A Multi-centre, Randomised, Open-label, Home Use, Parallel Group, Clinical Investigation of Topically-applied MED3000 Gel and Oral Tadalafil (5 mg) Tablets for the Treatment of Erectile Dysfunction (ED) Over a 24 Week Period
Phase: PHASE3
Conditions: Erectile Dysfunction
Sponsor: Futura Medical Developments Ltd.

Futura Medical Developments Ltd                            CONFIDENTIAL                                Page 1 of 74  
 
FM71 Clinical Investigation Plan  
 
Final version 7.0 dated 02Mar2022 
 
CLINICAL INVESTIGATION PLAN 
 
TITLE: A multi-centre, randomised, open-label, home use, parallel group, clinical investigation of 
topically-applied MED3000 gel and oral tadalafil (5 mg) tablets for the treatment of erectile 
dysfunction (ED) over a 24 week period 
 
SPONSORS REF. NUMBER: 
  
FM71 
 
 
VERSION AND DATE: 
 
 
7.0 dated 02Mar2022 
 
 
 
PHASE:  
 
 
 
Pivotal 
 
DEVICE: 
 
 
 
MED3000 
 
REVISION HISTORY: 
Version 1.0 
New clinical investigation plan prepared to form the basis of pre-
submission discussions with the US Food and Drugs Administration 
(CDRH) only. This version was not formally submitted for approval by 
any Regulatory Authority nor Ethics Committee.    
Version 2.0 
FM71 clinical investigation plan revised to include US Food and Drug 
Administration (CDRH) recommendations on the design of the 
proposed clinical investigation.  This version was not formally 
submitted for approval by any Regulatory Authority nor Ethics 
Committee. 
Version 3.0 
The age of eligibility has been increased from 18 to 22 years of age 
which is in accordance with the US Food and Drug Administration 
(CDRH) definition of an adult population.  
Version 4.0 
• 
Section 21 updated to include AE expectedness review as part 
of the FMD Medical Advisor’s assessment.  
• 
Corrected addresses in section 5. 
• 
Changed the term “Unexpected Serious Adverse Device Effect” 
to “Unanticipated Serious Adverse Device Effect” throughout. 
• 
Inclusion of an AE category of “expectedness”. 
• 
Clarification on how AEs from female partners will be collected. 
• 
Section 14.9 updated stating that the number of intercourse 
attempts during treatment will be estimated using the number 
of completed onset of action questionnaires. 

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FM71 Clinical Investigation Plan  
 
Final version 7.0 dated 02Mar2022 
 
 
 
Information in this Clinical Investigation Plan is confidential and should not be disclosed other 
than to those directly involved in the execution or the ethical regulatory review of the 
investigation without written authorisation from Futura Medical Developments Ltd (here in after 
known as FMD) 
 
 
Version 5.0 
• 
The volume of blood drawn from each patient during the 
investigation has been corrected from 50 mL to 150 mL 
(Section 13.1) 
Version 6.0 (US Only) 
• 
Section 12.1 updated to include text that patients will be 
expected to complete IIEF and SEAR questionnaires using a 
tablet device. 
Version 7.0 
• 
Deletion of text “who, in completing the relevant eCRF, must 
answer ‘yes’ or ‘no’ to the question: ‘Do you consider that there 
is a reasonable possibility that the event may have been caused 
by the investigation product?’” in section 13.11. As per the 
preceding sentence in section 13.11.1, the PI assesses the 
relatedness of AEs to investigation treatment as related, 
probably related, possibly related or unrelated, and this is what 
is captured in the eCRF. 
• 
Sections 6, 11, and 14.8.3 updated to include an exploratory 
objective, namely the comparison in onset of action times 
between patients receiving MED3000 and tadalafil, assessed 
whilst on treatment during the 24-week treatment period, as 
detailed in the Statistical Analysis Plan (V1.0 dated 02 Sep 
2021) which was finalised before first patient enrolled. 
• 
Sections 6 , 11 and 14.5 updated with a clarification on the 
statistical analysis if randomisation/treatment errors occur, as 
detailed in the Statistical Analysis Plan (V1.0 dated 02 Sep 
2021). In the case of randomisation/treatment errors, patients 
will be analysed according to treatment initially received at 
randomisation. 

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FM71 Clinical Investigation Plan  
 
Final version 7.0 dated 02Mar2022 
Investigator’s Agreement: 
 
I have read this FMD Clinical Investigation Plan No. FM71 
A multi-centre, randomised, open-label, home use, parallel group, clinical 
investigation of topically-applied MED3000 gel and oral tadalafil (5 mg) tablets for the 
treatment of erectile dysfunction (ED) over a 24 week period  
I have fully discussed the objectives of this clinical Investigation and the contents of this 
Clinical Investigation Plan (CIP) with FMD (the Sponsor). 
I understand that the information in this CIP is confidential and should not be disclosed, 
other than to those directly involved in the execution or the ethical/regulatory review of the 
investigation, without written authorisation from FMD.  It is, however, permissible to provide 
information to a patient in order to obtain consent. 
I agree to conduct this investigation according to this CIP and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to conduct the 
investigation in accordance with the EN ISO 14155:2020 standard on Good Clinical Practice 
(GCP) and with the applicable regulatory requirements. 
I understand that FMD may decide to suspend or prematurely terminate the clinical 
investigation at any time for whatever reason; such a decision will be communicated to me in 
writing.  Conversely, should I decide to withdraw from execution of the investigation I will 
communicate my intention immediately in writing to FMD. 
 
Principal Investigator:  
 
Printed 
Name: 
 
 
 
 
Signature: 
 
 
Date: 
 
 
 

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FM71 Clinical Investigation Plan  
 
Final version 7.0 dated 02Mar2022 
2. 
INVESTIGATION PERSONNEL 
 
 
 

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FM71 Clinical Investigation Plan  
 
Final version 7.0 dated 02Mar2022 
3. 
TABLE OF CONTENTS 
1. 
CLINICAL INVESTIGATION PLAN APPROVAL SIGNATURES ...................... 3 
2. 
INVESTIGATION PERSONNEL ....................................................................... 5 
3. 
TABLE OF CONTENTS ................................................................................... 6 
3.1 
List of Tables .................................................................................................... 8 
3.2 
List of Figures .................................................................................................. 8 
4. 
LIST OF ABBREVIATIONS AND ACRONYMS ................................................ 9 
5. 
SPONSOR, COORDINATING INVESTIGATOR, PRINCIPAL 
INVESTIGATORS AND INVESTIGATIONAL SITE(S) .................................... 12 
6. 
SYNOPSIS OF THE CLINICAL INVESTIGATION .......................................... 14 
7. 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATION DEVICE . 19 
7.1 
Description of the Medication/Device ............................................................. 19 
8. 
JUSTIFICATION OF THE DESIGN OF THE CLINICAL INVESTIGATION ..... 20 
8.1 
Introduction .................................................................................................... 20 
8.2 
Impact of Erectile Dysfunction ........................................................................ 22 
8.3 
Management of Erectile Dysfunction .............................................................. 22 
8.4 
Potential of MED3000 in the Market for Erectile Dysfunction .......................... 24 
8.5 
FM57 Study .................................................................................................... 26 
9. 
JUSTIFICATION OF CLINICAL ENDPOINTS ................................................ 27 
9.1 
International Index for Erectile Function (IIEF) questionnaire ......................... 27 
9.2 
Onset of Action (Erection) Questions ............................................................. 27 
9.3 
Self-Esteem And Relationship (SEAR) questionnaire ..................................... 28 
9.4 
Objective Performance Criteria and Clinically Meaningful Differences ............ 28 
9.5 
Safety Assessments ....................................................................................... 28 
9.6 
Patient Population .......................................................................................... 28 
10. 
BENEFITS AND RISKS OF THE DEVICE, CLINICAL PROCEDURES AND 
INVESTIGATION ........................................................................................... 29 
11. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION .... 29 
12. 
DESIGN OF THE CLINICAL INVESTIGATION .............................................. 31 
12.1 
General .......................................................................................................... 31 
12.2 
Investigational Device and Control ................................................................. 38 
12.3 
Patients .......................................................................................................... 39 
12.3.1 Inclusion and Exclusion Criteria ............................................................... 40 
12.4 
Post-Investigation Restrictions ....................................................................... 43 
12.5 
Withdrawal of Patients .................................................................................... 43 
12.5.1 Criteria for Withdrawal from Investigational Product ................................. 43 
12.5.2 Procedures for Patient Withdrawal ........................................................... 44 

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13. 
PROCEDURES .............................................................................................. 44 
13.1 
Haematology and Biochemistry ...................................................................... 45 
13.2 
Urinalysis ....................................................................................................... 46 
13.3 
Serology ......................................................................................................... 46 
13.4 
Endocrinology ................................................................................................ 46 
13.5 
Urine Drugs of Abuse ..................................................................................... 46 
13.6 
Alcohol Breath Test ........................................................................................ 47 
13.7 
Urine Pregnancy Test..................................................................................... 47 
13.8 
Vital Signs ...................................................................................................... 47 
13.8.1 Blood Pressure and Heart Rate ............................................................... 47 
13.8.2 Body Temperature ................................................................................... 47 
13.8.3 12-lead ECG ............................................................................................ 47 
13.9 
Other Assessments ........................................................................................ 47 
13.9.1 Eligibility ................................................................................................... 47 
13.9.2 Medical History ........................................................................................ 48 
13.9.3 Physical Examination ............................................................................... 48 
13.9.4 Height and Body Weight .......................................................................... 48 
13.10 Effectiveness Assessments ............................................................................ 48 
13.10.1 IIEF Questionnaire ................................................................................... 48 
13.10.2 SEAR Questionnaire ................................................................................ 48 
13.10.3 Onset of Action Questionnaire ................................................................. 48 
13.11 Safety Assessments ....................................................................................... 48 
13.11.1 Adverse Events ........................................................................................ 48 
13.11.2 Concomitant Medication .......................................................................... 50 
13.12 Rationale for the Follow-Up Period ................................................................. 50 
13.13 Monitoring ...................................................................................................... 50 
14. 
STATISTICAL DESIGN AND ANALYSIS ....................................................... 50 
14.1 
General .......................................................................................................... 50 
14.2 
Test of Hypotheses ........................................................................................ 51 
14.3 
Sample Size and Power ................................................................................. 52 
14.4 
Randomisation ............................................................................................... 53 
14.5 
Analysis Sets ................................................................................................. 53 
14.6 
Demographic and Baseline Measurements .................................................... 53 
14.7 
Prior and Concomitant Medication.................................................................. 53 
14.8 
Effectiveness Evaluation ................................................................................ 54 
14.8.1 Primary Effectiveness Analysis ................................................................ 54 
14.8.2 Secondary Effectiveness Analysis ........................................................... 54 
14.8.3 Exploratory Effectiveness Objectives ....................................................... 55 
14.9 
Safety Analysis............................................................................................... 56 
14.10 Missing Data .................................................................................................. 56 
15. 
DATA MANAGEMENT ................................................................................... 56 
16. 
AMENDMENTS TO THE CIP ......................................................................... 57 

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17. 
DEVIATIONS FROM THE CIP ....................................................................... 57 
18. 
DEVICE ACCOUNTABILITY .......................................................................... 58 
19. 
STATEMENTS OF COMPLIANCE ................................................................. 58 
20. 
INFORMED CONSENT PROCESS ............................................................... 59 
21. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS, AND DEVICE 
DEFICIENCIES .............................................................................................. 59 
21.1 
Definitions ...................................................................................................... 59 
22. 
VULNERABLE POPULATION ........................................................................ 61 
23. 
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL 
INVESTIGATION ........................................................................................... 61 
24. 
PUBLICATION POLICY ................................................................................. 61 
25. 
INVESTIGATOR RESPONSIBILITIES ........................................................... 62 
25.1 
GCP Compliance ........................................................................................... 62 
25.2 
CIP Adherence and Investigator Agreement .................................................. 62 
25.3 
Documentation and Retention of Records ...................................................... 62 
26. 
CONFIDENTIALITY ....................................................................................... 62 
27. 
QUALITY ASSURANCE AND QUALITY CONTROL ...................................... 63 
28. 
BIBLIOGRAPHY ............................................................................................ 64 
29. 
APPENDICES ................................................................................................ 68 
29.1 
APPENDIX 1 IIEF Questionnaire ................................................................... 68 
29.2 
APPENDIX 2 SEAR Questionnaire ................................................................ 70 
29.3 
APPENDIX 3 Onset of Action Questions ........................................................ 74 
 
3.1 
List of Tables 
Table 1 
MED3000 Qualitative Formula ................................................................. 20 
Table 2 
Schedule of Events .................................................................................. 34 
Table 3 
Schedule of Questionnaires ..................................................................... 37 
Table 4 
Biochemistry, Haematology, Urinalysis and Serology Assessments ........ 45 
 
3.2 
List of Figures 
Figure 1 
MED3000 mode of action......................................................................... 38 
 
 

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FM71 Clinical Investigation Plan  
 
Final version 7.0 dated 02Mar2022 
4. 
LIST OF ABBREVIATIONS AND ACRONYMS   
Abbreviation 
Explanation 
ABPI 
Association of the British Pharmaceutical Industry 
ACE  
Angiotensin Converting Enzyme  
ADE  
Adverse Device Effect 
AE  
Adverse Event  
ALP  
Alkaline Phosphatase  
ALT  
Alanine Aminotransferase  
ANCOVA 
Analysis of covariance 
AST  
Aspartate Aminotransferase  
AUA 
American Urological Association 
BMI  
Body Mass Index  
BP 
Blood Pressure  
CD 
Compact Disc 
CDRH 
Center for Devices and Radiological Health 
cGMP 
Cyclic Guanosine Monophosphate 
CIP 
Clinical Investigation Plan 
CIR  
Clinical Investigation Report  
CK 
Creatine Kinase  
CRO 
Clinical Research Organisation  
CRP  
C-reactive Protein  
CTCAE 
Common Terminology Criteria for Adverse Events 
CVD 
Cardiovascular Disease 
EC(s) 
Ethics Committee(s)  
ECG(s)  
Electrocardiogram(s)  
eCRF 
electronic Case Report Form  
ED 
Erectile Dysfunction  
EF 
Erectile Function  
EU 
European Union  
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FMD  
Futura Medical Developments Ltd  
GCP  
Good Clinical Practice  
GDPR 
General Data Protection Regulation 
GGT 
γ-Glutamyl Transpeptidase 

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Final version 7.0 dated 02Mar2022 
GP 
General Practitioner 
GTN 
Glyceryl Trinitrate  
HBc 
Hepatitis B Core antibodies 
HBsAG 
Hepatitis B Surface Antigen  
HCV 
Hepatitis C Virus 
HIV  
Human Immunodeficiency Virus  
HR 
Heart Rate  
IB 
Investigator’s Brochure 
ICF  
Informed Consent Form  
ICH 
International Council for Harmonisation 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IIEF  
International Index for Erectile Function  
IP 
Inorganic Phosphate  
IRB(s) 
Institutional Review Board(s)  
IUD 
Intrauterine Device  
IUS 
Intrauterine System  
IWRS 
Interactive Web Response System 
LDH 
Lactate Dehydrogenase  
LS 
Least-Squares 
MCID 
Minimal Clinically Important Difference 
MedDRA 
Medical Dictionary for Regulatory Activities  
NAION 
Non-arteritic Anterior Ischaemic Optic Neuropathy 
NF 
National Formulary 
NHS 
National Health Service 
NIH 
National Institutes of Health 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OPC 
Objective Performance Criteria 
OTC 
Over the Counter 
PDE-5 
Phosphodiesterase type 5  
PGE1 
Prostaglandin E1  
Ph.Eur 
Pharmacopoeia Europaea 
PI 
Principal Investigator  
PRO 
Patient-reported Outcome 
PT  
Preferred Term  

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QA 
Quality Assurance  
QC 
Quality Control  
QoL 
Quality of Life 
QP  
Qualified Person  
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation  
SEAR 
Self-Esteem And Relationship 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class  
SOP 
Standard Operating Procedure 
T½ 
Half-life  
TEAE 
Treatment-emergent adverse event  
TMF 
Trial Master File 
ULN 
Upper Limit of Normal  
US 
United States  
USADE 
Unanticipated Serious Adverse Device Effect 
USP 
United States Pharmacopeia 
v/v 
Volume per volume 
w/w 
Weight in weight 
 
 
 

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5. 
SPONSOR, 
COORDINATING 
INVESTIGATOR, 
PRINCIPAL 
INVESTIGATORS 
AND 
INVESTIGATIONAL SITE(S) 
SPONSOR 
 
 
COORDINATING INVESTIGATOR  
PRINCIPAL INVESTIGATORS, AND INVESTIGATION SITES: 
Details of the Principal Investigators (PIs) and sites involved in this investigation will be 
maintained in a separate tracker.   
CENTRAL LABORATORY:   
CLINICAL REASEARCH ORGANISATION 
 
 

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Final version 7.0 dated 02Mar2022 
European Union Legal Representative 
 

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Safety Objectives: 
The safety objectives are to evaluate the safety of MED3000 and tadalafil using occurrence and severity of 
treatment-emergent adverse events (TEAEs) and standard physical and laboratory assessments.  Safety will 
be evaluated using a “while on treatment” strategy. 
Investigation Design:  

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FM71 Clinical Investigation Plan  
 
Final version 7.0 dated 02Mar2022 

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FM71 Clinical Investigation Plan  
 
Final version 7.0 dated 02Mar2022 
Statistical Methods: 
Effectiveness Analyses: 
 
 
 
t 
 
 
Safety Analyses: 

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FM71 Clinical Investigation Plan  
 
Final version 7.0 dated 02Mar2022 
7. 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATION DEVICE  
7.1 
Description of the Medication/Device 
The clinical investigational device is MED3000, a gel formulation currently under development by 
Futura Medical Developments Ltd (FMD) as a topical treatment for erectile dysfunction (ED).  
MED3000 will be provided to patients in tubes, each tube containing 800 mg of MED3000 gel.  Each 
tube will contain sufficient gel to apply a single dose (approximately 300 mg) of MED3000 at each 
application.  
Tadalafil (5 mg) tablets will also be used in this clinical investigation.  The medication will be 
packaged in boxes; each box containing twelve 5 mg tablets.  
Neither investigational product will be administered using a specific dosing frequency regimen.  
Instead, they should be administered on an ‘as needed’ basis (i.e. the investigational product is 
taken prior to a sexual intercourse attempt). 
Details of the manufacturer:  
Name/Number of model to permit full identification:  
Not applicable.  
Device traceability:  
MED3000 gel will be supplied to the sites in single-dose tubes contained within an outer carton 
(i.e. each carton contains 4 tubes).  Both carton and tubes will display details of the investigational 
device’s batch number and unique kit identification number.  
Tadalafil (5 mg) tablets will be provided to patients in boxes; each box containing 12 tablets.  All 
boxes will be labelled with a unique kit identification number. 
Traceability of dispensed and returned investigational product (i.e. MED3000 gel and tadalafil [5 mg] 
tablets) will be managed using a combination of Interactive Web Response System (IWRS) and site 
maintained dispensing/return logs.  
Intended use:  
The intended use of MED3000 gel is for the treatment of ED in adult males.  The clinical investigation 
will be conducted in patients with ED in both the United States (US) and Europe to demonstrate the 
performance over a 24-week period.  The US site will recruit African-Americans exclusively to ensure 
patient ethnic diversity and associated comorbidities. 
Patients with hypogonadism, prostatectomy and uncontrolled or severe diabetes will be specifically 
excluded from the clinical investigation (see Section 12.3.1 Inclusion and exclusion criteria).  The 
rationale for this exclusion is based on the fact that these groups respond poorly to all current 
treatments for ED, including PDE5 inhibitors, and there is no evidence to suggest MED3000 will 
overcome this unresponsiveness.  

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Product labelling will reflect the absence of data in these groups.  The proposed indication for use of 
MED3000 will be for the treatment of ED in adult males and include an appropriate caveat excluding 
relevant comorbidities. 
Details of the device components:  
Table 1 
MED3000 Qualitative Formula 
Summary of required training: The device is applied to the glans penis immediately prior to sexual 
intercourse.  Training will be provided by the site staff using a model phallus to demonstrate how 
the patient or partner applies the medication.  Further training may be provided to the participants 
as required.  Previous studies have assessed that MED3000 is a safe product with an extremely 
favourable safety profile. 
Description of specific medical procedures: This product is intended for home use.  No specific 
medical or interventional procedures are necessary. 
Investigator’s Brochure: Details of previously conducted clinical and non-clinical studies can be 
found in the MED3000 investigator’s brochure (IB). 
8. 
JUSTIFICATION OF THE DESIGN OF THE CLINICAL INVESTIGATION 
8.1 
Introduction 
ED is the consistent or recurrent inability to attain and/or maintain a penile erection sufficient for 
satisfactory sexual performance.  Although not seen as life-threatening, ED is closely associated with 
a number of physical conditions and may affect psychosocial health [1]. 
ED is a highly prevalent condition.  The pivotal Massachusetts Male Aging Study estimated that as 
many as 52% of men aged 40 years or over have some degree of ED (combined prevalence of 
minimal, moderate and complete ED) [2].  More than 150 million men worldwide are thought to be 
affected by ED, and ED is projected to impact in excess of 320 million men worldwide by 2025 [3, 4].  

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Factors that might contribute to this increasing prevalence include the ageing of the world’s 
population, as well as dietary changes, health behaviours and an emerging diabetes pandemic [3, 4]. 
ED can affect all age groups; however, the frequency of ED clearly increases with age [2].  As an 
example, men aged 60–69 years of age experience more than four times the level of ED compared 
with men in the 40–49 year age group [3].  Nevertheless, ED is increasingly affecting men younger 
than 40 years with the prevalence of ED in young men estimated to be as high as 30% [5].  The 
burden of ED among differing racial and ethnic groups is uncertain and under studied.  While one 
study suggested that Asian and black men are less likely to have severe ED compared with white 
men, another suggested an increased risk in black and Hispanic men, and a third found no effect of 
race/ethnicity on ED [6, 7, 8].  Smith et al. (2009) suggests that the effects of race or ethnicity may 
depend on a complex interaction between socioeconomic, demographic, cultural and lifestyle 
characteristics [6].   
The degree of severity of ED is highly variable among men, but is often described as mild, moderate 
or severe.  The International Index for Erectile Function (IIEF), a widely used, multidimensional, 
self-report instrument for the assessment of ED, is commonly used for diagnostic evaluation of ED 
severity.  The IIEF consists of 15 questions divided into five domains of sexual function: erectile 
function (EF), orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction.  An 
evaluation of severity is based on the EF domain, classified into five categories based on the score 
achieved: no ED, mild ED, mild to moderate, moderate, and severe [9].  The IIEF is discussed further 
in Justification of Clinical Endpoints of the Clinical Investigation Plan (CIP) (Section 9). 
There are many potential causes of ED.  These can be psychological, organic or of mixed aetiology 
[10].   
The pathophysiology of ED is complex and may be anatomical, vascular, neuronal, hormonal, 
traumatic or drug-induced, among others.  ED is often attributable to organic causes such as altered 
blood flow to and from the penis possibly owing to damage to the arteries, endothelium or smooth 
muscle.  Damage can be the result of a chronic condition, with an increased risk particularly evident 
in men with cardiovascular diseases (CVD) such as hypertension, heart disease and diabetes [4].  
Indeed, the underlying risk factors associated with ED (e.g. age, sedentary lifestyle, obesity, smoking, 
metabolic syndrome) are common to CVD in general, and the pathophysiologies of ED and CVD are 
thought to share several similarities, including atherosclerosis, endothelial dysfunction, structural 
vascular damage and subclinical inflammation [1, 10, 11, 12].   
ED is also common in men with other conditions such as depression, spinal cord injury, chronic 
kidney disease, those undergoing cancer treatment and following prostatectomy [4].  Common 
medications, such as antihypertensives, non-steroidal anti-inflammatory drugs (NSAIDs) and 
antacids, may also be linked to ED [11, 13].  Furthermore, ED has been associated with the use of 
less common medications, such as psychotropic drugs (e.g. antidepressants, atypical antipsychotics 
and benzodiazepines) [13, 14]. 
Situational or psychosocial factors may also play a causative role and can be complex and 
multidimensional.  Situational/psychosocial causes can be related to performance anxiety, 
psychological distress (e.g. depression, general anxiety, post-traumatic stress disorder) or 
relationship problems, as well as age-related reductions in libido or chronic sexual intimacy disorders 
[5].  High levels of performance anxiety may worsen or maintain ED which can cause a vicious cycle 
of anxieties and stress leading to impaired sexual arousal and sexual avoidance [1, 5, 12]. 

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The genetic aspects of ED are not well studied or completely understood.  Multiple genetic variants 
potentially associated with ED have been identified, but few have been consistently replicated 
across ED models [15]. 
In summary, ED is a common but complex condition with a multifaceted aetiology that is still not 
fully understood. 
8.2 
Impact of Erectile Dysfunction 
ED is a chronic condition affecting male sexual function and has a significant health economic impact 
worldwide [16, 17, 18].   
On an individual level, ED can be a major factor contributing to an unsatisfactory sexual life, may 
impact physical and psychosocial health and can negatively affect a man’s quality of life (QoL), 
including his mental health (including causing anxiety and depression), his relationship and his 
general wellbeing [1, 2, 19].  There is a wealth of evidence suggesting ED has a detrimental effect of 
many aspects of QoL for both men and their partners, and that treatment can help [20].  
Nevertheless, despite the availability of treatments, many men avoid seeking medical help for the 
condition, which only adds to the problem [1]. 
ED is a serious public health problem and is costly to both the individual men who suffer from ED 
and also healthcare systems, with the largest costs attributable to diagnosis and treatment [17].  
Between 1997 and 2000, the costs to the UK National Health Service (NHS) increased from £29.4 to 
£73.8 million.  In 2000, most NHS costs came from specialist and general practitioner (GP) 
consultations, sildenafil prescriptions and psychosexual therapy.  The authors thought the increased 
costs were mainly owing to a three-fold increase in the number of men presenting to GPs with ED, 
many of whom were then referred for specialist consultations [21].  Of note, minimal research has 
been carried out to assess the costs of modern therapeutic approaches to ED, and many studies are 
dated [18].  The economic landscape for ED treatment is changing and costs to healthcare systems 
have increased owing to ageing populations, increasing ED prevalence accompanied by more severe 
comorbidities and increased demand for treatment [18]. 
In light of this, a correct diagnosis of ED and its comorbidities, as well as a better understanding of 
the causes and treatments of ED should not only improve QoL, sexual and general health, but also 
reduce the burden of ED on societies [4].  Furthermore, because of the strong link between ED and 
CVD (and other conditions), ED could potentially act as a marker for various other disorders, helping 
to cut healthcare costs in these areas as well. 
8.3 
Management of Erectile Dysfunction 
There are a number of published evidence-based and multidisciplinary expert consensus-based 
guidelines for the management of ED [1, 10, 12, 19, 22, 23].  The goal of ED treatment is to restore 
or enhance sexual function and to improve the individual and his partner’s physical health and QoL 
while minimising adverse events (AEs) and diagnosis- and treatment-associated burden [22]. 
The management of ED usually follows a stepwise progression. 
Following a thorough medical/sexual history, physical examination and appropriate laboratory 
testing (e.g. fasting serum glucose and/or glycated haemoglobin, lipid profile, morning total 
testosterone), the first-line approach for the treatment of ED is often lifestyle changes (e.g. changes 

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in diet and increased physical activity) and modifications to risk factors (e.g. smoking cessation, 
alcohol/drug intake, blood pressure [BP] treatment).   
If the ED is thought to be associated with an underlying medical condition, all of the guidelines 
recommended that this should be managed accordingly as a first step of treatment.  Most men will 
however be treated with therapeutic options that are not cause-specific.  Lifestyle modifications are 
usually followed by (or used concurrently with) first-line oral pharmacotherapy with a selective 
phosphodiesterase type 5 (PDE-5) inhibitor such as sildenafil (sold under the brand name Viagra® 
[Pfizer Inc], among others), tadalafil (sold under the brand name Cialis® [Eli Lilly and Company], 
among others), vardenafil (sold under the brand name Levitra® [Bayer Healthcare, GlaxoSmithKline, 
Schering-Plough], among others) and avanafil (sold under the brand names Stendra®/Spedra® 
[Vivus Inc, Mitsubishi Tanabe, Menarini]).   
The enzyme PDE-5 is found in relatively high concentrations in the blood vessels of the corpus 
cavernosum, or erectile body, of the penis.  PDE-5 inhibitors obstruct the PDE-5 enzyme from 
breaking down cyclic guanosine monophosphate (cGMP) in the cavernosal tissue, the accumulation 
of which acts to increase arterial blood flow which causes smooth muscle relaxation in the corpora 
cavernosa, vasodilation and consequent penile erection [2, 19, 22]. 
Although PDE-5 inhibitors are widely used in ED and their side-effects have been well documented, 
all PDE-5 drugs are contraindicated in men taking nitrates in any form (such as glyceryl trinitrate 
[GTN], isosorbide dinitrate and isosorbide mononitrate) for CVD; e.g. for angina or heart failure.  In 
addition, dose adjustments may be required in certain populations; for example, older men, those 
with hepatic or renal impairments and those taking certain medications [1].  As oral drugs, PDE-5 
inhibitors are commonly associated with systemic AEs such as headache, flushing and dyspepsia, 
which although often mild in intensity can contribute to significant treatment dropouts [20, 24, 25].  
Furthermore, PDE-5 inhibitors are associated with treatment failure in a sizeable proportion of users, 
and compliance with treatment has been shown to decrease over time [26, 27].  One estimate 
suggests oral therapies are effective in about 75% of users, but almost 50% of men discontinue 
PDE-5 inhibitor treatment within one year [1, 28].  This is discussed further in the next section 
(Section 8.4). 
PDE-5 inhibitors have to be taken sufficiently in advance of sexual intercourse because they are 
associated with a delayed speed of onset, leading to a lack of spontaneity.  The different oral PDE-5 
inhibitors take different times to reach maximal plasma concentrations and thus have an onset of 
effect ranging from 15 minutes to up to 1 hour, and peak circulating drug concentrations are 
typically attained only 1–2 hours following administration [19, 22].  Add to this their relatively 
long-half life, meaning effects last beyond the usual duration of sexual intercourse.  Furthermore, 
the absorption of sildenafil can be delayed by food ingestion, and absorption of vardenafil and 
avanafil can be delayed by a high fat meal [19, 22]. 
The British Society for Sexual Medicine mention the recent European Union (EU) approval of an over 
the counter (OTC) formulation of sildenafil (Viagra Connect® 50 mg; approved in November 2017 for 
commencement of sales in 2018) in their 2017 guidelines on the management of ED [1].  However, 
as the guidelines were published before Viagra Connect® went on general sale, it has not yet been 
incorporated into the treatment model. 
In general, PDE-5 inhibitors have a good benefit-risk profile but are associated with a number of 
issues that reduce the ratio and contribute to an unmet need in the therapy area. 

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For PDE-5 inhibitor non-responders, or in men who are not satisfied with PDE-5 inhibitors, stepwise 
progression from oral agents to other therapies occurs as needed.  Other second- and third-line 
treatment options include vacuum erection devices, intracavernosal injections (e.g. alprostadil, 
papaverine), intraurethral suppositories (e.g. alprostadil) and penile prosthesis implantations.  
Second/third-line therapies can be used alone or in combination with PDE-5 inhibitors.  However, 
these treatments are frequently associated with AEs such as local pain, fibrosis and priapism (a 
persistent and painful erection) and can lead to poor compliance owing to their invasive nature.  In 
light of this, the benefit-risk profile of these second-line therapies is quite poor related to their 
generally unacceptable safety risks.  Newer treatments include low-intensity extracorporeal shock 
wave therapy, intracavernosal stem cell therapy and platelet-rich plasma therapy; however, these 
treatments should be considered experimental as they are still undergoing testing and further 
studies are required to establish effectiveness. 
Owing to their less invasive route of administration and ease of use, topical therapies approved for 
other indications have recently been explored as alternative candidates for the treatment of ED. 
Alprostadil, a synthetic analogue of prostaglandin E1 (PGE1), has been marketed for many years as 
an intracavernosal injection and a urethral stick for the treatment of ED.  Alprostadil cream 
(Vitaros®/Virirec®), PGE1 combined with a skin permeation enhancing drug delivery system, has 
been developed for the treatment of ED, although clinical data are limited [1, 19].  Alprostadil cream 
is not approved for use in the US.  Administered at a dose of 300 µg inserted into the urethra, 
topically-applied alprostadil has shown to be safe and effective (increased penile blood flow, 
improved erections, increased successful intercourse attempts) versus baseline and placebo in a 
broad range of men with mild to severe ED [26, 29].  Side effects tend to be mild to moderate, 
transient and localised, including genital pain, burning, tenderness and erythema; but have been 
seen in up to 78% of patients [30].  Owing to its low systemic absorption, systemic AEs are usually 
rare or absent.  Furthermore, the effectiveness and safety of topical alprostadil has been 
demonstrated for up to 9 months in an open-label study in 1,161 men [26, 31]. 
There are little long-term safety data for alprostadil cream, and no published comparisons with 
other treatments [26, 32].  Furthermore, alprostadil cream should not be used in combination with 
oral PDE-5 inhibitors because an additive increased cardiovascular risk cannot be excluded [32]. 
In summary, there are a number of treatment options available to men with ED.  Most men will 
follow a structured treatment strategy that will depend on effectiveness, tolerability, invasiveness, 
cost and preference.  As there is a continually expanding literature on ED, management strategies 
should evolve as our understanding of ED expands.  Importantly, the American Urological 
Association (AUA) suggests a ‘shared decision-making’ approach is the cornerstone of the 
patient-centred management of ED, during which the man, in collaboration with his physician and in 
consultation with his partner when applicable, is enabled to fully consider all of the treatment 
options available to him and supported in the decision making process.  The AUA believe the model 
should rely on concepts of autonomy and respect for the individual; i.e. every man who presents 
with ED is unique, and the most effective approach for a particular man is best determined by that 
man [22]. 
8.4 
Potential of MED3000 in the Market for Erectile Dysfunction 
The aim of MED3000 is to target a large potential patient population with a clear unmet need. 

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The ED market is well-established with sales of ED treatments worth 5.6 billion US dollars in 2018 
[33].  Tadalafil (Cialis®) is the current market leader; however, brand and generic markets for ED 
medications are changing allowing patients and providers more flexibility in prescribing and in their 
treatment decisions and enabling tailoring to patient preference and needs.  For example, sildenafil 
and tadalafil are both now available as generic medications: Pfizer’s patent on sildenafil expired in 
2013, and the patent for tadalafil expired in most markets in 2017.  Previously only available via 
doctor’s prescription, the ED market is also changing with the EU approval of OTC pharmaceutical 
products such as Viagra Connect®. 
Existing treatments have significant limitations.  There are four main issues with the current 
treatment landscape: AEs, drug interactions, slow onset of action and treatment failure.   
Oral PDE-5 inhibitors may be the cornerstone of modern ED therapy, but do not meet the needs of 
many men and their partners.  Firstly, there is a subset of ED sufferers who are not able to be 
prescribed any of the PDE-5 inhibitors owing to contraindications with other medications taken by 
them for comorbid conditions.  PDE-5 inhibitors are contraindicated in men who are taking any form 
of organic nitrates or nitrate-containing compounds, both regularly or intermittently; e.g. in patients 
who have stable angina or heart failure.  Both PDE-5 inhibitors and nitrates are vasodilators, and 
when taken together their additive and synergistic effects may cause an augmented hypotensive 
response, potentially leading to unpredictable reductions in BP [34].  According to recent 
independent market research commissioned by Futura Medical, this group represents at least 10% 
of ED patients [data on file: market research from Cello Health Consulting amongst physicians 
carried out in the US, France and Germany and commissioned by Futura Medical in 2017].  
Interactions have also been reported in men taking concomitant antihypertensives or alpha blockers, 
and drugs inhibiting the P450 cytochrome pathway [26, 35, 36].  Secondly, in a significant proportion 
of men this class of drugs is associated with treatment failure; and thirdly, compliance with PDE-5 
inhibitors has been shown to decrease over time [26, 27].  In 2016, a review and meta-analysis of 
22 clinical trials, including more than 162,000 ED patients, found that the mean discontinuation rate 
was 4% per month, equivalent to almost 50% after 1 year.  The main reasons for discontinuation 
were partner-related problems and lack of effectiveness [28].  On top of this, many second- and 
third-line therapies and devices have issues with side effects and invasiveness. 
Access to therapies is also important.  Despite the availability of treatments, many men do not seek 
medical help for the condition [1].  Futura Medical’s market research indicates that only 15–30% of 
men with ED consult a doctor [data on file].  Apart from some limited products, existing treatments 
for ED require a prescription from a doctor, and there has been little innovation in the ED space in 
recent years. 
User satisfaction is also an issue: the currently available ED treatments do not always reflect a 
patient’s preference.  According to Futura Medical’s independent market research, 68% of ED 
patients are not fully satisfied with their treatment, citing concerns which include barriers to 
spontaneity and intimacy, insufficient effectiveness and side effects [data on file].  Doctors expect 
that within just one year of treatment initiation, 25% of all ED patients will have discontinued their 
therapy [data on file].  ED affects the patient’s emotions and relationships, and an ideal ED 
treatment should address more than the ability to have and maintain an erection.  The delayed 
speed of onset associated with PDE-5 inhibitor use is a major barrier to spontaneity and intimacy, 
which are important considerations in the treatment of ED.  In contrast, application of a topical 
treatment that relies on thermodynamic activity, and the cooling-warming action on the skin, may 
lead to an enhanced effect and is an attractive proposition [37].  The market research showed that 
72% of doctors considered that helping to restore spontaneity and intimacy in the relationship 

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would be very appealing to their patients and would be a key driver of initiation or switch 
to MED3000. 
In summary, although there is a large, established ED market, it is changing and there are also clear 
and significant unmet needs.  There remains a strong unmet need for an effective, fast-acting and 
non-invasive local therapy that is easy to administer and well-tolerated with a low risk of systemic 
AEs; i.e. with a more favourable benefit-risk balance than the majority of currently available 
treatments.  Any therapy matching this profile would make a prime candidate for OTC availability.  
Futura Medical suggest that a topical treatment such as MED3000 gel could offer an alternative to 
oral medications and represents a potential new treatment option for men contraindicated to oral 
PDE-5 inhibitors, for those who find the side-effects associated with PDE-5 inhibitors (or other 
second- or third-line therapies) unacceptable and for those who have – due to dissatisfaction with 
PDE-5 inhibitor treatment regimens – discontinued use of those products. 

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9. 
JUSTIFICATION OF CLINICAL ENDPOINTS 
9.1 
International Index for Erectile Function (IIEF) questionnaire 
The IIEF was developed and validated in 1996–1997 as part of the sildenafil clinical study program 
and in 1999, the IIEF was recommended by the first International Consultation on Erectile 
Dysfunction as the primary effectiveness endpoint of choice for clinical studies in ED [9, 39].  After 
years of use, the IIEF is considered the gold standard self-report questionnaire for measuring EF. 
The IIEF has been validated, is widely used in numerous countries, and has demonstrated specificity 
for detecting treatment-related changes in EF [40].  The IIEF consists of 15 questions divided into five 
domains of sexual function: EF (6 questions), orgasmic function (2 questions), sexual desire, 
(2 questions), intercourse satisfaction (3 questions) and overall satisfaction (2 questions).  A score of 
0 to 5 is awarded to each of the 15 questions [39].  Higher scores indicate better sexual function.  
The IIEF-EF, a subset of the IIEF measuring EF, is commonly used as the primary endpoint in clinical 
trials and comprises Questions 1–5 and 15 of the IIEF.  
The questionnaire is completed by a patient’s recollection of the effects that his erection problems 
have had on his sex life over the previous 4 weeks.  
9.2 
Onset of Action (Erection) Questions 
The purpose of the estimation of the time of onset is to provide useful clinical guidance to both 
patients and healthcare professionals.  An accessible presentation of the time of onset is the mean 
percentage of uses, per patient, that led to the onset of an erection and result in the ability to have 
penetrative sex within a stated timeframe.  
The Onset of Action (Erection) and Erection Hardness questionnaire was used in the FM57 study.  
This patient-reported outcome (PRO) instrument was designed to capture details of various 
time-related events associated with sexual intercourse, including the time that the patient and 
partner noticed the onset of an erection after the application of the MED3000 gel and when the 
patient and partner were able to have penetrative sexual intercourse.  An abbreviated version of this 
instrument will be used in this clinical investigation to determine how rapidly each treatment type 
(i.e. MED3000 or tadalafil [5 mg]) becomes effective after dosing (i.e. the onset of an erection and 
the ability of the patient to have penetrative intercourse).  
In this clinical investigation, the Onset of Action (Erection) questionnaire is completed by patients 
after the first intercourse attempt after each administration of the investigational product 
(i.e. MED3000 gel or tadalafil [5 mg]). 
The onset of action assessments using this questionnaire do not require the use of a stopwatch to 
time events as the questions have a time component included.  A study investigating the earliest 
time within 30 minutes to erectogenic effect of tadalafil 10 mg and 20 mg [41], suggested that a 
limitation of stopwatch studies in general is the potential lack of clinical application.  It is therefore 
concluded that using a stopwatch in this clinical investigation could have a potentially detrimental 
effect on the sexual experience which could, in turn, influence the IIEF scores (i.e. the Primary 
Objective) reported by the patients.  

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9.3 
Self-Esteem And Relationship (SEAR) questionnaire 
The Self-Esteem And Relationship (SEAR) questionnaire has strong psychometric properties that 
support its validity and reliability for measuring sexual relationship satisfaction, confidence and 
particularly self-esteem in men with ED [42].   
It consists of 14 items investigating two dimensions: sexual relationship satisfaction (8 items) and 
confidence (6 items; subdivided into self-esteem and overall relationship satisfaction).  All items are 
scored on a 5-point Likert-type scale.  A higher score signifies a more favourable response for all 
14 items. 
9.4 
Objective Performance Criteria and Clinically Meaningful Differences 
Objective performance criteria (OPC) are standardised numerical target values derived from 
historical data taken from clinical studies and/or registries that may be useful for the review and 
comparison of safety or effectiveness endpoints in novel trials.  OPC serve as additional evidence for 
the effectiveness of MED3000. 
In 2011 Rosen et al. published a paper titled ‘Minimally clinically important differences in the erectile 
function domain of the International Index of Erectile Function scale’ [43].  In this paper, the EF 
domain of the IIEF questionnaire were questions 1 to 5, inclusive, and question 15.  The study used 
anchor-based minimal clinically important differences (MCIDs) estimated using data from 
17 randomised, double-blind, placebo-controlled, parallel-group clinical trials of the PDE-5 inhibitor 
tadalafil (Cialis®) for 3,345 men with ED who received treatment for 12 weeks (meta-analysis).  The 
overall MCID for IIEF-EF change from baseline was established as 4.  MCIDs for IIEF-EF changes from 
baseline were also established for different ED severities as follows: mild, 2; moderate, 5; and 
severe, 7.  These ‘Rosen’ criteria have now been widely accepted and used for responder definitions 
by academia and leading experts in the field of ED, and are cited by the US FDA in a recent strategic 
review as an acceptable PRO.  
9.5 
 Safety Assessments  
Safety will be evaluated throughout the investigation, whilst patients are on treatment, using 
standard assessments including physical examinations and visual examination of the penis, vital 
signs (BP, heart rate [HR], body temperature), standard clinical laboratory safety tests (haematology, 
biochemistry, urinalysis), 12-lead electrocardiograms (ECGs) and monitoring of AEs and concomitant 
medications with paper diaries (any AEs experienced by the partner will be captured at site visits 
[Visits 1, 2 and 8] or in the paper diaries. If information is missing from the paper diaries then the 
site should make every effort to obtain the required information).  
9.6 
Patient Population 
All patients who meet the eligibility criteria may be enrolled in this investigation, irrespective of their 
ED severity (i.e. mild, moderate or severe).  However, limits will be imposed on the number of 
patients recruited into each severity cohort (i.e. mild, moderate or severe) to ensure that these are 
broadly similar to that in PDE-5 studies and the Massachusetts Aging Study [2].  It is anticipated that 
enrolled patients in this clinical investigation will be ethnically diverse as sites will be located in both 
the US and Europe.  The US site will enrol African-American patients exclusively to ensure that a 
representative population of this ethnic group are included in the clinical investigation. 

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A publication by Fisher et al. (2016) stated that the overwhelming majority of clinical trials involving 
patients with ED required the enrolment of patients in a heterosexual relationship for a minimum of 
3 months [44].  As the majority of ED studies involve heterosexual patients, an exclusively 
heterosexual population will be enrolled in this clinical investigation.   
10. 
BENEFITS AND RISKS OF THE DEVICE, CLINICAL PROCEDURES AND INVESTIGATION 
MED3000 is being developed for the treatment of ED and as such, the anticipated clinical benefits 
for patients receiving treatment with MED3000 are improvements in EF with consequent 
improvements in QoL for themselves and their partners. 
The risks associated with participation in the investigation are directly related to the two products 
involved, namely MED3000 and tadalafil 5 mg.  The safety profile of MED3000 is listed above.  The 
safety profile of tadalafil 5 mg is well established and tadalafil 5 mg is the lowest approved on 
demand dose in the US.  In common with other PDE-5 inhibitors, tadalafil is a well-tolerated 
medicine.  The most commonly reported adverse reactions in patients taking tadalafil for the 
treatment of ED are headache, dyspepsia, back pain and myalgia, in which the incidences increase 
with increasing dose of tadalafil.  The adverse reactions reported are transient, and generally mild or 
moderate.  As a 5 mg dose of tadalafil will be used in this clinical investigation, risks associated with 
participation are therefore mild and will further be mitigated by careful and regular monitoring by 
clinical investigators of any potential AEs throughout the investigation. 
The rationale for the benefit-risk ratio for both products is based on their individual safety profiles 
and clinical effectiveness.  In the case of MED3000 this has been established in developmental 
clinical trials.  In the case of tadalafil this has been established by virtue of its status as an approved 
drug. 
11. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
This clinical investigation is intended to assess the effectiveness and safety of MED3000 gel over a 
24-week period in male patients clinically diagnosed with ED.  
Primary Effectiveness Objective: 
• 
To demonstrate an improvement compared to baseline of the EF domain of the IIEF in patients 
randomised to MED3000, assessed at 24 weeks post-randomisation by rejecting the null 
hypothesis that the mean change from baseline is less than or equal to zero. 
• 
To observe a mean change from baseline of the IIEF-EF in patients randomised to MED3000, 
assessed at 24 weeks post-randomisation, greater than or equal to the MCID of 4, as published by 
Rosen et al 2011 [43]).  
The endpoint for the primary effectiveness objective is the EF domain of the IIEF, assessed at 
24 weeks post-randomisation. 

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The primary objective will be assessed according to the outcomes in all randomised patients at 
24 weeks attributed to the initially received treatment [45].  Treatment discontinuation reasons 
considered to be adversely related to randomised treatment (for example, lack of effectiveness or 
related AEs) are considered as attributable and will be treated as an unfavourable outcome; while a 
hypothetical estimand strategy, that is, as if the patient carried on treatment, will be used for 
intercurrent events not considered to be related to randomised treatment (for example lost to 
follow-up or unrelated AEs). 
Secondary Effectiveness Objectives: 
The secondary effectiveness objectives are: 
• 
To demonstrate a speed of onset of action from the application of MED3000 gel to the time when 
the patient notices their erection starting.  Specifically, the objective is to provide evidence that 
the mean percentage of MED3000 uses per patient that result in the patient noticing their erection 
starting within a certain period of time is greater than 30%, assessed whilst on treatment during 
the 24-week treatment period. 
• 
To demonstrate a speed of onset of action from the application of MED3000 gel to the time when 
the patient is able to have penetrative sex.  Specifically, the objective is to provide evidence that 
the mean percentage of MED3000 uses per patient that result in the ability to have penetrative 
sex within a certain period of time is greater than 30%, assessed whilst on treatment during the 
24-week treatment period.  
Only on-treatment assessments made up to the time of treatment discontinuation will be used.  
Time from application of MED3000 gel will be assessed at 5 minutes, 10 minutes and 15 minutes. 
The endpoints for the secondary effectiveness objectives are: 
• 
The percentage of times that a patient indicates that they began to notice their erection starting 
within 5 minutes (10 minutes, 15 minutes) out of the total number of intercourse attempts made 
using the product during the 24 week treatment period post-randomisation. 
• 
The percentage of times that a patient indicates that they were able to have penetrative sex within 
5 minutes (10 minutes, 15 minutes) out of the total number of intercourse attempts made using 
the product during the 24 week treatment period post-randomisation. 
The justification for the definitions is a clinically accepted and published precedent.  The objective is 
based on the results from a study which assessed the effectiveness of avanafil within approximately 
15 minutes after dosing in men with ED [46].  This study observed a mean of 29.1% for the per 
subject percentage of sexual attempts in which men were able to have penetrative sexual 
intercourse within 15 minutes of using avanafil (200 mg).  Subjects were encouraged to attempt 
intercourse approximately 15 minutes after dosing and made use of a stopwatch.  This study allowed 
the following text to be included on the avanafil on the prescribing information, “The starting dose is 
100 mg taken as early as approximately 15 minutes before sexual activity”. 
A study investigating the earliest time within 30 minutes to erectogenic effect of tadalafil 10 mg and 
20 mg [41], suggested that a limitation of stopwatch studies in general is the potential lack of clinical 
application.  

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Safety Objectives: 
12. 
DESIGN OF THE CLINICAL INVESTIGATION 

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Table 3 
Schedule of Questionnaires 

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12.3 
Patients  
Ethnicity and FM71: 
Patients will be recruited from across Europe and in the US.  The latter group will specifically focus 
on American Afro-Caribbeans for two reasons.  First, to guarantee that a selection of Afro-Caribbean 
patients are included in the investigation.  Second, because Afro-Caribbean ethnicity has a relatively 
higher prevalence of diabetes and CVD, which can frequently be associated with obesity, this can 
impact the severity of ED. 
The US population also includes Hispanics and Asians who may not be represented in the cohort of 
European patients.  However, these ethnicities do not have a similarly high prevalence for these 
comorbidities.  The prevalence of hypertension among Mexicans, for instance, is lower than the 
prevalence of hypertension in the general American population [57].  In the same publication The 
American Heart Association advised that there was “a remarkable lack of consistent information 
regarding the prevalence of hypertension among US Hispanics”. 
The American Heart Association has also stated that Asian Americans (Asian Indian, Chinese, Filipino, 
Japanese, Korean and Vietnamese) comprise a widespread ethnic group which has differing patterns 
of disease tendencies within its many sub-groups.  However, aggregated as a single group they are at 
lower risk of CVD [58]. 
The comparability of European and American populations within this context is further supported by 
the reliability and robustness of the IIEF as a measure of ED when used in different geographic 
populations or etiologic sub-groups.  Baseline and post treatment IIEF scores were “almost identical” 
in the first European and US studies [9]. 
In addition, a literature review (data on file) shows that the results reported on studies in the US 
were similar to those reported in the rest of the world thereby confirming that for the purposes of 

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studying the effectiveness and safety of treatments of ED, the US population is comparable with 
Europe. 
12.3.1 
Inclusion and Exclusion Criteria 
MED3000 is being developed to treat ED.  In this clinical investigation, patients with mild, moderate 
and severe ED will be enrolled.  The severity (i.e. mild, moderate or severe) of the patients’ ED at 
baseline (i.e. Visit 2) will be determined using the IIEF questionnaire.  Additionally, prior to 
randomisation, all patients must meet the eligibility criteria as detailed below. 
Inclusion criteria: All patients must meet all of the following inclusion criteria to be eligible for the 
investigation (following screening [Visit 1], an eligibility check will be carried out on Day 1 of the 
treatment period [Visit 2]): 
1. 
Patient is a male aged between 22 and 70 years inclusive, at screening 
2. 
Confirmed clinical diagnosis of ED for more than 3 months according to the National Institutes 
of Health (NIH) Consensus Statement (‘the inability to achieve or maintain penile erection 
sufficient for satisfactory sexual performance at least once’) 
3. 
Patient answers ‘yes’ to the question regarding the presence of residual EF over the past 
3 months: ‘At home over the past 3 months, have you experienced at least some growth of your 
penis in response to: (1) mechanical stimulation by yourself or your partner, or (2) visual 
stimulation?’ 
4. 
Patient has been involved in a continuous heterosexual relationship for at least 6 months prior 
to screening 
5. 
Documented written informed consent from both patient and his female partner 
6. 
If the male patient’s female partner is of childbearing potential from the time of first sexual 
intercourse attempt during the screening period until the last administration of investigational 
treatment, then the couple must have been using a medically acceptable form of contraception 
for at least 3 months prior to entering the clinical investigation, and agree to continue such use 
for at least 1 month after the last administration of MED3000 or tadalafil (5 mg) 
Acceptable methods of contraception are listed below; it should be noted that condoms, 
femidoms, diaphragms, caps or hormone rings are not permitted as a form of contraception in 
this investigation: 
− Surgical sterilisation of the male partner (vasectomy with documentation of azoospermia if 
possible) 
− The female partner has undergone documented tubal ligation (female sterilisation) 
− The female partner uses combined hormone injectables 
− The female partner uses medically prescribed hormonal implants 
− The female partner has undergone documented placement of an intrauterine device (IUD) 
or intrauterine system (IUS) 
− The female partner uses combined oral contraceptives 
− The female partner uses progesterone only contraceptives 
− The female partner uses combined hormonal patches 

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Other than for male/female sterilisation, if any of these above listed methods are being used 
then their effectiveness must be determined by the PI or their delegate, taking into 
consideration the compliance and tolerance of the female partner with this method of 
contraception. 
As an additional precaution against pregnancy, the date of the Last Menstrual Period (LMP) of 
the female partner will be recorded in the CRF before proceeding with the investigation.  Any 
history of irregularity of periods will also be recorded. 
Patients who are or wish to become pregnant will not be included in the investigation.  
7. 
Patient and his female partner are capable of understanding and complying with the 
requirements of the CIP and must have signed the informed consent form (ICF) prior to 
participation in any investigation-related procedures 
8. 
Low IIEF-EF scores (≤ 25) at the end of the screening period (i.e. Visit 2) 
Exclusion Criteria: Patients are prohibited from participating in the investigation if they meet any of 
the following exclusion criteria (following screening [Visit 1], an eligibility check will be carried out on 
Day 1 of the treatment period [Visit 2]): 
1. 
Any significant or serious cardiovascular, pulmonary, hepatic, renal, gastrointestinal, 
haematological, endocrinological, metabolic, neurological or psychiatric disease which, in the 
opinion of the PI, renders the patient unfit to take part in the investigation 
2. 
Patient has any history of an unstable medical or psychiatric condition or using any medication 
that, in the opinion of the PI, is likely to affect the patient’s ability to complete the investigation 
or precludes the patient’s participation in the investigation  
Certain concomitant medications; e.g. other vasodilators, calcium channel blockers, 
angiotensin converting enzyme (ACE) inhibitors, beta blockers, diuretics, anti-hypertensives, 
tricyclic anti-depressants and major tranquillisers, as well as the consumption of alcohol, may 
potentiate the BP lowering effects of tadalafil; therefore, the PI must consider this carefully 
and include patients at their discretion 
3. 
Any presence of a symptomatic, active urinary tract infection diagnosed by the PI or their 
delegate at screening or during the investigation 
4. 
Any presence of chronic indwelling urethral catheterisation or penile anatomical abnormalities 
(e.g. penile fibrosis) that would significantly impair EF 
5. 
Any history of operations for Peyronie’s disease 
6. 
Primary hypoactive sexual desire or any history of hypogonadism 
7. 
Any history of radical prostatectomy 
8. 
Any history of severe/uncontrolled diabetes 
9. 
Patients taking two or more anti-hypertensives for the treatment of BP 
10. 
Hypersensitivity to any of the excipients 
11. 
Concomitant treatment with sildenafil citrate, vardenafil and other PDE-5 inhibitors  
12. 
Patients taking alpha blockers, guanylate cyclase stimulators, such as riociguat, doxazocin, any 
form of organic nitrate 
13. 
Patients receiving testosterone pellets 

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14. 
Any penile surgery except circumcision 
15. 
Any treatment with acetyl cysteine within 6 months 
16. 
Any treatment with dihydroergotamine within 6 months 
17. 
Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic 
neuropathy (NAION) 
18. 
Increased intracranial pressure (e.g. head trauma or cerebral haemorrhage) or inadequate 
cerebral circulation 
19. 
Any history of migraine or recurrent headache 
20. 
Aortic or mitral stenosis 
21. 
Hypertrophic obstructive cardiomyopathy 
22. 
Constrictive pericarditis or pericardial tamponade 
23. 
Closed-angle glaucoma 
24. 
Patients with nursing partners, known pregnant partners or with partners who wish to become 
pregnant during the course of the investigation 
25. 
Confirmed positive results from urine drug screen (amphetamines, benzodiazepines, cocaine, 
cannabinoids, opiates, barbiturates, tricyclic antidepressants and methadone) or from the 
alcohol breath test at screening (for clarification, any positive result from the urine drug screen 
or alcohol breath tests at screening will mean the patient will be excluded from the 
investigation).  In the instance that a patient is using medication which may give a positive 
result, exclusion will be at the PI’s discretion 
26. 
Patient has recent (last 12 months) clinical evidence of alcoholism or drug abuse 
27. 
Patient has a positive screen for hepatitis B, consisting of hepatitis B surface antigen (HBsAG), 
hepatitis C antibody, and human immunodeficiency virus (HIV) 
28. 
Any clinically significant abnormal laboratory, vital signs or other safety findings as determined 
by medical history, physical examination or other evaluations conducted at screening or on 
admission 
29. 
Patients unwilling to cease use of vacuum devices, intracavernosal injections, PDE-5s or other 
non-clinical investigation therapies for ED for the entire course of the investigation 
30. 
Unwillingness of the patient or their partner to agree to make the required attempts at sexual 
intercourse during treatment period 
31. 
Any history of unresponsiveness to PDE-5 treatment or significant side-effects, excluding visual 
disturbances, with PDE-5s 
32. 
Fewer than four attempts at sexual intercourse during the screening period 
33. 
Patients or their partners who are illiterate or are unable to understand the language in which 
the questionnaires are available 
34. 
Patient has received any investigational product during the 90 days prior to dosing for this 
investigation 
35. 
Patient or his partner cannot communicate reliably with the PI 
36. 
Patients with severe premature ejaculation (little or no control of ejaculation at the time of 
penetration) 

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12.4 
Post-Investigation Restrictions 
Patients and their female partners will have to comply with the following restrictions:  
• 
Blood donation will not be allowed at any time during the investigation and up to 3 months 
(90 days) after completion of the investigation 
• 
Male patients should not donate sperm and their female partners should not donate egg(s) from 
the time of the first administration of investigational product  until 3 months after the last 
administration of investigational product 
12.5 
Withdrawal of Patients 
Each patient (and their female partner) will be informed of their right to withdraw from the 
investigation at any time and for any reason.  The reasons for any patient withdrawal will be 
recorded on the electronic Case Report Form (eCRF).  
Reasons for withdrawing a patient from the investigation can include: 
• 
Voluntary discontinuation by the patient and/or his female partner, who are free to discontinue 
participation in the investigation at any time 
• 
Severe non-compliance to the CIP as judged by the PI and/or Sponsor 
• 
Any other reason as judged by the PI 
Although a low dropout rate is anticipated in this clinical investigation, investigation sites should 
make every effort (in accordance with the CRO’s agreed standard operating procedures [SOPs] on 
follow-up) to encourage withdrawn patients (and their partners) to the site to undertake all required 
assessments. 
Various strategies will be employed throughout the clinical investigation to promote the retention of 
patients in the clinical investigation without compromising patients’ rights as stated in the 
Declaration of Helsinki.  
12.5.1 
Criteria for Withdrawal from Investigational Product 
Patients (and their female partners) may be withdrawn from the investigational product at any time.  
A PI will withdraw a patient from the investigational product at any time for any of the following 
reasons:  
• 
If a patient experiences a serious or intolerable AE, that prevents them from continuing 
• 
If a patient incurs a significant CIP violation which impacts on their safety (this will be discussed 
on a case-by-case basis with the Sponsor) 
• 
At the request of the Sponsor 
• 
If it is considered that the patient’s health is compromised by remaining in the clinical investigation 
or the patient is not sufficiently cooperative  

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12.5.2 
Procedures for Patient Withdrawal 
Patients who withdraw from the investigation (and their female partners) should always be asked 
about the specific reason(s) for withdrawal, the presence of any AEs and any concomitant 
medication that the patient (and/or partner) may be taking.  Investigation-related AEs will be 
monitored closely and provided with the appropriate medical care and follow-up as necessary.  
A patient will be enrolled into the investigation at Day 1 (i.e. the start of the screening period), 
having satisfied all of the eligibility.  After completing the run-in period (Visit 2), the patient’s 
eligibility will be reassessed, and the IIEF-EF scores evaluated.  If the patient satisfies the eligibility 
criteria and scores ≤ 25 on the IIEF-EF questionnaire, they will be randomised into the investigation 
and a treatment type (i.e. MED3000 gel or tadalafil [5 mg] tablets) assigned.  The investigation is 
expected to have a duration of 9 months (i.e. first patient first visit until last patient last visit) with 
each patient being on the investigation for up to 30 weeks (including the screening period and 
follow-up visit).  
One hundred randomised patients (50 patients on each treatment arm) with ED are required in this 
investigation.  The recruitment period is expected to be approximately 2 months.  If the female 
partner is of childbearing potential then the couple must use a medically acceptable form of 
contraception for at least 3 months prior to entering the clinical investigation and continue to use it 
for at least 1 month after the last dose of the investigational product.  A list of acceptable 
contraception is provided in inclusion criterion 6.  Patients whose partners are pregnant or breast 
feeding will be excluded from this investigation. 
13. 
PROCEDURES 
This list of activities can be found in the Schedule of Events table (Table 2).  

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Table 4 
Biochemistry, Haematology, Urinalysis and Serology Assessments 

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13.11.2 Concomitant Medication 
13.13 
Monitoring  
Details of the monitoring arrangements are specified in the investigation-specific Monitoring Plan. 
FMD and any third party to whom aspects of the investigation management or monitoring have 
been delegated will undertake their roles for this investigation in compliance with GCP and all 
applicable regulations. 
FMD will ensure that the CRO complies with GCP through a program of oversight activities including, 
but not limited to, review of project meeting minutes, review of site initiation visit reports, and 
review of monitoring reports, etc. 
Visits to the sites will be conducted to inspect investigation data, patient medical records and eCRFs 
in accordance with GCP and the respective local and national government regulations and 
guidelines.  Records and data may additionally be reviewed by auditors or by Regulatory Authorities 
14. 
STATISTICAL DESIGN AND ANALYSIS 
14.1 
General 
Methodology for summary and statistical analyses of the data collected in this investigation is 
described here.  Further details of the proposed statistical analysis will be documented in a statistical 
analysis plan (SAP), which will be written following completion of the CIP and prior to randomisation 
of any patient into the trial.  The SAP may modify what is outlined in the CIP where appropriate; 
however, any major modifications of the primary and secondary definitions or their analyses will 
also be reflected in a CIP amendment.  Any deviations from the planned statistical analyses post-SAP 
finalisation will be detailed in the investigation report. 

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This investigation plan includes the two treatment groups MED3000 and tadalafil.  The primary and 
secondary effectiveness objectives will be assessed by testing hypotheses that only use the results 
from the MED3000 treatment group, that is, by considering this single arm only.  Other analyses will 
primarily be descriptive and will consist of both within and between treatment group summaries.  
In general, safety and effectiveness variables will be presented by means of descriptive statistics and 
figures, as appropriate, by treatment group and by time point, where applicable.  Continuous 
variables will be summarised using the number of non-missing observations, mean, standard 
deviation (SD), median, first and third quartiles, minimum and maximum.  Categorical variables will 
be presented using number of patients and percentages, with percentages based on the number of 
non-missing values.  For ordered categorical variables, cumulative percentages may also be 
presented.  Two-sided, 95% confidence intervals will be presented as part of the descriptive 
statistics.  Summaries will be based on observed data.  In addition, multiple imputation will be used 
to produce summaries whilst taking into account treatment discontinuations and other missing data. 
Data will be pooled across all sites.  Descriptive statistics will be produced for sub-groups according 
to baseline ED severity and according to country. 
There will be no planned interim analyses.  Analyses will be conducted once all patients have 
completed the investigation and the database has been locked. 
14.2 
Test of Hypotheses 

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14.3 
Sample Size and Power 
A total sample size of 100 patients (50 per arm) is deemed appropriate for this investigation.  

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14.4 
Randomisation 
Patients will be randomised to receive MED3000 gel or tadalafil (5 mg) tablets using a 1:1 allocation 
ratio.  Randomisation will be stratified based on the patients baseline ED severity scores (from the 
end of the screening period); mild (IIEF-EF domain score of 17–25), moderate (IIEF-EF domain score 
of 11–16) or severe (IIEF-EF domain score ≤ 10).  Stratified recruitment will be used, with the aim to 
randomise and treat approximately 40, 36 and 24 mild, moderate and severe ED patients 
respectively.  The plan is to randomise and treat 20 African Americans from the US site. 
Cohort recruitment will be managed using an IWRS. 
14.5 
Analysis Sets 
14.6 
Demographic and Baseline Measurements 
Baseline values will be the last assessments prior to randomisation at Visit 2 unless stated otherwise. 
Assessments made at screening and at baseline will be summarised overall and for each treatment 
group.  These assessments will include demographic and other relevant baseline characteristics 
(such as medical history, physical examination and the assessments made during the screening 
period).  There will be no formal comparison of baseline data via statistical hypothesis testing as this 
is not appropriate methodology. 
14.7 
Prior and Concomitant Medication 
Prior and concomitant medication will be summarised overall and by treatment group. 

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14.8 
Effectiveness Evaluation 
14.8.1 
Primary Effectiveness Analysis 
14.8.2 
Secondary Effectiveness Analysis 

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14.8.3 
Exploratory Effectiveness Objectives 

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14.9 
Safety Analysis 
15. 
DATA MANAGEMENT  
A fully validated eCRF will be used to capture all required clinical investigation data throughout the 
Investigation.  Paper diaries will be used to collect AEs and concomitant medication, as well as 
responses to the onset of action questions.  
The eCRF will have controlled access (e.g. password protection) to ensure the privacy of the patient’s 
and partner’s information, whilst maintaining data integrity.  The clinical database used will be CFR 
21 part 11 compliant. 
The Monitor will check data at monitoring visits to the investigational sites.  Additionally, the 
Monitor will have secure access to the clinical database to allow remote monitoring where 
necessary.  The PI will ensure that the data in the eCRFs are accurate, complete, legible and 
consistent with that recorded in the source documents.  

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Throughout the investigation, the Data Manager or designee will review the data entered into the 
eCRF, requesting clarification where necessary.  A full audit trail will be maintained within the clinical 
database to capture all changes made to the data entered in the eCRF. 
All reported AEs will be coded using the most current version of the MedDRA dictionary.  Likewise, 
all concomitant medication will be coded using the most current version of the WHODrug dictionary.  
Listings of the coded AEs and concomitant medication will be reviewed by the Sponsor’s Medical 
Advisor prior to the database lock. 
Any missing, impossible (inconsistent with human life) or inconsistent recordings in the eCRFs will be 
referred back to the PI and documented for each individual patient before clean file status is 
declared. 
All data queries raised by Data Management or the Monitor will be addressed by the site prior to 
database lock.  Once all outstanding points requiring data clarification have been addressed, the 
Data Manager or designee will notify the Sponsor and request to lock the clinical database.  Only 
when permission has been given by the Sponsor may the database be locked.  No formal statistical 
analysis of the captured clinical investigation data will be performed until the database has been 
locked. 
A copy of the collected clinical investigation data will be provided to the Sponsor in a Compact Disc 
(CD) media format at the end of the clinical investigation.  This will be stored in a suitable archiving 
facility. 
Each site will also receive all eCRF data, pertinent to that site, in a CD media format.  All such CDs will 
be stored along with all site-related clinical investigation documentation. 
All clinical investigation related data will be stored for a minimum of 10 years. 
16. 
AMENDMENTS TO THE CIP 
If it becomes necessary to issue an amendment during the course of the investigation, the 
amendment will be developed by FMD and/or the CRO in consultation with the Coordinating 
Investigator and the Biostatistician as necessary.  
FMD will notify the CRO and collect documented Investigator Agreements to the amendment.  No 
amendments to the CIP may be implemented until the Regulatory Authorities and ECs (as 
appropriate) provide a favourable opinion in writing or the necessary review timeframe has elapsed. 
17. 
DEVIATIONS FROM THE CIP 
Emergencies excepting, under no circumstances will prospective deviations (waivers) from the 
approved CIP and subsequent amendments be permitted.  Any changes to the CIP should be covered 
by an amendment which will be approved by the necessary Regulatory Authorities and ECs as 
necessary. 
The Sponsor will be notified of all major deviations from the CIP within 24 hours of their discovery.  
All deviations that are identified during the course of the investigation, be they major or minor in 
severity, will be recorded on a CIP deviations tracking log.  This log will be reviewed by the Sponsor 
periodically for risk and trend evaluation purposes, and corrective and preventative action taken as 
necessary.  

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18. 
DEVICE ACCOUNTABILITY 
The PI, trained delegate or pharmacy staff (as applicable) is responsible for the correct storage of the 
investigational product according to the manufacturer’s recommendations (see current version of 
the IB or SmPC as applicable).  The investigational products made available for this clinical 
investigation must be used in accordance with the CIP and must only be handled by the pharmacist 
or other site authorised personnel.  The pharmacy staff must maintain complete and accurate 
records, showing the receipt and disposition of all supplies of the investigational product.  These 
records must include a master record which lists the date of receipt of all investigational products 
(i.e. MED3000 or tadalafil [5 mg]) and the quantities received, and a dispensing record which 
includes all quantities dispensed, the patient numbers to whom the medication was dispensed, the 
date of each dispensing and the identification of the dispenser.  Patients will be expected to return 
all dispensed investigational product (used and unused) to the site to allow full reconciliation to be 
undertaken. 
No investigational products will be destroyed until full reconciliation has been performed nor 
without prior written confirmation from the Sponsor.  The CRO will be responsible for coordinating 
the destruction of any unused or returned medication at the sites.  Written proof of destruction 
must be kept in the Sponsor Oversight File and/or the Trial Master File (TMF) and Investigator Site 
File. 
19. 
STATEMENTS OF COMPLIANCE 
This clinical investigation will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki, the requirements of GCP, and all necessary regional or national 
regulatory and ethical legislation. 
The clinical investigation may not commence in a particular country or region until all required 
approvals have been provided, in writing, by the appropriate Regulatory Authority and ECs or 
Institutional Review Boards (IRBs) or the required review timeframe has elapsed, as necessary.  Any 
additional requirements imposed by the IRB/EC or the Regulatory Authority as a condition of 
approval must also be followed.  
FMD will ensure that local Regulatory Authority requirements are met, if required, before the start 
of the clinical investigation.  FMD (or a nominated delegate) will be responsible for the preparation, 
submission and confirmation of receipt of any Regulatory Authority approvals required prior to 
clinical investigation commencement. 
It is the responsibility of the CRO to submit this CIP, the informed consent documents (approved by 
FMD), relevant supporting information and all types of patient recruitment information to the 
relevant EC for review, and all must be approved prior to the start of patient screening.  
Advertisements must be approved by the EC prior to their use at the investigation site, if applicable.  
Prior to implementing changes in the investigation, FMD and the ECs must also approve any 
substantial amendments to the CIP and corresponding updates to the informed consent documents.  
For non-substantial CIP amendments (that do not require EC approval) and subsequent updates of 
the informed consent documents, all changes will be done in agreement with FMD and the 
investigation sites. 

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The CRO is responsible for keeping the relevant EC apprised of the progress of the investigation and 
of any changes made to the CIP.  FMD (or a nominated delegate) will keep the ECs informed of any 
serious and significant AEs.  
The Sponsor will ensure that suitable insurance cover is in place prior to the start of the 
investigation.  The Sponsor will adhere to the recommendations of the Association of the British 
Pharmaceutical Industry (ABPI) guidelines and all other requirements of insurance in the countries 
where the clinical investigation will be conducted. 
This investigation is being sponsored by Futura Medical Developments Limited (FMD).  Before a site 
can begin any investigation related activity a fully executed clinical trial agreement is in place 
between FMD and each site. 
20. 
INFORMED CONSENT PROCESS 
It is the responsibility of the PI or suitable qualified designee (e.g. sub-investigators) to obtain 
written informed consent from all patients and their female partners at Visit 1 before any 
investigation related procedures are undertaken.  All consent documentation must be in accordance 
with applicable regulations and GCP.  Each patient and his partner is required to sign the patient and 
partner ICF after they have both read the written patient information and received an explanation of 
what the investigation involves.  This can include, but is not limited to: the objectives, potential 
benefits and risks, inconveniences and the patient’s/partner’s rights and responsibilities.  Signed 
consent forms must remain on file and must be available for verification by Investigation Monitors at 
any time.  A signed original copy of the informed consent documentation (ICF or Patient Information 
and ICF, as applicable) must be given to the patient and his partner or the patient’s/partner’s legally 
authorised representative. 
The CRO will provide the Sponsor with a copy of the EC approved consent forms, and a copy of the 
EC written approval, prior to the start of the investigation.  Additionally, if the EC required 
modification of the sample Patient Information and ICF documents provided by the Sponsor, the 
documentation supporting this requirement must be provided to the Sponsor. 
It is not anticipated that there will be any circumstances whereby a patient or his female partner will 
not be able to provide their informed consent in this investigation.  
21. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS, AND DEVICE DEFICIENCIES 
21.1 
Definitions 
Adverse Event (AE): Any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in patients and their partners whether or not 
related to the investigational medical device or the control used in the investigation. 
Adverse Device Effect (ADE): An AE related to the use of the investigational medical device.  This 
definition includes: 
• 
AEs resulting from insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device (malfunction is 
the failure of an investigational medical device to perform in accordance with its intended purpose 
when used in accordance with the CIP) 

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• 
Any event resulting from use error or from intentional misuse of the investigational medical device 
(use error is user action or lack of user action while using the medical device that leads to a 
different result than that intended by the manufacturer or expected by the user) 
Serious Adverse Event (SAE): An AE that leads to any of the following: 
• 
Death 
• 
A serious deterioration in the health of the patient or the patient’s partner by one or more of the 
following: 
o A life-threatening illness or injury, or 
o A permanent impairment of a body structure or a body function including chronic diseases, or 
o In-patient or prolongation of hospitalisation, or  
o Medical or surgical intervention to prevent life-threatening illness or injury, or permanent 
impairment to a body structure or body function 
• 
Foetal distress, foetal death, a congenital abnormality, or birth defect including physical or mental 
impairment 
Note: In this investigation, planned hospitalisation for a pre-existing condition, or procedure required 
by the CIP without serious deterioration in health, is not considered an SAE. 
Serious Adverse Device Effect (SADE): An ADE which results in any of the consequences as 
characterised in an SAE. 
Serious Health Threat: Signal from any AE or device deficiency that indicates an imminent risk of 
death or a serious deterioration in the health in patients, users or other persons, and that requires 
prompt remedial action for other patients, users or other persons.  A device deficiency is the 
inadequacy of a medical device with respect to its identity, quality, durability, reliability, usability, 
safety or performance. 
Unanticipated Serious Adverse Device Effect (USADE): A SADE which by its nature, incidence, 
severity or outcome has not been identified in the current risk assessment.  In some regions, this 
may be referred to as an Unanticipated Adverse Device Effect. 
AEs/ADEs will be collected from the signing of the ICF at screening (Visit 1) until the end of the 
investigation.  Any AEs that are unresolved at the patient’s last AE assessment during the 
investigation (i.e. at the patient’s final investigation visit) are to be followed up by the PI for as long 
as medically indicated, but without further recording in the eCRF.  FMD retains the right to request 
additional information for any patient and/or their female partner with ongoing AE(s)/SAE(s) at the 
end of the investigation, if judged necessary. 
All AEs/ADEs will be recorded in the patient’s paper diary and entered into the eCRF after review by 
the PI or suitable qualified designee (e.g. sub-investigators) at the next investigation visit.  The 
details to be recorded are: 
• 
The date of the AE/ADE onset and its resolution 
• 
Treatment (if any) 

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• 
Seriousness 
• 
Relationship to the investigational device or control and the related procedure 
Any SAE/SADE/USADE will be notified by the PI to the Medical Device Vigilance Service Provider and 
Medical Monitor designated by the Sponsor within 24 hours by email or fax.  Contact details for the 
Medical Device Vigilance Service Provider are included in the Medical Device Vigilance manual. 
Assessment of relationship and seriousness will be made by the site Physician (see Section 13.11.1).  
The FMD Medical Advisor will not be able to downgrade the opinion of the site Physician with 
regards to the relationship or seriousness.  Assessment of expectedness of all AEs will be conducted 
by the FMD Medical Advisor with reference to the ‘Reference Safety Information’ section of the IB. 
Occurrence of SAEs/SADE/USADEs will be notified to the Regulatory Authority and/or the IRB/ECs by 
the Medical Device Vigilance Service Provider or their delegate within the requisite timeframes for 
the countries where the clinical investigation is being conducted. 
SAEs/SADE/USADEs must be recorded and reported whether or not the PI considers the 
SAE/SADE/USADEs to be related to the investigational device or the control. 
Photocopies of results, consultant report(s), a summary of the outcome of the reaction and the PI’s 
opinion of the investigational device’s relationship to the SAE/SADE/USADE will accompany the 
SAE/SADE/USADE reporting form if and when available. 
A Data Monitoring Committee will not be established for this clinical investigation. 
22. 
VULNERABLE POPULATION 
This investigation will involve adult male patients (i.e. 22 to 70 years of age) who are not vulnerable.  
23. 
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION 
The Sponsor may take the decision to prematurely terminate the investigation at any time and for 
whatever reason; such a decision will be communicated to all PIs participating in the investigation. 
As this is an open-label investigation, unblinding of treatment allocation will not be necessary if the 
investigation is suspended or terminated.  
If the investigation is terminated, all ongoing patients will be invited to attend the Follow-up Visit 
and undertake the assessments scheduled for that visit. 
24. 
PUBLICATION POLICY 
Details of the clinical investigation will be registered on a publicly accessible database 
(e.g. clinicaltrials.gov).  Upon completion of the investigation and publication of the Clinical 
Investigation Report (CIR).  FMD will provide a summary of the CIR within 1 year of the end of the 
investigation to the Competent Regulatory Authority of the Member States concerned, as required 
by the regulatory requirement and to comply with the community guideline on GCP.  FMD will 
provide the PI with a copy of the summary report to forward to the relevant EC. 
The results of the investigation will be made available publicly.  This is expected to occur up to 
6 months after the publication of the CIR. 

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If the Sponsor, CRO and Coordinating Investigator agree that it is desirable to publish the results of 
this investigation; all parties will liaise in good faith to publish the results.  The CRO/Coordinating 
Investigator agree to obtain the Sponsor’s prior written approval of such publications. 
25. 
INVESTIGATOR RESPONSIBILITIES  
25.1 
GCP Compliance 
The PI will have been assigned by FMD to perform the investigation in accordance with the EN ISO 
14155:2020 GCP standard, the ethical principles that have their origin in the Declaration of Helsinki, 
EU Directive 2001/20/EC and all other applicable regulatory and ethical requirements.  
It is the PI’s responsibility to ensure that adequate time and appropriate resources are available at 
the individual investigation sites prior to commitment to participate in this investigation.  The PI 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable patients within the agreed recruitment period. 
The PI will maintain a list of appropriately Qualified Persons (QPs) to whom the PI has delegated 
significant investigation-related tasks.  Up-to-date copies of the curriculum vitae for the PI, 
Sub-Investigator(s) and essential investigation staff will be provided to FMD (or their delegate) 
before starting the investigation. 
Agreement with the final CIR will be documented by a dated signature of the Coordinating 
Investigator and local regulatory requirements. 
25.2 
CIP Adherence and Investigator Agreement 
The PI must adhere to the CIP as detailed in this document.  The PI will be responsible for enrolling 
only those patients who have met CIP eligibility criteria.  The PI will be required to sign an 
Investigator Agreement to confirm acceptance and willingness for themselves and the 
Co-Investigator(s) to comply with the CIP. 
25.3 
Documentation and Retention of Records 
After completion of the investigation, all data and documents relating to the investigation will be 
kept in a secure and orderly manner by the CRO or their delegate in a secure file in an electronic or 
paper TMF.  The data will be available for inspection by FMD or their representatives.  Unless other 
union law requires archiving for a longer period, the Sponsor and the CRO shall archive the 
content of the TMF for at least 10 years after the end of the investigation.  However, the 
medical files of patients shall be archived in accordance with national law.  The CRO or their 
delegate must contact FMD before destroying any investigation-related documentation and it is the 
responsibility of FMD to inform the investigative sites of when these documents can be 
destroyed.  
26. 
CONFIDENTIALITY 
Data collected during this investigation may be used to support the development, registration or 
marketing of a medicinal product.  FMD will control all data collected during the investigation and 
will abide by the General Data Protection Regulation (GDPR) (EU) 2016/679 concerning the 
processing and use of patients’ personal data.  For the purpose of GDPR, FMD will be the data 
controller. 

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After patients have consented to take part in the investigation, their medical records and the data 
collected during the investigation will be reviewed by FMD and/or its representatives.  These records 
and data may, in addition, be reviewed by the following: independent auditors who validate the data 
on behalf of FMD, national or local Regulatory Authorities, and the ECs which gave approval for this 
investigation to proceed. 
Patients will be known by a unique patient number.  The results of this investigation containing the 
unique patient number and relevant medical information including ethnicity may be recorded and 
transferred to and used in other countries throughout the world, which may not afford the same 
level of protection that applies within the EU and countries participating this investigation.  The 
purpose of any such transfer would be to support regulatory submissions made by FMD in such 
countries. 
27. 
QUALITY ASSURANCE AND QUALITY CONTROL 
To ensure GCP compliance and compliance with all applicable regulatory requirements, the Sponsor 
or site may conduct a quality assurance (QA) audit.  A regulatory inspection of this investigation may 
be carried out by regulatory agencies.  Such audits/inspections can occur at any time during or after 
completion of the investigation.  If an audit or inspection occurs, the PI and the site will agree to 
allow the auditor/inspector direct access to all relevant documents and to allocate their time and 
the time of their staff to the auditor/inspector to discuss any findings or relevant issues.  Quality 
control (QC) procedures at the site will be implemented to ensure data recorded into the eCRFs are 
accurate before eCRFs are sent for data entry purposes.  
 
 

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28. 
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29. 
APPENDICES 
29.1 
APPENDIX 1 
IIEF Questionnaire 
 
 
 

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29.2 
APPENDIX 2 
SEAR Questionnaire 
 

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29.3 
APPENDIX 3 
Onset of Action Questions