.14.   
CGIC 
The Clinical Global Impression of Change (CGIC) is a simple and validated instrument that 
allows the patient to rate the change in his condition (PE) at the end of treatment on a 7-point 
scale ranging from “much worse” to “much better.”15  
Change To 
LogPad 
The LogPad has been specifically designed to enable patients to record details of sexual 
intercourse attempts and study drug use throughout the study. The key data to be recorded by 
the patients are date and time of study drug caplets taken, date and time of any intercourse 
attempt, IELT, level of control of timing of ejaculation; and level of ejaculation-related 
personal distress. The patient also will use the LogPad at each study visit to complete the 
PEP, PGIS, IIEF, and PHQ-9 (PEP, PGIS and IIEF are not completed at Visit 3/Week 2). At 
the final treatment visit (Visit 5 or Early Termination), the CGIC is also collected via the 


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LogPad. For further details of the LogPad design and function, refer to the Study Training 
Manual. 
 
PEP 
The PEP is a widely used self-administered tool that includes measures of perceived control 
over ejaculation, ejaculation-related personal distress, ejaculation-related interpersonal 
difficulty, and satisfaction with intercourse. It has been used in many previous studies of PE 
and is considered validated for this purpose. All of the domains are relevant to a patient with 
PE, and the instrument has the advantage of being simple and quick to use.14.  In this study 
an additional exploratory question on bother will be included in the 4-week recall 
version used at baseline, week 4 and week 8. 
PGIS 
The Patient Global Impression of Severity is a questionnaire that asks the patient to 
assess the severity of their condition (categories of response are no PE, mild, moderate, 
severe). 
CGIC 
The Clinical Global Impression of Change (CGIC) (also referred to as PGIC) is a simple 
and validated instrument that allows the patient to rate the change in his condition (PE) at the 
end of treatment on a 7-point scale ranging from “much worse” to “much better.”15  In this 
study the CGIC will be administered after the PEP at the final visit and will include two 
additional questions.  See Appendix 2.   
Section 7.2.2 Other Secondary Efficacy Endpoints 
Change From 


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The following other secondary efficacy endpoints will be analyzed: 
1. Fold change from baseline in (arithmetic) mean IELT over the treatment assessment 
period. 
2. Change from baseline in (arithmetic) mean IELT over the treatment assessment period. 
3. Proportion of patients with GM IELT of ≥1 minute over the treatment assessment period. 
4. Proportion of patients with GM IELT of ≥2 minutes over the treatment assessment period. 
5. Proportion of patients with GM IELT of ≥3 minutes over the treatment assessment period. 
6. Proportion of patients with GM IELT of ≥4 minutes over the treatment assessment period. 
7. Proportion of patients with GM IELT of ≥5 minutes over the treatment assessment period. 
8. Proportion of patients with GM IELT increase over the treatment assessment period of 
≥45 seconds compared with baseline. 
9. Proportion of patients with GM IELT increase over the treatment assessment period of 
≥1 minute compared with baseline. 
10. Percentage of intercourse attempts lasting >1 minute over the treatment assessment 
period. 
11. Percentage of intercourse attempts lasting >2 minutes over the treatment assessment 
period. 
12. Percentage of intercourse attempts lasting >3 minutes over the treatment assessment 
period. 
13. Percentage of intercourse attempts lasting >4 minutes over the treatment assessment 
period. 
14. Percentage of intercourse attempts lasting >5 minutes over the treatment assessment 
period. 
15. Proportion of patients achieving ≥1 category of improvement from baseline to end of 
treatment in each of the following (from 4-weekly PEP questionnaire): 
a. Satisfaction with sexual intercourse 
b. Control over ejaculation during sexual intercourse 


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c. Ejaculation-related distress 
d. Ejaculation-related interpersonal difficulty 
16. Change in score from baseline in each of the following (from 4-weekly PEP 
questionnaire): 
a. Satisfaction with sexual intercourse 
b. Control over ejaculation during sexual intercourse 
c. Ejaculation-related distress 
d. Ejaculation-related interpersonal difficulty 
Change To 
The following other secondary efficacy endpoints will be analyzed: 
1. Fold change from baseline in (arithmetic) mean IELT over the treatment assessment 
period. 
2. Change from baseline in (arithmetic) mean IELT over the treatment assessment period. 
3. Proportion of patients with GM IELT of ≥1 minute over the treatment assessment period. 
4. Proportion of patients with GM IELT of ≥2 minutes over the treatment assessment period. 
5. Proportion of patients with GM IELT of ≥3 minutes over the treatment assessment period. 
6. Proportion of patients with GM IELT of ≥4 minutes over the treatment assessment period. 
7. Proportion of patients with GM IELT of ≥5 minutes over the treatment assessment period. 
8. Proportion of patients with GM IELT increase over the treatment assessment period of 
≥45 seconds compared with baseline. 
9. Proportion of patients with GM IELT increase over the treatment assessment period of 
≥1 minute compared with baseline. 
10. Percentage of intercourse attempts lasting >1 minute over the treatment assessment 
period. 
11. Percentage of intercourse attempts lasting >2 minutes over the treatment assessment 
period. 


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12. Percentage of intercourse attempts lasting >3 minutes over the treatment assessment 
period. 
13. Percentage of intercourse attempts lasting >4 minutes over the treatment assessment 
period. 
14. Percentage of intercourse attempts lasting >5 minutes over the treatment assessment 
period. 
15. Proportion of patients improving on PGIS 
16. Proportion of patients achieving ≥1 category of improvement from baseline to end of 
treatment in each of the following (from 4-weekly PEP questionnaire): 
a. Satisfaction with sexual intercourse 
b. Control over ejaculation during sexual intercourse 
c. Ejaculation-related distress 
d. Ejaculation-related interpersonal difficulty 
e. Ejaculation-related bother 
19. Change in score from baseline in each of the following (from 4-weekly PEP 
questionnaire): 
a. Satisfaction with sexual intercourse 
b. Control over ejaculation during sexual intercourse 
c. Ejaculation-related distress 
d. Ejaculation-related interpersonal difficulty 
e. Ejaculation-related bother 
Section 7.5  Description of Subgroups to be Analyzed 
Change From 
Details will be provided in the Statistical Analysis Plan (SAP) for any proposed subgroup 
analyses  


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Change To 
Details will be provided in the Statistical Analysis Plan (SAP) for any proposed subgroup 
analyses (e.g patients with all baseline IELTs were <= 60 seconds) 
7.6.2.1 Change From Baseline Endpoints 
Change From 
Analyses of e-diary data expressed in change from baseline over the treatment assessment 
period will be carried out using a mixed linear model. All analyses should include treatment, 
baseline IELT, and the baseline score of the analyzed endpoint as fixed effects and the type of 
site as a random effect. In addition to the mixed linear model, a nonparametric approach may 
be carried out for specific secondary endpoints. Further details will be provided in the SAP. 
Change in score from baseline in each of the 4 PEP questions (ie, Endpoint 17 of 
Section 7.2.2) will be carried out using a mixed-effect model repeated measure model. All 
analyses should include treatment, baseline IELT, the baseline score of the analyzed 
endpoint, the visit, and the interaction between visit and treatment as fixed effects and the 
type of site as a random effect. Visit will be considered as the repeated measurement. 
Change To 
Analyses of e-diary data expressed in change from baseline over the treatment assessment 
period will be carried out using a mixed linear model. All analyses should include treatment, 
baseline IELT, and the baseline score of the analyzed endpoint as fixed effects and the type 
of site as a random effect. In addition to the mixed linear model, a nonparametric approach 
may be carried out for specific secondary endpoints. Further details will be provided in the 
SAP. 
Change in score from baseline in each of the 4 PEP questions (ie, Endpoint 177 of 
Section 7.2.2) will be carried out using a mixed-effect model repeated measure model. All 
analyses should include treatment, baseline IELT, the baseline score of the analyzed 
endpoint, the visit, and the interaction between visit and treatment as fixed effects and the 
type of site as a random effect. Visit will be considered as the repeated measurement. 


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Section 7.6.3 Safety Analyses 
Change From 
Concomitant Medications: Previous and concomitant medications will be summarized 
according to the WHO Drug Dictionary (WHO-DD). The number and percentage of patients 
for each treatment group will be presented for previous and concomitant medications. 
Change To 
Concomitant Medications: Previous and concomitant medications will be summarized 
according to the WHO Drug Dictionary (WHO-DD). The number and percentage of patients 
for each treatment group will be presented for previous and concomitant medications. 
The patient will record in the LogPad whether he had any alcoholic drinks within 4 
hours prior to sexual intercourse.  
 
 


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Table 13-2 
Schedule of Events 
Change From 
IX-0105 
Study Schedule and Events 
 
For Patients on 
Chronic SSRIs only 
Prescreening Visit1 
(Week -8) 
Visit 11 
Screening 
 
(Week -4) 
Visit 22 
Baseline 
 
(Week 0) 
Visit 32 
 
 
(Week 2) 
Visit 42 
 
 
(Week 4) 
Visit 5 or  
Early Termination2 
 
(Week 8) 
Visit 6  
Follow Up 
 
(Week 10) 
Days Post First Dose (Window) 
-56 
-28 (±3) 
0 (±7) 
14 (±3) 
28 (±7) 
56 (±7) 
70 (±7) 
Informed Consent 
X 
X1 
 
 
 
 
 
Medical History and Demography 
X 
X1 
 
 
 
 
 
Inclusion/Exclusion Criteria and 
Eligibility Review 
X 
X 
X3 
 
 
 
 
Physical Examination 
 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Weight 
 
X 
X 
 
 
X 
X 
Blood Pressure and Heart Rate  
 
X 
X 
 
X 
X 
X 
Oral Temperature 
 
 
X 
 
 
 
 
12-lead ECG (single) 
 
X 
X  
 
 
X  
X 
Safety Laboratory Tests (Clinical 
Chemistry, Hematology, and 
Coagulation4)  
 
X 
X 
X 
X 
X 
X 
Urinalysis  
 
X 
X 
 
X 
X 
X 
Serology (HBsAg, HCV Ab, HIV 1, 
HIV 2) 
 
X 
 
 
 
 
 
Urine Drug Screen 
 
X 
X 
 
 
X 
 
Randomization  
 
 
X 
 
 
 
 
e-Diary Supply5 
 
X 
X 
X 
X 
 
 
Diary Evaluation5 
 
 
X 
X 
X 
X 
 
Study Drug Supply 
 
 
X 
X 
X 
 
 
Study Drug Compliance 
 
 
 
X 
X 
X 
 


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IX-0105 
Study Schedule and Events 
 
For Patients on 
Chronic SSRIs only 
Prescreening Visit1 
(Week -8) 
Visit 11 
Screening 
 
(Week -4) 
Visit 22 
Baseline 
 
(Week 0) 
Visit 32 
 
 
(Week 2) 
Visit 42 
 
 
(Week 4) 
Visit 5 or  
Early Termination2 
 
(Week 8) 
Visit 6  
Follow Up 
 
(Week 10) 
Days Post First Dose (Window) 
-56 
-28 (±3) 
0 (±7) 
14 (±3) 
28 (±7) 
56 (±7) 
70 (±7) 
IIEF6 
 
 
X 
 
X 
X 
 
PEP6 
 
 
X 
 
X 
X 
 
CGIC 
 
 
 
 
 
X 
 
PHQ-9 
 
 
X 
X 
X 
X 
 
Columbia-Suicide Severity Rating 
Scale7 
 
 
X 
(X) 
(X) 
(X) 
(X) 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: CGIC, Clinical Global Impression of Change; ECG, electrocardiogram; HBsAg, hepatitis B surface antigen; HCV Ab, hepatitis C virus antibody; 
HIV, human immunodeficiency virus; IELT, intravaginal ejaculatory latency time; IIEF, International Index of Erectile Function; PEP, Premature Ejaculation 
Profile; PHQ-9, Patient Health Questionnaire 9; SSRI, selective serotonin reuptake inhibitor. 
1. 
Only patients taking chronic SSRIs will have an additional 4-week washout prior to the 4-week run-in period. They will attend a Prescreening Visit and will 
return to the site for a complete screening (Visit 1) once their washout period is complete. Informed consent and medical history will be obtained at the 
Prescreening Visit for patients who are receiving chronic SSRIs. 
2. 
Refer to the Study Training Manual for instructions if a patient does not remember to return the LogPad. 
3. 
The patient will return the LogPad to the investigator. The LogPad will provide a summary of the IELT data collected during the run-in period, and will 
indicate whether the patient is eligible to continue in the study based on the IELT criteria 
4. 
Coagulation (prothrombin time and activated partial thromboplastin time) will be tested at baseline (Visit 2). Only prothrombin time will be taken at other 
time points if certain laboratory test criteria defined in Section 4.2 are fulfilled. 
5. 
Medication use, IELT, ejaculation control, and ejaculation-related distress are collected after each event via e-diary. 
6. 
IIEF and PEP have 4-week recall periods, and so these questionnaires are completed by the patients at study visits as above. 
7. 
Columbia-Suicide Severity Rating Scale is only mandatory at baseline but may be administered at other visits if clinically indicated. 
 


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Change To 
Table 13-3 
Schedule of Events 
IX-0105 
Study Schedule and Events 
 
For Patients on 
Chronic SSRIs only 
Prescreening Visit1 
(Week -8) 
Visit 11 
Screening 
 
(Week -4) 
Visit 22 
Baseline 
 
(Week 0) 
Visit 32 
 
 
(Week 2) 
Visit 42 
 
 
(Week 4) 
Visit 5 or  
Early Termination2 
 
(Week 8) 
Visit 6  
Follow Up 
 
(Week 10) 
Days Post First Dose (Window) 
-56 
-28 (±3) 
0 (±7) 
14 (±3) 
28 (±7) 
56 (±7) 
70 (±7) 
Informed Consent 
X 
X1 
 
 
 
 
 
Medical History and Demography 
X 
X1 
 
 
 
 
 
Inclusion/Exclusion Criteria and 
Eligibility Review 
X 
X 
X3 
 
 
 
 
Physical Examination 
 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Weight 
 
X 
X 
 
 
X 
X 
Blood Pressure and Heart Rate  
 
X 
X 
 
X 
X 
X 
Oral Temperature 
 
 
X 
 
 
 
 
12-lead ECG (single) 
 
X 
X  
 
 
X  
X 
Safety Laboratory Tests (Clinical 
Chemistry, Hematology, and 
Coagulation4)  
 
X 
X 
X 
X 
X 
X 
Urinalysis  
 
X 
X 
 
X 
X 
X 
Serology (HBsAg, HCV Ab, HIV 1, 
HIV 2) 
 
X 
 
 
 
 
 
Urine Drug Screen 
 
X 
X 
 
 
X 
 
Randomization  
 
 
X 
 
 
 
 
e-Diary Supply5 
 
X 
X 
X 
X 
 
 
Diary Evaluation5 
 
 
X 
X 
X 
X 
 
Study Drug Supply 
 
 
X 
X 
X 
 
 
Study Drug Compliance 
 
 
 
X 
X 
X 
 


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IX-0105 
Study Schedule and Events 
 
For Patients on 
Chronic SSRIs only 
Prescreening Visit1 
(Week -8) 
Visit 11 
Screening 
 
(Week -4) 
Visit 22 
Baseline 
 
(Week 0) 
Visit 32 
 
 
(Week 2) 
Visit 42 
 
 
(Week 4) 
Visit 5 or  
Early Termination2 
 
(Week 8) 
Visit 6  
Follow Up 
 
(Week 10) 
Days Post First Dose (Window) 
-56 
-28 (±3) 
0 (±7) 
14 (±3) 
28 (±7) 
56 (±7) 
70 (±7) 
IIEF6 
 
 
X 
 
X 
X 
 
PEP6 (with additional question) 
 
 
X 
 
X 
X 
 
PGIS 
 
 
X 
 
X 
X 
 
CGIC 
 
 
 
 
 
X 
 
PHQ-9 
 
 
X 
X 
X 
X 
 
Columbia-Suicide Severity Rating 
Scale7 
 
 
X 
(X) 
(X) 
(X) 
(X) 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: CGIC, Clinical Global Impression of Change; ECG, electrocardiogram; HBsAg, hepatitis B surface antigen; HCV Ab, hepatitis C virus antibody; 
HIV, human immunodeficiency virus; IELT, intravaginal ejaculatory latency time; IIEF, International Index of Erectile Function; PEP, Premature Ejaculation 
Profile; PHQ-9, Patient Health Questionnaire 9; SSRI, selective serotonin reuptake inhibitor. 
1. 
Only patients taking chronic SSRIs will have an additional 4-week washout prior to the 4-week run-in period. They will attend a Prescreening Visit and will 
return to the site for a complete screening (Visit 1) once their washout period is complete. Informed consent and medical history will be obtained at the 
Prescreening Visit for patients who are receiving chronic SSRIs. 
2. 
Refer to the Study Training Manual for instructions if a patient does not remember to return the LogPad. 
3. 
The patient will return the LogPad to the investigator. The LogPad will provide a summary of the IELT data collected during the run-in period, and will 
indicate whether the patient is eligible to continue in the study based on the IELT criteria 
4. 
Coagulation (prothrombin time and activated partial thromboplastin time) will be tested at baseline (Visit 2). Only prothrombin time will be taken at other 
time points if certain laboratory test criteria defined in Section 4.2 are fulfilled. 
5. 
Medication use, IELT, ejaculation control, and ejaculation-related distress and alcohol intake are collected after each event via e-diary. 
6. 
IIEF and PEP have 4-week recall periods, and so these questionnaires are completed by the patients at study visits as above. 
7. 
Columbia-Suicide Severity Rating Scale is only mandatory at baseline but may be administered at other visits if clinically indicated. 


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Appendix 2: Evaluation Instruments 
13.2.1 Clinical Global Impression of Change (CGIC) 
Change From 
The CGIC question is the following: 
Compared to the start of the study, would you describe your premature ejaculation problem 
as: 
3 = Much worse 
2 = Worse 
1 = Slightly worse 
 0 = No change 
 1 = Slightly better 
 2 = Better 
 3 = Much better 
 
Change To 
This patient-completed questionnaire is often referred to as PGIC (Patient Global Impression 
of Change). The following questions will be asked after the patient has completed the PEP at 
the final visit: 
Compared to the start of the study, would you describe your premature ejaculation problem 
as: 
3 = Much worse 
2 = Worse 
1 = Slightly worse 
 0 = No change 


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 1 = Slightly better 
 2 = Better 
 3 = Much better 
 
Compared to the start of the study did you experience a meaningful change in the time 
you took to ejaculate (cum)?   (Yes/No) 
Compared to the start of the study did you experience a meaningful change in your 
level of distress related to your premature ejaculation?  (Yes/No) 
13.2.1 Premature Ejaculation Profile (PEP) 
Change From 
1. Over the past month, was your control over ejaculation during sexual intercourse: 
1 – Very Poor 
2 – Poor 
3 – Fair 
4 – Good 
5 – Very Good 
2. Over the past month, was your satisfaction with sexual intercourse: 
1 – Very Poor 
2 – Poor 
3 – Fair 
4 – Good 
5 – Very Good 
3. Over the past month, how distressed were you by how fast you ejaculated during sexual 
intercourse: 
1 – Extremely 
2 – Quite a bit     3 – Moderately      4 – A little bit 5 – Not at all 
4. Over the past month, to what extent did how fast you ejaculated during sexual intercourse 
cause difficulty in your relationship with your partner: 
1 – Extremely 
2 – Quite a bit     3 – Moderately      4 – A little bit 5 – Not at all 
Change To 
1. Over the past month, was your control over ejaculation during sexual intercourse: 
1 – Very Poor 
2 – Poor 
3 – Fair 
4 – Good 
5 – Very Good 
2. Over the past month, was your satisfaction with sexual intercourse: 
1 – Very Poor 
2 – Poor 
3 – Fair 
4 – Good 
5 – Very Good 


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3. Over the past month, how distressed were you by how fast you ejaculated during sexual 
intercourse: 
1 – Extremely 
2 – Quite a bit     3 – Moderately      4 – A little bit 5 – Not at all 
4. Over the past month, to what extent did how fast you ejaculated during sexual intercourse 
cause difficulty in your relationship with your partner: 
1 – Extremely 
2 – Quite a bit     3 – Moderately      4 – A little bit 5 – Not at all 
Additional Question 
5. Over the past month, how bothered were you by how fast you ejaculated during 
sexual intercourse: 
1 – Extremely 
2 – Quite a bit    3 – Moderately      4 – A little bit 5 – Not at all 
Patient Global Impression of Severity (PGIS)  
This questionnaire will be completed after the patient has completed the PEP.   
How would you rate your premature ejaculation (PE) now?  1 No PE (none), 2 Mild 
3 Moderate 4 Severe