Conditions: Erectile Dysfunction
Keywords: ED
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 26
Healthy volunteers: no

Brief summary:
To evaluate the safety and efficacy of a single intracavernous injection of hMaxi K (8000 µg and 16000 µg) or placebo upon penile rigidity or erection in males with erectile dysfunction longer than six months that is attributable to an underlying, stable medical condition.

Detailed description:
This study is a double-blind, placebo controlled, parallel design, Phase 2A study evaluating the potential activity and safety of a single administration of hMaxi-K (8000 or 16000 µg) or placebo (PBS sucrose 20%) injected into the corpus cavernosum of the penis in men who have been unable to tolerate, do not wish to continue, or have had unsuccessful results with, prior therapy for ED.

The study population is men with erectile dysfunction attributable to an underlying, stable medical condition but who are otherwise in good health. The target population is men with erectile dysfunction and those who have been unable to tolerate, do not wish to continue, or have had unsuccessful results with, prior therapy for ED and with an erectile function domain score of IIEF \< 21 at screening and baseline.

Following screening and study drug administration at Week 0 (Visit 2 \[V2\]), eligible participants will be evaluated at Weeks 1 (V3), 4 (V4), 8 (V5), 12 (V6), and 24 (V7). At each study visit, participants will have a physical examination including examination of the penis (all visits), vital signs, electrocardiogram (ECG) (all visits). Laboratory evaluations including chemistry and hematology will be done at V1, V3, V4, V6, and V7. Urinalysis will be done V1, V2 (prior to dosing), V3, V4, V6, and V7. Endocrine parameters and PTT, PT, sed rate and CRP will be evaluated at V1, V3, and V7. The participant will complete the erectile function domain of the IIEF and Sexual Encounter Profile (SEP) at screening/baseline and at V2, (SEP and IIEF at V2 prior to dosing) V3, V4, V5, V6, and V7. In all participants, plasma specimens will be collected to assay for the presence of hSlo DNA by PCR (V2-V7). These will be kept frozen at -20°C or less at the site for eventual assay by Sponsor.

The primary efficacy outcome measures will include the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP), Questions 2 and 3 from SEP. The IIEF EF domain has a 30-point total score, where higher scores reflect better erectile function. SEP is a diary in which participants record each sexual attempt made throughout the study. The two questions from the Sexual Encounter Profile (SEP) deal with the ability to achieve vaginal penetration (SEP2), and the ability to maintain an erection long enough for successful intercourse (SEP3). The erectile function domain category of the IIEF will be used to evaluate the change in erectile status from baseline following administration of hMaxi-K. Change from baseline on the six questions of the IIEF's Erectile function domain category at every visit after administration of study drug will be calculated and compared among the two dose and one placebo groups.

Safety will be assessed by analysis of adverse experiences, and abnormal findings on clinical laboratory tests, electrocardiogram, and physical examinations.

6 months per participant (approximately 2 years to enroll all participants)

A total of 35 participants were planned to be enrolled; N=11 on 8000 µg; N=11 on 16000 µg; N=13 on placebo.

Both the safety data and data to assess activity will be presented as means and standard deviations or medians and ranges as appropriate for continuous data, and analyzed using either paired t- or Wilcox on Sign Rank tests for within group changes, and with mixed effects or marginal models to determine differences in trends among the three cohorts over time. Incidence of adverse events will be presented as relative frequencies within groups.

Arms:
arm 1: Single Treatment/ two escalating dose levels (8000 µg and 16,000 µg injection). In each dose level, 11 participants will receive hMaxi-K and 6 will receive placebo (only one injection per each participant) arm 2: PBS-20% sucrose administered during two single treatment dose levels (8000 µg and 16000 µg) by injection (only one injection per each participant)

Interventions: intervention 1: hMaxi-K Single Treatment/ 2 escalating dose levels (8000 µg and 16000 µg injection) intervention 2: Placebo (PBS-20% sucrose)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
1
 
 
 
A Double-blind,  Placebo-controlled, 
Parallel Design,  Randomized, Phase 2A 
Clinical Trial Evaluating the Potential 
Activity and Safety of hMaxi-K Gene 
Transfer in Males with Erectile Dysfunction 
 
 
Protocol No. ION04-ED  
 
 
 
 
Sponsor 
Ion Channel Innovations, LLC 
969 Park Ave., 1G 
New York, NY 10028 
Tel: 212-639-1561 
Version 1.2 dated Mar 01, 2016 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
 
This document is the property of Ion Channel Innovations. The information is confidential and is 
be used only in connection with matters authorized by Ion Channel Innovations and no part of it  
is to be disclosed to others without prior written permission from Ion Channel 
Innovations.  
 
 
 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
2
Table of Contents 
Table of Contents ...........................................................................................................................2 
List of Figures .................................................................................................................................3 
List of Tables ..................................................................................................................................3 
Protocol Synopsis ...........................................................................................................................4 
Introduction ....................................................................................................................................6 
1.1 Overview .............................................................................................................................6 
1.2 Physiology of Penile Erection ............................................................................................7 
1.3 Maxi-K Channels .............................................................................................................9 
1.4 Rationale for Development of hMaxi-K ...........................................................................9 
1.5 Description of hMaxi-K .................................................................................................11 
1.6 
Clinical Data ................................................................................................................12 
2.0 Objectives ............................................................................................................................14 
3.0 Study Design .......................................................................................................................14 
4.0 Study Population ................................................................................................................14 
4.1 Inclusion Criteria ............................................................................................................14 
4.2 Exclusion Criteria ...........................................................................................................15 
5.0 Test Material and Administration ...................................................................................16 
5.1 Study Medication ...........................................................................................................16 
5.2 Dose Selection and Administration ................................................................................17 
5.2.1 Dose Limiting Toxicity .............................................................................................18 
5.3 Concomitant Medications/Therapies ..............................................................................19 
6.0 Outcome Assessments and Procedures ...........................................................................19 
6.1 International Index of Erectile Function (IIEF) .............................................................19 
6.2 Sexual encounter profile (SEP) .........................................................................................19 
6.3 Physical Examination .......................................................................................................19 
6.3.1 Physical Examination ..................................................................................................19 
6.3.2 Physical Examination of the Penis ..............................................................................20 
6.4 
Electrocardiograms ......................................................................................................20 
6.5 
Vital Signs ...................................................................................................................20 
6.6 Laboratory Safety Tests and Pharmacokinetics Evaluations .........................................20 
6.7  Pharmacokinetics ..........................................................................................................21 
7.0 Schedule of Evaluations ....................................................................................................21 
7.1 Visit 1 (Study Week (-) 2 - Screening) ...........................................................................21 
7.2 Visit 2 (Study Week 0 - Administration of study drug) .................................................22 
7.3 Visit 3 (Study Week 1) ....................................................................................................22 
7.4 Visit 4 (Study Week 4) ...................................................................................................23 
7.5 Visit 5 (Study Week 8) ...................................................................................................23 
7.6 Visit 6 (Study Week 12) ..................................................................................................24 
7.7 Visit 7 (Study Week 24) or Exit Visit: ...........................................................................24 
7.8 
Long-term follow-up .....................................................................................................25 
8.0 Participant Withdrawal ....................................................................................................25 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
3
9.0 Adverse Events Definitions and Monitoring ..................................................................26 
9.1 Adverse Event ................................................................................................................26 
9.2 Serious Adverse Event ...................................................................................................26 
9.3 Assessment of Causality .................................................................................................27 
9.4 Severity of Adverse Event ..............................................................................................27 
9.5 Monitoring of Adverse events ........................................................................................28 
10.0 Assessment of Endpoints .................................................................................................28 
10.1 Safety ............................................................................................................................28 
10.2 Efficacy ........................................................................................................................29 
10.3 Analysis of Endpoints ..................................................................................................29 
10.3.1   Safety .........................................................................................................................29 
10.3.2   Efficacy ......................................................................................................................29 
11.0 Monitoring of Participant Safety ...................................................................................30 
11.1 Informed Consent ...........................................................................................................30 
12.0 Regulatory Standards ......................................................................................................30 
12.1   Electronic case report forms .........................................................................................30 
12.2 Clinical and Regulatory Monitoring .............................................................................30 
12.2.1 Study Conduct (Site) .................................................................................................30 
12.2.2 Adherence to Reporting Requirements .....................................................................31 
12.3 Participant Confidentiality ...........................................................................................31 
12.4 Records .........................................................................................................................32 
13.0 References .........................................................................................................................32 
Appendix A. Grading of Averse Events .................................................................................36 
Appendix B.  Schedule of Events ................................................................................................38 
Appendix C. Sexual Encounter Profile (SEP) .......................................................................39 
Appendix D. International Index Erectile Function ..............................................................40 
 
List of Figures 
Figure 1: Regulation of Myocyte Tone ............................................................................................8 
Figure 2.   Interaction of Maxi-K channel and nitric oxide.   See text for explanation ..............10 
List of Tables 
Table 1.  - Final Dose – hMaxi-K ..................................................................................................16 
Table 2.  Statistical Power .............................................................................................................29 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
4
Protocol Synopsis 
 
Title 
A Double-blind, Placebo-controlled, Parallel Design, Randomized Phase 
2A Trial Evaluating the Potential Activity and Safety of hMaxi-K Gene 
Transfer in Males with Erectile Dysfunction 
Study Number 
ION 04-ED 
Clinical Study 
Phase 
Phase 2A 
Number of 
Centers 
 
One site  
Study 
Objectives 
 
To evaluate the safety  and efficacy of a single intracavernous injection of 
hMaxi K (8000 µg  and 16000 µg) or placebo upon penile rigidity or 
erection in males with erectile dysfunction longer than six months that is 
attributable to an underlying, stable medical condition. 
Study Design 
This study is a double-blind, placebo controlled, parallel design, Phase 2A 
study evaluating the potential activity and safety of a single administration 
of hMaxi-K (8000 or 16000 µg) or placebo (PBS sucrose 20%) injected 
into the corpus cavernosum of the penis in men who have been unable to 
tolerate, do not wish to continue, or have had unsuccessful results with, 
prior therapy for ED.  
Study 
Participant 
Population 
The study population is men with erectile dysfunction attributable to an 
underlying, stable medical condition but who are otherwise in good health.  
The target population is men with erectile dysfunction and those who have 
been unable to tolerate, do not wish to continue, or have had unsuccessful 
results with, prior therapy for ED and with an erectile function domain score 
of IIEF >10 and < 21 at screening and baseline. 
Study 
Procedures 
 
Following screening and study drug administration at week 0, eligible 
participants will be evaluated at weeks 1, 4, 8, 12, and 24. At each study 
visit, participants will have a physical examination including examination 
of the penis (all visits), vital signs, electrocardiogram (ECG) (all visits).  
Laboratory evaluations including chemistry and hematology will be done 
at V1, 3, 4, 6, and 7.  Urinalysis will be done V1, 2 (prior to dosing), 3, 4, 
6, and 7.  Endocrine parameters and PTT, PT, sed rate and CRP will be 
evaluated at Visit 1, 3 and 7.  The participant will complete the erectile 
function domain of the IIEF and Sexual Encounter Profile (SEP) at 
screening/baseline and at V2, (SEP and IIEF at V2 prior to dosing) V3, V4, 
V5, V6, and V7.  In all participants, plasma specimens will be collected to 
assay for the presence of hSlo DNA by PCR (V2-V7). These will be kept 
frozen at -20o C or less at the site for eventual assay by Sponsor. 
Primary Study 
Outcomes 
The primary outcome measures will include the Erectile Function (EF) 
domain of the International Index of Erectile Function (IIEF), Sexual 
Encounter Profile (SEP), Questions 2 and 3 from SEP. The IIEF EF 
domain has a 30-point total score, where higher scores reflect better 
erectile function. SEP is a diary in which participants record each sexual 
attempt made throughout the study. The two questions from the Sexual 
Encounter Profile (SEP) deal with the ability to achieve vaginal penetration 
(SEP2), and the ability to maintain an erection long enough for successful 
intercourse (SEP3). The erectile function domain category of the IIEF will 
be used to evaluate the change in erectile status from baseline following 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
5
administration of hMaxi-K. Change from baseline on the six questions of 
the IIEF’s Erectile function domain category at every visit after 
administration of study drug will be calculated and compared among the 
two dose and one placebo groups.    
Secondary 
Study 
Outcome 
Safety will be assessed by analysis of adverse experiences, and abnormal 
findings on clinical laboratory tests, electrocardiogram, and physical 
examinations. 
Study Duration 
6 months per participant (approximately 1 year to enroll all particpants) 
Study Start 
TBD 
Sample Size  
35 participants; N=11 on 8000 µg; N= 11 on 16000 µg; N= 13 on placebo 
Statistical 
Analysis 
 
Both the safety data and data to assess activity will be presented as means 
and standard deviations or medians and ranges as appropriate for 
continusous data, and analyzed using either paired t- or Wilcoxon Sign 
Rank tests for within group changes, and with mixed effects or marginal 
models to determine differences in trends among the three cohorts over 
time. Incidence of adverse events will be presented as relative frequencies 
within groups. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
6
Introduction 
1.1 Overview 
Erectile Dysfunction (ED) is a disease defined as the inability to achieve or maintain an erection 
sufficient for satisfactory sexual function. ED is a common and significant problem that afflicts  
approximately 20 – 30 million men in the United States and 150 million men worldwide.1-4  
Overall, 52% percent of men have some degree of erectile dysfunction and 25% of 75-year old  
men have complete erectile dysfunction. The disease has a significant negative impact on the  
quality of life of the patient and their sexual partners and can cause depression and a feeling of  
inadequacy.  
The most common cause of ED is advanced age. Proposed causes of age-induced ED include  
reduction of NO production, increased contractility of the smooth muscle of the penile corpora,  
increased myofilament calcium sensitivity due to altered Rho kinase expression/activity, and  
reduction in the relative percentage of smooth muscle fibers and an increase in collagen content 
thus decreasing the compliance of the cavernous tissue.5-8 The second most common cause is  
diminished blood flow to the penis due to cardiovascular disease.  
ED can either be reversible or nonreversible. Men over 50 years tend to have permanent causes  
of ED that are disease-related. The most frequently associated diseases include atherosclerosis,  
hypertension, anti-hypertensive medications, diabetes mellitus, and pelvic surgery and radiation. 
Treatment for nonreversible ED include: 1) oral phosphodiesterase inhibitors e.g., sildenafil  
(ViagraTM); 2) vacuum erection devices; 3) intraurethral alprostadil (Muse™); 4) intracavernous 
injection of prostaglandin E1 (Caverject™ or Edex™) or a combination of PGE1, papaverine  
and phentolamine; and 5) surgical placement of penile prosthetic implants for physiological  
disease. Despite the availability of these therapies, the lack of efficacy, their potential side  
effects, and the loss of spontaneity (the treatment must be planned and taken or used prior to  
initiating the sex act) have limited therapy for ED to about 10% of the overall patient population 
with nonreversible ED.  
In younger men (ages 20 – 40), psychological causes for ED often predominate and this  
reversible form of ED can be treated with sex therapy and the drugs listed above. Current  
therapies for reversible forms of ED include: 1) sex therapy for psychological disease; 2)  
correction of endocrine abnormality with appropriate hormone therapy in a small percentage of 
men (<5%); 3) surgical correction for men diagnosed with Peyronie’s disease; 4) penile bypass  
surgery in men who have suffered pelvic or perineal trauma with injury to the penile arteries.  
ED as a consequence of all other etiologies (more then 90%) is not reversible.  
There are many reasons why acceptance by physicians and participants for currently available  
therapies is limited. Sex therapy has limited efficacy and is only suitable for men with a normal  
penile function and a psychological cause of the ED. Overall, Vacuum Erection Devices (VED)  
are effective in about 30% of men who use them, phosphodiesterase inhibitors such as Viagra®,  
(sildenafil), Cialis® (tadenafil), and Levitra® (vardenafil) in about 70%, intracavernous injections 
in 85%, intraurethral alprostadil in about 40%, and penile implants in over 95%. Medical  
intervention with drugs is least effective in men with long-standing diabetes because the  
physiological effects of severe autonomic neuropathy and small vessel atherosclerosis limit the  
effective action of the medications. Although penile prosthetic 
implants can be inserted into  
nearly every man with ED, the negative stigmata of having an operation and a mechanical 
erection have limited acceptance of the devices by participants since their introduction in the 
late1960’s. Furthermore, the rate of infection in penile prosthetic implants is reported between 3 
to 9% and inflatable prostheses have a long-term mechanical failure rate of about 10%. Ion 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
7
Channel Innovations has developed hMaxi-K to treat ED using the same principal as drugs that 
have been used since 1982, i.e., treatment with medicines causing relaxation of the penile smooth 
muscle resulting in rigid erections. hMaxi-K consists of the gene for the α-pore subunitof the 
maxi-K channel, hSlo, inserted into a plasmid vector. Administration of this gene into the 
corpora increases expression of the maxi-K channel in the smooth muscle cells and an increased 
efflux of K+ across the cell membrane resulting in decreased entry of Ca++ ions. This effect on 
ion exchange across the smooth muscle cells allows the smooth muscle of the corpora to relax; 
the corporal sinusoids become engorged with blood, and the penis to stay rigid. In preclinical 
studies, a single administration of hMaxi-K to aging rats with ED has been shown to last at least 
up to six months.9 Furthermore, results from these preclinical studies suggest that expression of 
the α-pore subunit for the maxi-K channel following administration of hMaxi-K may have a 
long-term effect on the erectile mechanism.9 This activity of hMaxi-K may represent a distinct 
advantage over current drug therapy for ED where the effect of treatment is temporary.  
1.2 Physiology of Penile Erection  
In order to better understand ED and the mechanism of action for gene transfer using hMaxi-K, a 
description of the normal function of the penis is useful. Normal erection is a neurovascular  
event that depends upon proper function of two, well-vascularized cylinders of spongy tissue in  
the penis: the two corpora cavernosa (the corpora). A third channel, the corpus spongiosum,  
contains the urethra through which either urine or semen passes but is not involved in causing  
penile rigidity.  
Blood flows into the corpora from two pudendal arteries that emerge from the pelvis and  
separately fork into two smaller branches, the dorsal and cavernous arteries, and enter the penis.  
The cavernous arteries are the arteries most responsible for erection. Branches of the cavernous  
artery enter directly into the endothelial-lined, expansible, sinusoidal spaces that comprise the  
cavernous bodies. Two other branches of the pudendal artery supply the corpus spongiosum and 
glans penis. When the penis is flaccid the cavernous arteries are only 0.4 millimeter in diameter  
while during sexual excitement these arteries will double in diameter. These narrow blood  
vessels are extremely susceptible to blockage in participants with diseases associated with  
arterial narrowing, e.g., hypertension and atherosclerosis.  
During sexual excitement there is a ten-fold increased blood flow to the erectile chambers of the  
penis. As the sinusoids fill with blood at systemic pressure the smooth muscle cells within the  
corpora relax, become compressed by the arterial filling pressure and compress the out flowing  
veins against the thick elastic covering of the corpora, the tunica albuginea, and a rigid erection  
occurs. Consequently, the penis function as a tone organ, i.e., when tone is high the smooth  
muscle cells of the corpora are partially contracted and the penis is flaccid. When the tone is low 
and the myocytes are relaxed, the penis is fully engorged with blood and becomes erect.  
However, with increased age, diseases (e.g., diabetes mellitus), or states where the smooth  
muscle cells fail to relax (e.g., anxiety), the occlusion of venous outflow by the corporal smooth  
muscle is incomplete with a resultant soft, or partial, erection. Regulation of the state of  
contraction/relaxation of smooth muscle and its effect on the erectile process depends primarily  
upon the intracellular concentrations of certain ions, in particular potassium and calcium.  
 
Contraction and relaxation of smooth muscle, is critical to the storage and/or conduit function(s)  
of hollow organs such as the bladder, gut, blood vessels and penis. K channels play an important  
role in this process by virtue of their ability to alter the membrane potential and excitability of  
smooth muscle cells.10-12 Their primary effect is to modulate Ca2+ influx through Ca channels  
(i.e., L-Type, voltage-dependent). The amount of Ca2+ that enters the cell through these channels 
is a major determinant of the free intracellular calcium levels inside the smooth muscle cell,  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
8
which in turn, determine the degree of smooth muscle cell contraction. Overall, regulation of the  
contractile process is organ-specific and modulated by a variety of K channel subtypes.13--16  
Prominent amongst the K channel subtypes found in smooth muscle is the large conductance,  
calcium sensitive K channel, referred to as the maxi-K channel. Increased maxi-K channel  
activity is associated with corporal smooth muscle cell relaxation and penile erection. Moreover,  
alterations in K channel physiology/function are increasingly being recognized as a major  
contributing factor to the development of the vascular pathologies associated with diabetes,17,18  
as well as urogenital disorders, including erectile dysfunction .11,14 
Intracellular concentrations of ions and second messengers (e.g., (K+, Ca++,cAMP, cGMP, etc.) 
are affected by release of neurotransmitters and in turn the changes can be rapidly propagated  
from cell to cell through specialized intercellular protein pores called gap-junctions.19-22 The  
importance of gap junctions to coordinate smooth muscle function cannot be overstated. Even  
after severe nerve loss such as can occur with diabetes or radical prostatectomy there remains  
sufficient level of intercellular coupling to allow the corporal tissue to function normally  
following membrane or receptor stimulation. For example, oral administration or by  
intracavernous or intraurethral injection of a drug that stimulates the exchange of ions across the  
cell membranes can allow the penis to become erect. This approach has proven successful with  
FDA approved intracavernous (EdexTM, CaverjectTM) and intraurethral (Muse TM) injection with  
prostaglandin E1.  
Thus, cellular mechanisms that influence cell membrane potential are of critical importance in  
regulating the moment-to-moment tone of any organ composed predominantly of smooth muscle 
whether it is the penis, urinary bladder, blood vessels or gut. The relationship of ions, ion  
channels, and second messenger interaction in smooth muscle cells is depicted in Figure 1.  
Figure 1: Regulation of Myocyte Tone 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhibitory interaction of K+ efflux and Ca++ influx. Persistent Ca++ influx is necessary to 
maintain myofilament contraction.  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
9
1.3 Maxi-K Channels 
At least four K channel subtypes are present in human corporal smooth muscle cells. These  
channels include: (1) the voltage and calcium-sensitive maxi-K, (2) ATP dependent K channels  
(KATP), (3) inwardly rectifying channels (Kir), and (4) voltage-gated K channels (KV).7 The  
primary function of K channels is to modulate Ca++ influx through Ca-channels (i.e., L-Type,  
voltage-dependent). The amount of Ca++ that enters the cell through these channels is a major  
determinant of the free intracellular calcium levels inside the smooth muscle cell, which in turn, 
determine the degree of smooth muscle cell contraction.  
Overall, regulation of the contractile process is organ-specific and modulated by a variety of K  
channel subtypes. 16,23-25 The maxi-K channel is the most prominent (numbering approximately 
1000 to 1500/cell22) and well-studied K-channel subtype involved in corporal smooth muscle  
relaxation. Increased maxi-K channel activity is associated with corporal smooth muscle cell  
relaxation and penile erection. Moreover, alterations in K channel physiology/function are  
increasingly being recognized as a major contributing factor to the development of the vascular 
pathologies associated with diabetes 17,18 as well as urogenital disorders 14 including erectile  
dysfunction. 10, 11 
The maxi-K channel is composed of α and β subunits.12 The α, or pore forming, unit of the maxi- 
K channel is a tetramer of homologous units. Each α subunit is composed of 11 hydrophobic  
domains. Seven of the domains are transmembrane spanning (S0-S6) and the remaining 4  
domains are cytoplasmic (S7-S10). The α subunit has intrinsic sensitivity to Ca++ via the  
cytoplasmic tail region.25 Even in the absence of the β subunit, expression of the α subunit of 
the maxi-K channel can form a functional unit; however, expression of the β subunit alone does  
not form a functional channel.17 It has been proposed that the role of the β subunit is to modulate 
the α subunit activity or sensitivity to Ca++. 25  
1.4 Rationale for Development of hMaxi-K  
Ion Channel Innovations has developed a gene transfer product, hMaxi-K, and plans to  
investigate the effect of increased expression of maxi-K channels in the smooth muscle of the  
penis in participants with ED. hMaxi-K consists of the gene for the α pore of the maxi-K  
channel, hSlo, inserted into a plasmid vector, pVAX. Because heightened smooth muscle tone  
may be a causative factor of erectile dysfunction, increased numbers of maxi-K channels  
following gene expression of hMaxi-K may effectively correct ED.9, 26 This approach to treat  
ED uses the same principal as drugs developed since 1982, i.e., treatment with medicines causing 
relaxation of the penile smooth muscle results in rigid erections.  
How does Maxi-K channel gene transfer work? The rationale for the utility of K channel gene  
therapy is related to the important contributions that ion channels make to the contraction and  
relaxation of smooth muscle cells (i.e., myocytes). Ion channels are membrane proteins that  
provide a selective permeability barrier to the movement of ions across the cell membrane  
(influx and efflux of ions, i.e., K+ and Ca2+.) In short, these membrane proteins provide a  
selective channel through which ions can flow (K+ flows through K channels, and Ca2+ flows  
through Ca channels, but not vice versa). The opening and closing of these channels is regulated  
by numerous cellular processes. However, anything that increases the extent that they are open  
will increase the amount of ion that can move through the channel over any given period of time.  
The idea behind maxi-K channel gene transfer is to increase the number of maxi-K channels in  
the cell membrane, so that when the cells are activated by the normal erectile stimulus (i.e., nitric 
oxide released from nerves), there will be an increase in the efflux of K+ from the cell.  
The role of the maxi-K channel in generation of an erection can be illustrated by its interaction 
with nitric oxide (NO) as shown in Figure 2.  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
10 
 
Arousal 
 
NOS activation 
 
(NANC nerves, vascular endothelium) 
 
 
Soluble guanylate cyclase 
 
TYPE V PD 
GMP 
X  
PD Inhibitors, sildenafil 
 
 
 
 
 
 
 
 
Maxi-K 
 
 
Smooth Muscle Cell Hyperpolarization 
 
Lower cytosolic Ca++ 
 
Vasodilation 
 
 
Erection 
 
Figure 2.   Interaction of Maxi-K channel and nitric oxide.   See text for explanation 
 
 
The production of NO leads to erection through a pathway that involves cGMP-mediated  
activation of maxi-K channels resulting in hyperpolarization of vascular and cavernosal smooth  
muscle cells. As described above, hyperpolarization inhibits the influx of the calcium ion and  
causes the smooth muscle cells of the corpora to relax allowing increased blood flow into the  
corpora at systolic pressure and cause erection. Note the central role for protein kinase G (PKG) 
and ion channels in this pathway and the critical position at the end of the pathway to erection  
that potassium channel activation has in the erectile mechanism. Thus, loss or erectile function in  
cGMP 
PKG 
KATP, KV  
Gene transfer


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
11 
diseases associated with a reduction in the expression of the maxi-K channel, in NO release, or in 
PKG production should be reversed with therapies that increase the number and/or expression of  
the maxi-K channel. (Modified from Archer 11)  
1.5 Description of hMaxi-K 
The gene for the α or pore-forming subunit, hSlo, has been cloned and linked to the kanamycin- 
resistant plasmid vector, pVAX, to construct hMaxi-K. The gene, hSlo, is transcribed from the  
CMV promoter.  
Transfection and functional activity of the hSlo gene using this vector has been demonstrated in  
several in vitro experiments. In two separate experiments, intracellular uptake and expression of 
the gene was demonstrated on fluorescence, microscopic, and patch clamp electrophysiological  
examination of transfected Xenopus oocytes and human embryonic kidney cells.27 Endothelin-1 
stimulation causes a transient increase in the intracellular concentration of calcium 28,29 A  
significant decrease was observed in both the resting Ca++ levels and the peak amplitude of the  
ET-1 – induced intracellular Ca++ transient in hSlo-transfected human corporal smooth muscle  
cells. Thus, transfer of plasmid-hSlo into the smooth muscle cells of the corpora should result in  
gene expression that allows hyperpolarization of the cells and smooth muscle relaxation with  
subsequent erection.  
The safety and activity of intracorporal injection of varying doses of the hSlo gene has been  
evaluated in 265 aged rats and 256 streptozotocin-induced diabetic rats. The ability of the  
plasmid-hSlo construct to express physiologically functional maxi-K channels has been  
demonstrated in at least 3 experiments using these two animal models of ED.9,26 Animals  
administered the hSlo gene were able to achieve penile rigidity with electrical stimulation of the 
cavernous nerves.  
In order to assay the effect of pcDNA/hSlo on the erectile response under conditions that might  
better mimic natural stimulation for penile erection, two experiments were conducted using  
either central neural stimulation or apomorphine administration with measurement of the  
ICP/BP ratio in rats administered a single injection of 100 μg pcDNA/hSlo. In those  
experiments the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the  
hypothalamus are known to be important to erectile function/capacity in humans and rats.30-33  
The drug apomorphine has a higher affinity for D2-like receptors than other dopamine receptor 
subtypes (i.e., D1-D5) and it is this receptor subtype that is thought to be the main site for the  
induction of erections in the paraventricular nucleus of the hypothalamus. Apomorphine is  
therefore postulated to increase erectile responses by acting as a conditioner in the PVN,  
increasing the response to sexual stimuli resulting in enhanced erections  
Retired breeder Sprague-Dawley rats were injected intracorporally with 100 μg pcDNA/hSlo.  
Following electrostimulation of the MPOA, expression of hSlo in the rat corporal tissue was  
confirmed by RT-PCR. Rats injected intracorporally with pcDNA/hSlo had significantly higher 
ICP response compared to untreated age-matched control animals following central stimulation.  
There was no significant difference in the ICP/BP between the hSlo-treated and young control  
animals following MPOA electrostimulation.  
In the second experiment, the hypothalamic region involved in erection was stimulated  
pharmacologically using apomorphine in the retired breeder rat model of erectile dysfunction.  
Apomorphine acts in the CNS to elicit erectile responses within several minutes of  
administration. The hSlo-treated retired breeder rats received a single intracavernous injection of 
100 μg pcDNA/hSlo. Following administration of apomorphine one week later, the hSlo- 
transfected rats had significantly higher ICP/BP ratios than the placebo-treated age-matched  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
12 
control rats. 34 Overall, these experiments evaluating the effect of central neural stimulation on  
the ICP/BP ratio in hSlo-treated rats, suggest that expression of hSlo and increased maxi-K  
channels in the membrane of corporal smooth muscle of penis can be responsive to normal  
physiological mechanisms involved in erection.  
 
Although this phase 1 study is designed to evaluate a single administration of hMaxi-K, the  
safety of hMaxi-K following multiple administrations has also been investigated in preclinical  
studies. Doses of hMaxi-K evaluated were 10, 30, 100, 300, and 1000 μg. Histopathological  
examination of the major organs (heart, lung, liver, spleen, kidney, brain, and testes)  
demonstrated normal tissues among all treatment groups. Importantly, no cardiac toxicity was 
detected in any animal at any dose of hMaxi-K. Laboratory parameters were within normal  
limits at all timepoints for all doses tested. No adverse clinical effects were seen in  
cardiovascular parameters.  
 
Extensive biodistribution studies at the ten-copy level of hMaxi-K have been conducted in rats  
administered 1000 μg of intracavernous hMaxi-K. Fourteen organs were examined at 1, 4, 8,  
and 24 hours and 1, 2, and 4 weeks after transfer. Importantly, no signal of gene transfer was  
detected at any time point in either cardiac myocytes or testis tissue following administration of 
hMaxi-K. In a separate study, the half-life of hMaxi-K in human blood was found to be less  
then 30 minutes. Given the results of the biodistribution studies, the known half-life of hMaxi- 
K, and the proposed use of a penile tourniquet, the amount of hMaxi-K able to access the  
systemic circulation is expected to be negligible.  
 
1.6 
Clinical Data 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
  
13 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
14 
2.0 Objectives 
The primary objective of this study is to evaluate thesafety of a single intracavernous injection  
of hMaxi-K (either 8, 0000 or 16,000 µg) compared to placebo in males with erectile dysfunction 
longer than six months that was attributable to an underlying, stable medical condition upon 
penile rigidity or erection in males with erectile dysfunction longer than six months that is 
attributable to underlying, stable medical condition. 
The secondary objective of this study is to evaluate the  efficacy  of a single intracavernous 
injection of hMaxi-K, either 8,000 or16,000 µg, compared to placebo.   
3.0 Study Design 
This study is double-blind, placebo controlled parallel design Phase 2A trial evaluating the 
potential activity and safety of two different doses of  hMaxi-K (16000 µg, and 8000µg) given in 
a single administration relative to placebo injected into the corpus cavernosum of the penis.  
The proposed study period is approximately 6 months following  the single injection of study 
drug  
per participant. This study will  enroll  11 participants at hMaxi-K doses of 8000 μg, 11 
participants at hMaxi-K doses of 16000 μg and  13 on placebo. A maximum of 35 participants 
will be enrolled.  
 
4.0 Study Population  
The study population includes men with erectile dysfunction attributable to an underlying, stable  
medical condition but who are otherwise in good health. The most common stable medical  
diseases that cause erectile dysfunction include hypertension and atherosclerosis,  
antihypertensive medication, type I and type II diabetes mellitus, pelvic surgery and pelvic  
radiation, cerebrovascular accidents (stroke), multiple sclerosis, and Parkinson’s disease. Men  
with erectile dysfunction secondary to aging as a solitary cause will not be included in the trial. 
. The target population is men with erectile dysfunction who have been  
unable to tolerate, do not wish to continue, or have had unsuccessful results with, prior therapy  
for ED.  
Only participants considered eligible according to the protocol-specified eligibility criteria will 
be able to receive study drug.  
 
4.1 Inclusion Criteria 
Eligible participants must meet the following inclusion criteria: 
a) Signed Informed Consent 
b) Be adult males over 18 years of age diagnosed with erectile dysfunction and whose ED is 
attributable to an underlying, stable medical condition such as hypertension and  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
15 
atherosclerosis, antihypertensive medication, type I and type II diabetes mellitus, pelvic 
surgery and pelvic radiation, cerebrovascular accidents (stroke), multiple sclerosis, and  
Parkinson’s disease;  
c) Participants must have been unable to have successful sexual intercourse for 3 months  
prior to study entry without specific ED therapy such as Vacuum Erection device (VED), 
ViagraTM (sildenafil), Cialis TM (tadalafil), MuseTM (alprostadil), or intracavernous  
injection therapy with an erectile function domain score of IIEF >10 and < 21 at 
screening and  
baseline;  
d) Have been unable to tolerate, do not wish to continue, or have had unsuccessful results  
with, prior therapy for ED, e.g., ViagraTM, intracavernous injection therapy, MuseTM, or 
VED;  
e) If diabetic, documentation of HgA1c less than or equal to 8.5 % prior to enrollment; 
f) If receiving medication for hypertension, documentation of blood pressure has been 
stable on the same medication for at least 2 months prior to enrollment;  
g) Be heterosexual and in a stable, monogamous relationship of at least six months duration; 
h) Agree to attempt intercourse with their partner at least four times per month while 
participating in the study;  
i) Agree not to use other treatments for ED while participating in this study; 
k) Have screening laboratory values and ECG that are within the normal range. See 
exclusion criterion below.  
l) Have a normal physical examination of the penis; 
      m)  If participant had a radical prostatectomy a PSA <0.4 for at least one year documented  
by 2 measurements during the preceding year;  
n)  Be literate, able to give written informed consent, and comply with all study 
procedures and requirements.  
4.2 Exclusion Criteria 
Participants will be excluded who have: 
a) A history of sickle-cell disease, sickle cell trait, or any other medical condition that, in the 
judgment of the investigator, would contraindicate the administration of study medication  
or interfere with the study evaluations;  
b) In the judgment of the investigator any condition that would interfere with participation 
in the study (including geographical inaccessibility), that would contraindicate the  
administration of study medication or interfere with the study evaluations.  
c) Had within six months prior to enrollment any of the following: 
• Myocardial infarction 
• 
Cerebrovascular accident 
• 
Uncontrolled hypertension (systolic >160 or diastolic >100mmHg) 
• Arrhythmia 
• Congestive heart failure (dyspnea on minimal exertion or while supine) 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
16 
• Unstable angina (chest pain greater than three times weekly while on therapy) 
• Required treatment with calcium channel, beta-blocker medicationnitrates, or anti- 
epileptic drugs for less than 6 months at the time of randomization 
d) Poorly controlled diabetes mellitus as defined by HgA1c > 8.5 mg% at time of enrollment; 
e) Change in medication for diabetes or hypertension within 2 months of study enrollment; 
f) Gonadal failure (testosterone < 200 ng/dl) not treated with hormone replacement; 
g) History of malignancy except non-melanomatous skin cancers 
h) A life expectancy of less than 12 months; 
i) An indwelling urethral catheter; 
j) A prior penile prosthetic implant 
l) Received an investigational drug, investigational therapy, or other form of ED therapy, 
including approved treatments, within the past 30 days;  
m) Peyronie’s disease; 
n) Any screening laboratory values outside of the normal laboratory range as defined by the 
central laboratory normal ranges and in the judgment of the investigator is considered  
clinically significant (hepatic biochemical markers [AST, ALT, GGT, alkaline  
phosphatase, and bilirubin] > twice the upper limit of the normal reference range may be  
accepted with written consent of the sponsor).  
o) Any clinically significant ECG abnormality 
NOTE: Sinus bradycardia of 50-59 bpm is permissible. Other abnormalities that can be 
normal variants (and considered clinically insignificant) may be permissible. 
However, participants with such abnormalities cannot be randomized without review 
of their medical history and prior written approval of the sponsor (or designee).  
5.0 Test Material and Administration 
5.1 Study Medication  
hMaxi-K is a double stranded naked plasmid DNA molecule carrying the human cDNA  
encoding the gene for the α, or pore forming, subunit of the human smooth muscle Maxi-K  
channel, hSlo. Expression of the hSlo gene is under control of the CMV promoter positioned  
upstream of the transgene and the construct also contains the Bovine Growth Hormone poly A 
site.  
Table A below provides information on the dosing of h Maxi-K dosing  8000 µg, 16000 µg and 
placebo. Each 2 mL vial contains 4000 µg per mL. The sites will store the participant  vials at -
20oC in a locked freezer prior to use. Vials can be kept at -20oC for up to 360 days.  
Participant vials will be retained at the site until study completion and after the drug accounting  
processes have been completed, when they will either be returned to the Sponsor or destroyed  
with Sponsor approval.  
 
Table 1.  - Final Dose – hMaxi-K 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
17 
 
 
 
 
 
 
 
 
*Each vial contains 4000 µg per mL.  
 
 
5.1.1 Packaging and Labeling 
Each assigned vial will have a double blinded 2 part detachable label (tear off part to be placed 
in the participant’s source documents). Each vial  label will contain the following information:  
 
• 
Study ION 04-ED  
• 
Participant identification number  
 
INSTRUCTIONS: Inject contents of both vials into corpora cavernosa 
 
Store at controlled room temperature once constituted: 
C to 
C 
 F to 
 F).   
• 
CAUTION: New Drug – Limited to investigational use  
• 
Manufactured for Ion Channel Innovations, LLC by Althea Technologies, Inc., San 
Diego, CA 92121  
 
Note:  In each dosing arm, 11 participants will receive hMaxi-K and 13 will receive PBS-20% 
sucrose (placebo). 
 
Sharp Clinical Services, Inc. will prepare 40 kits of product using randomization schedule 
generated by a Statistical Group. The kits will be shipped to the central pharmacy at Dasman and 
stored at -20C.   Following notification by the site that an eligible participant is to be giventhe 
study medication the pharmacy will send the blinded kit to the investigaro for use.  
The individual participants’ double blind patient drug kit will contain a two-part (tear-off) label. 
The duplicate portion of this label will be detached and affixed to a label page (to be retrieved at 
study close out by Ion Channel Innovations designated monitor) at the time of randomization and 
test drug administration.   There will be central randomization. The site will be instructed to call 
the Sponsor or designee for the assigned subject number after each participant’s screening visit 
allowing ample time prior to Visit 2 for shipment of the drug.  
The duplicate label from each patient drug kit will be affixed to a separate log in the source 
documents at Visit 2. 
5.2 Dose Selection and Administration 
Two doses of hMaxi-K will be evaluated: 8,000 µg and 16,000 µg compared to  PBS-20% 
sucrose (control group).  
The gene product or PBS-20% sucrose will be administered in the office.  The blinded 
participant kit will be taken from the freezer and the vials warmed to room temperature. The 
rubber cap of the vial will be wiped with alcohol.  The 8 ml contents of  the 2 vials (4 ml each) in 
the kit will be drawn into an 10 ml syringe and administered by the investigator through a 25 
gauge needle into the corpora of each participant.    
 
8000 g 
16000 g 
PBS-20% sucrose 
hMaxi-K  
2 ml 
4 ml 
0 ml  
PBS-20% sucrose 
2 ml 
0 ml 
4 ml 
Number of Vials* 
2 
2 
2 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
18 
The investigator’s pharmacy or a designee will be responsible for dispensing the drug in a timely 
fashion for use on the day of the participant’s Visit 2 and accounting of all drug provided by the 
sponsor.  Records of document control numbers and dates received will be kept on a Drug 
Inventory Form provided by the sponsor for accounting purposes.   Under no circumstances will 
the investigator supply study drug to other investigators, allow study drug to be used other than 
directed by this protocol, or destroy or dispose of study drug in any other manner without prior 
written authorization from the sponsor. 
All partially used clinical trial kits will be accounted for and destroyed at the investigative site 
according to IBC guidance.  The investigator or designee, upon completion of the drug 
accounting process, will send all unused clinical materials back to the Sponsor or designee for 
disposition. 
The investigator or designee will administer study drug and be responsible for the accounting of  
all drug provided by the sponsor. Records of document control numbers and dates received will  
be kept on a Drug Inventory Form provided by the sponsor or designee. Under no circumstances 
will the investigator supply study drug to other investigators, allow study drug to be used other  
than directed by this protocol, or destroy or dispose of study drug in any other manner without  
prior authorization from the sponsor. In the event that study drug is only partially administered  
(e.g., an adverse event occurs during injection), then any partially used vials must be retained for  
drug accountability. After the Sponsor’s designee has completed the drug accountability and  
approval for drug disposal, study drug may be disposed using the site’s standard operating  
procedure for biohazard waste.   
   If a clinically serious sign or symptom is reported the medical monitor will contact the sponsor 
and no further enrollment will be done until the medical monitor or sponsor gives permission.    
In the previously completed clinical study evaluating intracorporal administration of up to 16000 
g hMaxi-K in 20 participants with ED, there was only one adverse event considered possibly 
related to hMaxi-K (“tingling warmth in the glans”). 
  To minimize the possibility of dehydration and/or a vasovagal response following injection of 
the hMaxi-K, participants will be instructed to eat breakfast and drink fluids on that morning.  
 
5.2.1 Dose Limiting Toxicity  
A DLT is defined as the occurrence within the first 4 weeks following a single administration of 
hMaxi-K of an unacceptable toxicity, as described below. Adverse events for cardiovascular,  
blood chemistry, complete blood count, or urine categories of adverse events will be graded  
according to the criteria provided in Appendix A.  
No acute toxicity was seen in the preclinical studies with administered doses up to 1000 μg  
(approximately 1500 μg/kg) or in men and women gien doses up to 16000 μg. Potential 
toxicities would be those that could occur due to enhanced efflux of K+ with resultant decreased 
intracellular Ca++ concentration thus altering  smooth muscle function in diverse organ systems.  
 
The following criteria will be used to define: 
DLT:  
1) Any adverse events of Grade 2 or higher in the cardiovascular category of adverse event 
criteria listed in Appendix A;  
2) Any adverse events of Grade 2 or higher in the blood chemistry, complete blood 
count, or 
urine categories of adverse event criteria listed in Appendix A.  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
19 
3) Penile pain and/or erection that persists for more than four hours after gene transfer;  
4) Change in random hormone levels greater than 2 times the upper or lower limits of 
normal at any time post dosing..  
Stopping Rule 
If within 4 weeks following the single administration of hMaxi-K, if any participant 
experiences a grade 3 or higher dose limiting toxicity, no additional participants will be 
accrued and no further doses of hMaxi-K (or placebo) will be administered. Clinical data 
regarding the event will be collected, reviewed, and discussed with the Ethics Committee 
(EC) and Kuwait  Ministry of Healh (MOH). After review of these data with EC and MOH  
the clinical study may resume only with concurrence of EC and MOH.  
 
5.3 Concomitant Medications/Therapies 
Participants will continue any medications they are receiving at study entry for underlying  
medical conditions with the exception of those described below. All medications taken by  
participants within two weeks of study entry (including over-the-counter preparations) will be  
recorded on the Medical History Form. Any changes in concomitant medication, including  
additions, discontinuations, and dose changes, occurring during the study will be recorded on the 
concomitant medication form.  
Participants are not allowed to concomitantly use any approved, unapproved, or investigational  
medications or therapies intended to treat erectile dysfunction. These medications/therapies  
include, but are not exclusively: Viagra™, Cialis™, Levitra™, Muse™, prostaglandin E1 as  
Caverject™ or Edex™, Trimix, yohimbine, apomorphine (Uprima™), vacuum erection devices, 
or penile prosthetic implants.  
6.0 Outcome Assessments and Procedures 
6.1 International Index of Erectile Function (IIEF)  
The International Index of Erectile Function (IIEF) 35 is a validated, self-administered  
questionnaire that has been shown to be a cross-culturally and psychometrically valid measure of 
male erectile dysfunction.  
The test contains 15 questions in five domains: (a) erectile duration (six items); (b) orgasmic  
function (two items); (c) sexual desire (two items); (d) intercourse satisfaction (three items); and 
overall sexual satisfaction (two items). The questionnaire has been accepted by the FDA and  
peer-reviewed scientific journals and is used currently as the clinical endpoint in all pivotal  
studies evaluating new drugs for erectile function.  
The erectile function domain, questions 1-5, and 15 of the IIEF has been validated to assess  
erectile changes only.36, 37 The EF domain of the IIEF will be completed at Visit 1 and V2-V7.  
 6.2 Sexual encounter profile (SEP) 
The SEP is a questionnaire composed of 5 questions assessing sexual function. SEP 2 evaluates 
the penetrability of the erection and SEP 3 the maintenance of the erection. This questionnaire 
will be completed at V2-V7. See Appendix C.  
6.3 Physical Examination 
6.3.1 Physical Examination 
A complete physical examination, including a complete urogenital exam (see below), and review 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
20 
of body systems will be performed at all visits. Vital signs (heart rate and blood pressure) and an 
examination of the penis (see below) will be performed at all visits. Height will be obtained at 
Screening only. Weight and oral temperature will be obtained at Screening and V7. Any 
untoward clinically significant change from Screening will be recorded on the CRF as an adverse 
event.  
6.3.2 Physical Examination of the Penis 
Physical examination of the penis will be done at each visit and will include inspection, and 
palpation.  
6.4 
Electrocardiograms 
A 12-lead ECG will be performed at all visits: Screening (V1) Baseline (V2 -prior to treatment 
and at 1 and 2 hours post treatment), V3, V4, V5, V6,  and V7. These ECGs obtained at the study 
centers, will be forwarded to a central reader for final interpretation. The over reader will return 
the results to the study center within 48 hours. This does not negate the responsibility of the 
staffconducting the study to initially review the ECG and to take appropriate clinical actions. 
The following parameters will be assessed: heart rate, rhythm, PR interval, QT interval, QTcF, 
QTcB, QRS duration, and overall evaluation.  
 
6.5 
Vital Signs 
 
Vital signs will be performed at all visits. Vital signs should include an apical heart rate and  
brachial blood pressure (BP) both taken after 5 minutes resting in the sitting position (standard  
sphygmomanometry). Any clinically significant changes from screening will be recorded on the 
CRF as an adverse event. Following administration of study drug at V2, BP and heart rate will  
be measured and recorded every 15 minutes for 2 hours.  
 
6.6 Laboratory Safety Tests and Pharmacokinetics Evaluations  
An accredited laboratory will function as the central laboratory for all plasma and urine 
specimens.  
 
Laboratory safety tests will be performed as follows.  The laboratory safety tests include: 
 Hematology: Complete blood count (CBC) with differential: Screening (V1), Week 1 
(V 3), Week 4 (V4), 12 weeks (V6) and 24 weeks (V7) post dosing with study drug. 
 Platelet count, PT, PTT, sedimentation rate (sed. rate), CRP only at Visits 1, 3 and 7 
only.  
 Chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, K+, Mg++, 
Ca++, CO2, Cl), albumin, alkaline phosphatase, ALT, AST, LDH, GGT, total bilirubin, 
total protein, glucose at Screening (V1),  Week 1 (V3) , Week 4 (V4), 12 weeks (V7) 
and 24 weeks (V7)  post dosing with study drug. 
 Urinalysis: Microscopic RBC and WBC, protein, glucose, nitrites, and specific 
gravity at Screening (V1),  Week 1 (V 3), Week 4 (V4), 12 weeks (V6) and 24 weeks 
(V7) post dosing with study drug. 
 Endocrine: Total testosterone, random cortisol, TSH, T4 (V1, V3, and V7 only);  
 At screening visit only, participants must have a hemoglobin A1c  
 At V2 –V7, plasma specimens will be collected to assay for the presence of hSlo 
DNA by PCR. These will be kept frozen at -20o C or less at the site for eventual assay 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
21 
by Sponsor. At Visit 2 specimens should be collected both pre-dosing (to serve as a 
baseline) and 2 hours post-dosing 
 
6.7  
Pharmacokinetics 
Blood specimens will be obtained at Visit 2 (predose) and Visits V3-7 for analysis of hSlo cDNA 
with PCR.  
Instructions for collection of blood for DNA testing:  
Blood 
 
  Collect specimen in heparinized tube 
 
   Centrifuge for 10 minutes at 3000 rpm 
 
  Pipette plasma, freeze immediately and store in labeled plastic vial at -20 (or 
colder) 
 
7.0 Schedule of Evaluations  
The schedule of evaluations is summarized in Appendix B and described in detail below.  
7.1 Visit 1 (Study Week (-) 2 - Screening)  
The following evaluations and tests will be performed:  
• Preliminary Screening:  
• Obtain written informed consent process for study participant ;  
• Medical history including history of erectile dysfunction to assess eligibility for study  
treatment;  
 Physical examination including physical examination of penis;  
 Vital signs (BP, heart rate, oral temperature, weight and height)  
 Participant completes the IIEF (screening) 
 Complete screening if entry criteria are met on preliminary screening:  
• Obtain urine for routine urine analysis: microscopic RBC and WBC, protein, glucose,  
nitrites and specific gravity;  
• Electrocardiogram;  
• Fasting blood specimens for the following laboratory determinations:  
o Hematology: Complete Blood Count (CBC) with differential, platelet count,  
Partial Thromboplastin (PTT), Prothrombin Time (PT), sedimentation rate  
(sed rate), C-reactive protein (CRP).  
o Chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, K+,  
Mg++, Ca++, CO2, Cl), albumin, alkaline phosphatase, ALT, AST, LDH, GGT,  
total bilirubin, total protein, glucose;  
o Hemoglobin A1c (diabetic participants);  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
22 
o Endocrine: total testosterone, random cortisol, TSH, T4  
• Schedule next study visit when screening laboratory results are available.  
7.2 Visit 2 (Study Week 0 - Administration of study drug)  
Based on the participant fulfilling all eligibility criteria following the screening procedures (Visit  
1), the participant will be considered eligible to receive study drug. If a participant is unable to  
receive test material because a clinically significant condition has evolved which, in the  
investigator's opinion, represents a potential safety risk the patient will be considered a screen  
failure.  
The following tests and evaluations will be performed on eligible participants:  
 Adverse events since screening visit;  
 Physical examination including examination of the penis for changes since the screening 
visit;  
 Vital signs (BP, heart rate);  
 ECG prior to administration of study drug and at 1 and 2 hours post study drug;  
 Participant completes SEP and IIEF  Urine analysis: microscopic RBC and WBC, 
protein, glucose, nitrites and specific gravity;  
 Plasma specimens will be collected to assay for the presence of hSlo DNA by 
PCR. These will be kept frozen at -20o C or less at the site for eventual assay 
by Sponsor.  Samples will be collected pre-dosing and at 2 hours post dosing. 
 Administer study drug. The participant will be observed in the clinic for two hours after 
the injection. During that time blood pressure and heart rate will be measured and 
recorded by the nurse every 15 minutes. ECG will be done at one and two hours after 
administration of study drug and reviewed by a physician at those times. The penis will 
be inspected for ecchymosis or persistent erection. The participant will be asked if there 
is any persistent pain at the injection site and will be treated symptomatically, if needed. 
The participant will be asked if symptoms of malaise, vertigo, light-headedness, and 
nausea are present. Emergency equipment for resuscitation will be immediately available 
in the event of an unexpected serious reaction to the study drug.  
7.3 Visit 3 (Study Week 1)  
The following tests and evaluations will be performed:  
 Adverse events and concomitant medications since the last visit;  
 Physical examination including examination of penis;  
 Vital signs (BP, heart rate);  
 Electrocardiogram;  
 Obtain plasma for the following laboratory determinations:  
 Hematology: Complete Blood Count (CBC) with differential, platelet count,  
Partial Thromboplastin (PTT), Prothrombin time (PT), sedimentation rate, C- 
reactive protein;  
 Chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, K+,  
Mg++, Ca++, CO2, Cl), albumin, alkaline phosphatase, , LDH, GGT, ALT,  
AST, total bilirubin, total protein, glucose;  
 Endocrine: total testosterone, random cortisol, TSH, T4;  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
23 
 Urine analysis: microscopic RBC and WBC, protein, glucose, nitrites and specific 
gravity;  
 
 
Plasma specimens will be collected to assay for the presence of hSlo DNA by PCR. 
These will be kept frozen at -20o C or less at the site for eventual assay by Sponsor.  
  
 Participant completes the IIEF and SEP.  
 Schedule next study visit.  
7.4 Visit 4 (Study Week 4)  
The following tests and evaluations will be performed:  
 Adverse events and concomitant medications since last study visit;  
 Physical examination including examination of penis  
 Vital signs (BP, heart rate);  
 Electrocardiogram;  
 Obtain plasma for the following laboratory determinations:  
 Hematology: Complete Blood Count (CBC) with differential, platelet count;  
 
 Chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, K+, Mg++, Ca++, 
CO2, Cl), albumin, alkaline phosphatase, , LDH, GGT, ALT, AST, total bilirubin, total 
protein, glucose;  
 
 Urine analysis: microscopic RBC and WBC, protein, glucose, nitrites and specific  
 gravity;  
 Blood specimens will be collected to assay for the presence of hSlo DNA by PCR. These 
will be kept frozen at -20o C or less at the site for eventual assay by Sponsor.  
 
 Participant completes the IIEF and SEP;  
 Schedule next study visit.  
7.5 Visit 5 (Study Week 8)  
The following tests and evaluations will be performed:  
 Adverse events and concomitant medications since last study visit;  
 Physical examination including examination of penis;  
 Vital signs (BP, heart rate);  
 Blasma specimens will be collected to assay for the presence of hSlo DNA by PCR. 
These will be kept frozen at -20o C or less at the site for eventual assay by Sponsor.  
 Electrocardiogram;  
 Participant completes the IIEF and SEP;  
 Schedule next study visit.  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
24 
7.6 Visit 6 (Study Week 12)  
The following tests and evaluations will be performed:  
 
 Adverse events and concomitant medications since last study visit; 
 Physical examination including examination of penis; 
 Vital signs (BP, heart rate); 
 Electrocardiogram; 
 Obtain plasma for the following laboratory determinations:  
 Hematology: Complete Blood Count (CBC) with differential, platelet count,  
 Chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, K+, Mg++, Ca++, 
CO2, Cl), albumin, alkaline phosphatase, , LDH, GGT, ALT, AST, total bilirubin, total 
protein, glucose;  
 Urine analysis: microscopic RBC and WBC, protein, glucose, nitrites and specific  
gravity;  
 
 Plasma specimens will be collected to assay for the presence of hSlo DNA by PCR. 
These will be kept frozen at -20o C or less at the site for eventual assay by Sponsor.  
 
 Participant completes the IIEF and SEP;  
 Schedule next study visit. 
7.7 Visit 7 (Study Week 24) or Exit Visit: 
The following tests and evaluations will be performed: 
 Adverse events and concomitant medications since last study visit; 
 Physical examination including examination of penis; 
 Vital signs (BP, heart rate, oral temperature, weight); 
 Electrocardiogram; 
 Obtain plasma for the following laboratory determinations: 
 Hematology: Complete Blood Count (CBC) with differential, platelet count, Partial 
Thromboplastin (PTT), Prothrombin time (PT), sedimentation rate, C-reactive protein;  
 
 Chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, K+, Mg++, Ca++, 
CO2, Cl), albumin, alkaline phosphatase, ALT, AST, LDH, GGT,total bilirubin, total 
protein, glucose;  
 
 Endocrine: total testosterone, random cortisol, TSH, T4; 
 Urine analysis: microscopic RBC and WBC, protein, glucose, nitrites and specific 
gravity;  
 
 Plasma specimens will be collected to assay for the presence of hSlo DNA by PCR. 
These will be kept frozen at -20o C or less at the site for eventual assay by Sponsor.  
 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
25 
 Participant completes the IIEF and SEP. 
7.8 
Long-term follow-up  
All participants upon completion or exit from the study will be presented with written 
instructions on how to contact the sponsor if they experience any serious adverse event that they 
consider possibly related to study treatment or study participation.  All participants receiving an 
injection of hMaxi-K will continue to be followed after the completion of all study related 
procedures (Visit 7 or last study visit) for an additional 18 months.  These subjects will be 
contacted by the site at 6 month intervals to evaluate for any safety concerns.   
 
 
8.0 Participant Withdrawal  
While participants are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason irrespective of the reason, or at the Investigator’s decision. 
Participants who have been withdrawn from the study cannot be re-included in the study. Their 
inclusion and treatment number must not be re-used.  
 
Participation is voluntary, and refusal to participate will involve no penalty, or loss of benefits to 
which the participant is otherwise entitled. The participant will be encouraged to maintain  
contact with the investigator and report any serious adverse events experienced for the 6 months  
study period. Follow-up following the study period is described in Section 7.9.  
An evaluable participant will be any participant who receives at least one dose of test material 
and has at least one post dose assessment.  
Screen failures will include any participant who consented and entered into the screening  
process appropriately, but subsequently did not meet the entry criteria and was not administered 
study drug. Participants who fail screening will not be followed for safety or activity of study 
drug, and no other study procedures will be performed.  
Those participants who do not complete the study for any reason will be considered a premature 
termination. (eg. Adverse Event and/or lack of therapeutic effect and/or participants desire to  
discontinue study procedures/testing but allows for safety follow-up). The procedures for the  
Visit 7 should be completed when a participant discontinues the study.  
• 
Adverse Events: Subjects with adverse events, severe enough to necessitate  
discontinuation of study drug administration as judged by the investigator. The treating  
physician should take appropriate clinical action. The condition should be treated  
according to routines of the clinic. The participant should be followed up regarding the 
safety measurements stated in the protocol.  
• 
Consent Withdrawn: participant decided to withdraw his consent to participate in the  
study for any reason. In this event the participant refuses to participate in any additional  
evaluations and is withdrawing their consent for the site to utilize their data going  
forward. In this event the participant’s data post the consent withdrawn will not be  
utilized in the clinical trial summary in accordance with enactment of 1996 (HIPAA) and 
subsequent Privacy Rule, required as of April 14, 2003.  
• 
Lost to Follow-up: participant failed to return for required visits and cannot be  
contacted. Reasonable effort should be made by the investigator to contact any  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
26 
participant who fails to return to the clinic for a scheduled visit in order to complete  
assessments and retrieve any outstanding data or supplies of study medication. All such 
efforts should be documented in the source notes. Up to three participants “lost to  
Follow-up” can be replaced in each dosage cohort for participants that received gene  
transfer but failed to complete the Visit 4 (week 4) evaluations.  
• 
Sponsor/Investigator Decision: A participant may be withdrawn at any time at the 
discretion of the Sponsor/investigator.  
• 
Lack of Therapeutic Effect: A participant may choose to withdraw at any time if they 
feel that they want to pursue alternative treatment for their ED based on their perceived 
lack of therapeutic effect.  
 
 
9.0 Adverse Events Definitions and Monitoring 
9.1 Adverse Event 
An adverse event is any unfavorable and unintended diagnosis, symptom, sign (including an  
abnormal laboratory finding), syndrome or disease which either occurs during the study, having 
been absent at baseline, or, if present at baseline, appears to worsen.  
A treatment emergent adverse event (TEAE) will be considered an event that is temporally  
associated with the use of the study drug, whether or not considered related to the study drug. 
Examples of AEs are as follows: 
 
• 
Changes in the general condition of the participant 
 
• Subjective symptoms offered by or elicited from the participant 
 
• Objective signs observed by the Investigator or other study personnel 
 
• All concurrent diseases that occur after the start of the study, including any change in 
severity or frequency of preexisting disease  
 
• All clinically relevant abnormalities in laboratory values or clinically relevant 
physical findings that occur during the study.  
9.2 Serious Adverse Event 
A serious adverse event (experience) is defined (21 CFR 312.32) as any adverse experience that 
suggests a significant hazard, contraindication, side effect or untoward medical occurrence that:  
• Results in death, 
• Is life threatening, 
Note: The term "life-threatening" in the definition of "serious" refers to an event in which the participant  
was at risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe.  
• Requires (or prolongs) hospitalization, 
• Causes persistent or significant disability/incapacity, 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
27 
• Results in congenital anomalies or birth defects, or 
• Other conditions which in the judgment of the investigators represent significant hazards. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately  
life-threatening or result in death or hospitalization but may jeopardize the participant or may  
require intervention to prevent one of the other outcomes listed in the definition above.  
These should also usually be considered serious. 
Note: Examples of such events are intensive treatment in an emergency room or at home for allergic  
bronchospasm, blood dyscrasias, convulsions or asymptomatic ALT increase > 10 ULN that do  
not result in hospitalization, or development of drug dependency or drug abuse.  
 
9.3 Assessment of Causality  
The relatedness of an adverse event to the study drug is the best estimate of the principal 
investigator at the time of reporting of the causal relationship between an experimental  
intervention and an adverse event.  
The following study drug relationships will be used for this clinical trial: 
 
Unrelated: There is no temporal relationship between the event and the administration 
of the study drug or the event is clearly due to the patient’s medical condition, other  
therapies or accident.  
Possibly Related: There is some temporal relationship between the event and the  
administration of the study drug and the event is unlikely to be explained by the patient’s 
medical condition or other therapies.  
Probably Related: The temporal relationship between the event and the administration 
of the study drug is compelling, and the patient’s medical condition or other therapies  
cannot explain the event.  
Certainly Related: The event follows a reasonable temporal sequence from  
administration of the medication or follows a known or suspected response pattern to the 
medication.  
The categories of “Certainly”, “Probably” and “Possibly Related” are considered study drug 
related.  
9.4 Severity of Adverse Event  
Adverse events included in the toxicity table (Appendix A) will be graded according to the  
definitions provided. For adverse events not listed in the toxicity table, assignment of grade  
based on intensity of symptoms, degree of limitation of usual daily activities, or level of  
abnormality of objective clinical signs or laboratory parameters will be according to severity 
using the following criteria:  
• Grade 1: transient or minimal symptoms; not interfering in function or ability to perform 
activity of daily living or require a medication change. No medical intervention  
required.  
• Grade 2: symptoms interfering in function but not with activities of daily living. 
Minimal or no medical intervention required.  
• Grade 3: incapacitating symptoms that interfere with function and activities of daily 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
28 
living; required bed rest and/or resulted in loss of work or cancellation of social  
activities. Medical intervention required. Hospitalization possible.  
• Grade 4: Considered potentially life threatening (see definition under section 9.2) 
A serious adverse event (SAE) requires medical intervention to prevent permanent impairment or 
death, permanently disability: (bed-ridden or disabling AE), required significant medical  
intervention/therapy, hospitalization or hospice care or in the judgment of the investigator was a  
medically significant event. Serious adverse events may be mild, moderate or severe in intensity  
(e.g., mild stroke).  
9.5 Monitoring of Adverse events 
The investigator(s) will monitor their  participants for the occurrence of adverse events during 
the course of the study and record all observed adverse events in the case report form.  
Adverse Events regardless of seriousness or relationship to study drug, including those  
occurring during the Screening period (where applicable), are to be recorded  
in the CRF. Whenever possible, symptoms should be grouped as a single 
syndrome or diagnosis. The Investigator should specify the date of onset, maximal intensity,  
corrective therapy given, outcome, and his/her opinion as to whether there is a reasonable  
possibility that the Adverse Event was caused by the study drug.  
Any adverse events that meet the 4 criteria under Stopping Rules (Section 5.2.1) must be  
communicated to the sponsor (or designee) within 24 hours of first knowledge of such event 
The investigator must provide the sponsor appropriate information concerning any findings  
suggesting significant hazards, contraindications, side effects or precautions pertinent to the  
safety of the study drug. The investigator will instruct participants prior to administration of  
study drug to report any physical changes or new symptoms that they notice during the course of 
the study. The investigator must report all serious adverse events (defined above) within 24  
hours of their onset to Ion Channel Innovations, LLC.:  
M.D.  
969 park Avenue, Suite 1G 
New York, NY 10028  
Fax 212 249 5140 
Telephone 212 639 1561 
In case of prolongation of QTcF ≥ 500 ms, or an increase in QTcF ≥ 60 ms from baseline, a  
blood sample should be drawn for measurement of serum potassium, calcium, magnesium, and 
hSlo cDNA. 
A cardiologist should be consulted, and the participant should continue to have his ECG 
monitored until the ECG abnormality resolves or becomes stable.  
10.0 Assessment of Endpoints 
10.1 Safety 
Safety and tolerability of the study drug will be evaluated by analysis of adverse experiences, 
clinical laboratory tests, electrocardiogram, and physical examinations. It will be conducted in all 
subjects who received treatment or there was an attempt to provide treatment. 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
29 
10.2 Efficacy 
The erectile function domain category of the IIEF and the SEP will be used to evaluate the 
change in erectile status from baseline following administration of hMaxi-K.35-37 It will be done 
in those who received treatment. 
10.3 Analysis of Endpoints 
The methods described in this section will be updated during the course of the study.  The final 
version of the statistical analysis plan (SAP) will be issued before the treatment code is broken.  
This double blind, phase 2A study is designed to evaluate the safety and efficacy of a single 
injection of hMaxi-K (8000 and 16000 µg) compared to placebo in individual participants.  Both 
the safety data and data to assess efficacy will be analyzed using summary descriptive statistics 
for the two cohorts and the total study population.  Associations between study therapy and the 
outcomes will be assessed using-repeated measures analyses, and explored in multivariate 
models, as needed.   
10.3.1   Safety 
Safety and tolerability of the study drug will be evaluated by tabulating incidence of adverse 
experiences, clinical laboratory tests, electrocardiogram, and physical examinations in the safety 
population. 
10.3.2   Efficacy 
The sample size has been estimated assuming a standard deviation of 2.5 and a two sample t-test 
to have 80% power.  
Table 2.  Statistical Power 
Power, 
N1 
N2 
Placebo 
Ratio 
Alpha` 
Mean1 
Mean2 
SD1 
SD2 
80% 
11 
11 
13 
1.111 
0.0167 
10.0 
6.6 
2.5 
2.5 
 
The mean change in IIEF and SEP and participant questionnaire (unmedicated and active phase) 
questions will be evaluated at all visits and changes compared to baseline and placebo.  
Alpha' is the alpha level adjusted for three multiple comparisons (the two doses compared with 
each other, and each dose compared with the placebo).  Given the three comparisons that 
incorporated a Bonferroni multiple comparison procedure, the overall alpha level is preserved 
at .05. 
A 10% attrition rate over the 24 weeks of followup is anticipated, which inflates the sample size 
to approximately 40 subjects in total. 
Descriptive statistics will be presented as means and standard deviations for normally distributed 
data at each timepoint by group, and medians and ranges otherwise.  Incidence of adverse events 
will be presented as relative frequencies.  All estimates of differences will be presented with 95% 
confidence limits. The mean change in IIEF and SEP and participant questionnaire (unmedicated 
and active phase) questions will be evaluated at all visits and changes compared to baseline and 
placebo using either paired t-tests for normally distributed changes, or Wilcoxon Sign Rank tests, 
otherwise. A mixed effects or marginal model will be used to assess trends in changes over time 
among treatment groups.  With regard to missing data, the assumption of missing at random will 
be assessed by looking for patterns over time, and by comparing those with missing values to all 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
30 
other subjects with regard to baseline characteristics. Chi-square or Exact tests will be used to 
compare incidence rates among the treatment groups.  All tests of significance with regard to 
efficacy will be one-tailed, and performed at an overall alpha level of .05 using SAS Version 9.3 
or higher, Cary, NC. 
11.0 Monitoring of Participant Safety 
11.1 Informed Consent 
The investigator will be responsible for obtaining from every participant in the study a written 
Informed Consent signed and dated in accordance with U.S. federal regulations (21 CFR 50 and 
21 CFR 312.60). The written Informed Consents will be obtained after the investigator has 
provided a full explanation, both verbally and in writing, of the purpose, risks and discomforts 
involved and potential benefits of the study  to both the participant and his partner. The original 
signed and dated copy of the Informed Consents must be maintained in the institution’s records. 
The names of the participants enrolled  
during this study will be considered confidential.  
A copy of the informed consent for both the participant and his partner is provided in Attachment 
2.  
12.0 Regulatory Standards  
12.1   Electronic case report forms 
An electronic case report form (E-CRF) will be completed for every participant who signed a 
written Informed Consent form and receives study drug.  Any correction of data recorded onto 
the E-CRF will be entered in to the E-CRF which will create an electronic audit trail of the 
corrections and electronic signature of the study personnel who made the changes.  
The principal investigator must sign and date the certification form of each case report upon 
completion.  This signature will indicate that thorough inspection of the data has been made and 
will thereby certify the contents of the electronic case report forms. 
The investigator or institution will retain all original source documentation (e.g., laboratory 
results, treatment records, audit queries, etc.) unless specified otherwise by the protocol.  The 
results as they become available will be entered on the appropriate electronic case report forms.  
Electronic case report forms will be reviewed at the study site by a clinical monitor who will 
make a decision as to their acceptability in regard to completeness and accuracy of the data.  
Audit queries will be generated for omissions, corrections, and clarifications.  
12.2 Clinical and Regulatory Monitoring  
The study will be monitored in compliance with the relevant parts of 21 CFR and according to  
the ICH GCP Guidelines.  
12.2.1 Study Conduct (Site)  
Ion Channel Innovations will have an independent monitor, knowledgeable in GCP guidelines  
and regulations, monitor the clinical study. This representative of the sponsor will  
visit the institution prior to initiating the study and periodically thereafter to monitor  
acceptability of facilities, the agreement between CRF entries and original source  
documentation, adherence to the protocol, Good Clinical Practice (GCP) and to applicable FDA  
regulations and the maintenance of adequate clinical records. The monitor will have access to  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
31 
participant records, medication sheets, laboratory data and other source documentation.  
 
 
 
 
In addition to the initiation visit, the clinical site will be audited after enrollment into each cohort  
has been completed. Once the study has been completed or terminated, a close-out or  
termination visit will be made. The Investigator and/or Study Coordinator will receive  
reasonable notification before each monitoring visit during the course of the study. At each visit,  
the Investigator will cooperate with the Sponsor's representative(s) for the review and  
verification of all CRFs, drug supply and inventory records, and any additional records requested  
for review. The monitor will ensure that all safety reports are submitted to the sponsor who is  
responsible for reporting required safety reports to the IRB, FDA, and OBA (see Section 12.2.2).  
All information contained in a participant's eCRF must have corresponding source 
documentation.  
This source documentation includes, but is not limited to, notes taken at participant visits  
recording the date of the visit, vital signs, physical findings, adverse events, or concomitant  
medications; laboratory reports; hospital records; and clinic records. Any correction of errors in  
the eCRF will be first reviewed with the investigator prior to correction. The reason for any  
correction to the eCRF will be noted along with the date and initials of the person making the  
correction.  
The records of the study may be participant to audit by Sponsor representatives (Clinical Quality  
Assurance or designee) or by government regulatory authorities. The Investigator agrees to 
allow access to the required participant records in the event of such an audit.  
12.2.2 Adherence to Reporting Requirements  
Ion Channel Innovations will have an independent monitor, knowledgeable in GCP guidelines  
and regulations, monitor adherence to the reporting requirements. This designee will ensure that  
the sponsor submitted any modifications to the protocol to the IRB and FDA. They will also  
review all safety reports submitted to the sponsor and ensure that those safety events requiring  
expedited reporting are submitted to the IRB within the required timeframes.  
 
 
 
 
 
 
 
 
 
Within a reasonable time following completion of the study, a final study report will be written,  
reviewed by the sponsor’s designee/CRO (CE3 Inc), and submitted to FDA.  
12.3 Participant Confidentiality  
Individual participant medical information obtained as a result of this study is considered  
confidential and disclosure to third parties, other than those cited below, is prohibited.  
Participant confidentiality will be further ensured by utilizing participant identification code  
numbers for all reports.  
Independent  
designee audits site.  
Reports to 
MD,  
Directing Member, Ion  
Channel Innovations  
Reports findings  
to
 
MD, Directing  
Member, Ion  
Channel  
Innovations 
MD  
responsible to  
reporting  
requirements to IRB,  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
32 
In compliance with regulatory guidelines regarding the monitoring of clinical studies and in  
fulfillment of the Investigator’s obligations to Ion Channel Innovations, it is required that data  
generated as a result of the study be available for inspection, on request, by personnel from Ion  
Channel Innovations and regulatory agencies. These shall include all study-relevant 
documentation, including medical histories to verify eligibility, laboratory test results to verify 
transcription accuracy, treatment and diagnostic reports, admission/discharge summaries for 
hospital admissions occurring while the participant is on-study, and autopsy reports (if 
available)for deaths occurring during or in temporal proximity to the study.  
As part of the required content of the informed consent, participants must be informed that their  
records will be reviewed by Ion Channel Innovations and regulatory agencies. Should access to  
medical record require a separate waiver or authorization, it is the Investigator’s responsibility to 
obtain such permission from the participant in writing before the participant is entered into the  
study.  
12.4 Records 
The investigator should ensure that the following records are maintained: 
Participant files containing copies of completed case reports and supporting documentation and a 
copy of the signed, Informed Consent form.  
Investigator files containing copies of the documents required for the initiation of the study  
(executed form FDA 1572, signed Investigator’s Agreement, Curricula Vitae for the principal  
investigator, copy of the IRB approval of the protocol and Informed Consent forms), copies of 
correspondence received from and sent to Ion Channel.  
Pharmacy files containing copies of the record of use for the Investigational Drug, instructions 
for completion of these records, and the Investigator’s Brochure.  
 
 
13.0 References 
1. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its  
medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 
151: 54-61, 1994.  
2. Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. Urol 
161: 5-11, 1999.  
3. Feldman, H.A., Goldstein, I., Hatzichristou, D.G., et al. Impotence and its medical and  
psychosocial correlates: results of the Massachusetts male aging study. J. Urol 151: 54-61, 
1994.  
4. Benet, A.E., Melman, A. The epidemiology of erectile dysfunction. Urol Clin. N Am 22:699- 
707, 1995  
5. Saenz de Tejada, I., Goldstein,I., Azadzoi,K., Krane, R.J., Cohen, R.A.: Impaired neurogenic  
and endothelium- mediated relaxation of penile smooth from diabetic men with impotence. N 
Engl J Med 320:1025-1030, 1989.  
6. Christ, G. J., Stone, B., Melman, A.: Age-dependent alterations in the efficacy of  
phenylephrine-induced contractions in vascular smooth muscle isolated from the corpus 
cavernosum of impotent men. Can J Physiol Pharmacol, 69: 909-913, 1991.  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
33 
7. Mills, T.M., Chitaley, K., Wingard, C.J., Lewis, R.W.,,Webb, R.C. Effect of Rho-kinase  
inhibition on vasoconstriction in the penile circulation. J Appl Physiol 91:1269-1273, 2001. 
8. Wespes, E.: Erectile dysfunction in the ageing man. Curr Opin Urol, 10: 625-629, 2000. 
9. Melman, A., Zhao, W., Davies, K.P., Bakal, R., Christ, G.J. The successful Long-term  
treatment of age-related erectile dysfunction with hSlo cDNA in rats in vivo. J Urol 170:285- 
290, 2003.  
10. Christ, G.J.: K channels as molecular targets for the treatment of erectile dysfunction. J. 
Androl. 23: S10-9, 2002.  
 
11. Archer, S.L. Potassium channels and erectile dysfunction. Vasc Pharm 38:61-71, 2002 
12. Karicheti, V., and Christ, G.J. Physiological roles for K+ channels and gap junctions in  
Urogenital Smooth muscle: Implication for Improved understanding of Urogenital Function, 
Disease and therapy. Current Drug Targets 2:1-20, 2001.  
13. Nelson, MY,Quayle, JM. Physiological roles and properties of K channels in arterial smooth 
muscle. Am J Physiol 264:C799-822, 1995.  
14. Lawson, K., Dunne, MJ.: Peripheral channelopathies as target for potassium channel 
openers. Expert Opinion on Investigational Drugs. 10: 1345-1259, 2001.  
15. Somlyo, AP, Wu, X, Walker, LA, and Somlyo, AV.: Pharmacomechanical coupling: the role 
of calcium, G- proteins kinases and phosphatases. Rev Physiol Biochem.& Pharmacol  
134:202-234,1999.  
16. Cole, W.C., Clement-Chomienne, O. Properties, Regulation, and role of potassium channels 
of smooth muscle. In A functional view of Smooth muscle , p247-318. Eds Barr,L., and  
Christ, G.J. JAI Press, Stanford, CT. 2000.  
17. Korovkina VP, England SK.: Detection and implications of potassium channel 
alterations.Vascul Pharmacol. 38:3-12, 2002.  
18. Sobey CG. Potassium channel function in vascular disease. Arterioscler Thromb Vasc 
Biol.21:28-38., 2001.  
19. Christ GJ, Brink PR, Melman A, Spray DC. The role of gap junctions and ion channels in the 
modulation of electrical and chemical signals in human corpus cavernosum smooth muscle.  
Int J Impot Res 5: 77, 1993.  
20. Christ GJ. The penis as a vascular organ. The importance of corporal smooth muscle tone in 
the control of erection. Urol Clin N Am: 727-745, 1995.  
21. Christ GJ, Moreno AP, Parker ME, Gondre CM, Valcic M, Melman A, Spray DC.  
Intercellular communication through gap junctions: potential role in pharmacomechanical  
coupling and syncytial tissue contraction in vascular smooth muscle isolated from the human 
corpus cavernosum. Life Sci 49:PL195, 1991.  
22. Melman, A, Christ,GJ. Integrative erectile biology. The effects of age and disease on gap  
junctions and ion channels and their potential value to the treatment of erectile dysfunction. 
Urol Clin N Am 28:217-231, 2001.  
23. Fan, S.F., Brink, P.R., Melman, A., and Christ, G.J. An analysis of the maxi-K+ (KCa)  


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
34 
channel in cultured human corporal smooth muscle cells. J Urology 153:818-825, 1995. 
24. Spektor, M., Rodriquez, Rosenbaum, R.S., Wang, H.Z., Melman, A., and Christ, G.J.  
Potassium channels and human corporeal smooth muscle cells tone: further evidence for the 
physiological relevance of the Max-K channel subtype to the regulation of human corporeal 
smooth muscle tone in vitro. J Urol 167: 2628-2635, 2002.  
25. Tanaguchi, J., Furakawa, K.I., Shigekawa, M. Maxi-K+ channels are stimulated by cyclic  
guanosine monophosphate dependent protein kinase in canine coronary artery smooth muscle 
cells. Pfluegers. Arch 423:167-172, 1993.  
26. Christ, G.J., Rehman, J., Day, N., Salkoff, L., Valcic, M., Melman, A., and Geliebter, J.  
Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in 
penile function. Am J Physiol 275: H600-608, 1998.  
27. Shipston, M.J., Duncan, R.R., Clark, A.G., Antoni, F.A., Tian, L. Molecular components of 
large conductance calcium-activated potassium (BK) channels in mouse pituitary  
corticotropes. Mol Endocrinol 13:1728-1737, 1999.  
28. Kim, D.C., Gondre, C.M, Christ, G.J.: Endothelin-1-induced modulation of contractile  
responses elicited by an α1-adrenergic agonist on human corpus cavernosum smooth muscle. 
Int. J. Impotence Res., 8:17-24, 1996.  
29. Zhao, W. & Christ, G.J.: Endothelin-1 as a putative modulator of erectile dysfunction. II.  
Calcium mobilization in cultured human corporal smooth muscle cells. J. Urol., 154:1571- 
1579, 1995.  
30. Ariolas, Hedlund, H. The pharmacology and clinical pharmacokinetics of apomorphine SL. . 
BJU. Int 88 suppl 3, 18-21, 2001.  
31. Chen, K.K., Chan, J.Y., Chang, L.S. Dopaminergic neurotransmission at the paraventricular 
nucleus of hypothalamus in central regulation of penile erection in the rat. J Urol. 162: 237- 
242, 1999.  
32. Andersson, KE. Pharmacology of erectile function and dysfunction. Urol Clin N Am 28: 233- 
247, 2001.  
33. Rampin, O. Mode of action of a new oral treatment for erectile dysfunction:apomorphine SL. 
BJU Int Suppl 3, 22-24, 2001.  
34. Sato, Y., Day, N., Valcic, M., Melman, A., Christ, G.J. Gene therapy with maxi-K channels 
restores diminished erectile response in older animals during electrical stimulation of the  
medial pre-optic area (MPOA). J Urol 165: 220 (A), 2001.  
35. Rosen, C.R., Riley, A., Wagner, G., Osterloh, I.H., Kirkpatrick, J., Mishra, A. The  
International Index of Erectile Function (IIEF): A Multidimensional Scale for Assessment of 
Erectile Dysfunction.. Urology 49:822-830, 1997.  
36. Cappelleri, J.C., Rosen, R.C., Smith, M.D., Mishra, A., Osterloh, I.H. Diagnostic Evaluation 
of the Erectile Function Domain of the International Index of Erectile Function. Urology  
54:346-351, 1999.  
37. Cappelleri, J.C., Siegel, R.L., Osterloh, I.H., Rosen, R. Relationship Between Patient Self- 
Assessment of Erectile Function and the Erectile Function Domain of the International Index 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
35 
of Erectile Function. Urology 56:477-481, 2000.  
 
38. Melman, A., Bar-Chama, N., McCullough, A., Cavies, K., Christ, G.: Results of a phase I 
HMAXI-K gene transfer trial for erectile dysfunction. Eur Urol Suppl5 (2):140, 2006.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
36 
Appendix A. Grading of Averse Events 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
HEMATOLOGY 
 
 
 
 
Hemoglobin 
10.0 g/dL – 11.0 g/dL 
OR 
any decrease  2.5 g/dL 
9.0 g/dL – 9.9 g/dL 
OR 
any decrease  3.5 g/dL 
7.0 g/dL – 8.9 g/dL 
OR 
any decrease  4.5 g/dL 
< 7.0 g/dL 
WBC—Elevated 
13,000 – 14,999/mm3 
15,000 – 19,999/mm3 
20,000 – 24,999/mm3 
> 25,000/mm3 
WBC—Decreased 
2001 – 2499/mm3 
1501 – 2000/mm3 
1000 – 1500/mm3 
< 1000/mm3 
Platelets—Decreased 
100,000 – 124,999/mm3 
50,000 – 99,999/mm3 
25,000 – 49,999/mm3 
< 25,000/mm3 
Platelets—Elevated 
NA 
550,000 – 600,000/mm3 
> 600,000/mm3 
NA 
PT 
1.1-1.24 X ULN 
1.25 – 1.49 X ULN 
1.5 – 3.0 X ULN 
>3.0 XULN 
PTT 
>1  – 1.5 X ULN 
>1.5 – 2.0 X ULN  
>2 X ULN 
- 
CHEMISTRIES 
 
 
 
 
BUN 
25 - 30 mg/dL 
31 - 40 mg/dL 
41 – 50 mg/dL 
>50 mg/dL 
LDH 
1.5 – 2.5 X ULN 
2.6 – 3.5 X ULN 
3.6 – 5.0 X ULN 
>5.0 X ULN 
Hyponatremia 
<LLN – 130 mEq/L 
123 – <130 mEq/L 
116 – <123 mEq/L 
<116 mEq/L 
Hypernatremia 
>ULN – 150 mEq/L 
>150 – 155 mEq/L 
>155 – 160 mEq/L 
>160 mEq/L 
Hyperkalemia 
>ULN – 5.5 mEq/L 
>5.5 – 6.0 mEq/L 
>6.0 – 7.0 mEq/L 
>7.0 mEq/L 
Hypokalemia 
<LLN – 3.2 mEq/L 
3.0 – <3.2 mEq/L 
2.5 – <3.0 mEq/L 
<2.5 mEq/L 
Bicarbonate (serum) 
<LLN – 16 mEq/L 
10 – <16 mEq/L 
8 – < 10 mEq/L 
<8 mEq/L 
Phosphate 
<LLN  – 2.5 mg/dL 
 2.0 – <2.5 mg/dL 
 1.0 – <2.0 mg/dL 
<1.0 mg/dL 
Hypocalcemia 
<LLN – 8.0 mg/dL 
7.0 – <8.0 mg/dL 
6.0 – <7.0 mg/dL 
<6.0 mg/dL 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>11.5 – 12.5 mg/dL 
>12.5 – 13.5 mg/dL 
>13.5 mg/dL 
Magnesium 
<LLN - 1.2 mEq/L 
0.9 – <1.2 mEq/L 
0.7 – <0.9 mEq/L 
<0.7 mEq/L 
Total bilirubin 
>ULN  – 1.5 X ULN 
>1.5 – 3.0 X ULN  
>3.0  – 10.0 X ULN 
>10.0 X ULN 
Hypoglycemia 
<LLN - 55 mg/dL 
40 - <55 mg/dL 
30 – <40 mg/dL 
<30 mg/dL 
Hyperglycemia 
(nonfasting & no 
history of diabetes) 
>ULN – 160 mg/dL 
>160  – 250 mg/dL 
>250 – 500 mg/dL 
>500 mg/dL 
CPK 
>ULN – 2.5 X ULN 
>2.5 – 5.0 X ULN 
>5.0 - 10.0 X ULN 
>10 X ULN 
Creatinine 
>1.0 – 1.5 X ULN 
>1.5 – 3.0 X ULN 
>3.0  – 6.0 X ULN 
>6.0 X ULN 
AST (SGOT) 
ULN  – 2.5 X ULN 
>2.5– 5.0 X ULN 
>5.0 – 20.0 X ULN 
> 20.0 X ULN 
ALT (SGPT) 
>ULN – 2.5 X ULN 
>2.5 – 5.0 X ULN 
>5.0 – 20.0 X ULN 
> 20.0 X ULN 
GGT 
>ULN– 2.5 X ULN 
>2.5 – 5.0 X ULN 
>5.0 – 20.0 X ULN 
>20.0 X ULN 
Alkaline Phosphatase 
>ULN – 2.5 X ULN 
>2.5 – 5.0 X ULN 
>5.0 – 20.0 X ULN 
>20.0 X ULN 
 
 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
37 
 
 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
URINALYSIS 
 
 
 
 
Proteinuria (random 
urine sample) 
1+  
2-3+ 
4+ 
- 
Microscopic RBC 
(exception is urine 
sample post- 
catherization) 
6 – 10 RBC/hpf  
>10 RBC/hpf 
Gross hematuria 
- 
CARDIOVASCULAR 
 
 
 
 
Hypertension 
Asymptomatic, transient 
(<24 H) increase by >20 
mmHg (diastolic) or 
>150/100 if previously 
WNL; not requiring 
treatment 
Recurrent or persistent 
(>24H) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; may 
require monotherapy 
Requiring more than one 
drug or more intensive 
therapy than previously 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Hypotension 
Transient orthostatic 
hypotension, intervention 
not indicated 
Symptoms corrected with 
oral fluid replacement 
IV fluid required; 
hospitalization not 
required 
Hospitalization required 
Conduction 
abnormality/ 
atrioventricular heart 
block 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic & 
incompletely controlled 
medically or controlled 
with device (e.g., 
pacemaker) 
Life-threatening 
Prolonged QTc interval 
Asymptomatic, QTc 
interval 0.43 – 0.48 sec 
Asymptomatic, QTc 
interval >0.48 sec 
Symptomatic 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Supraventricular & 
nodal arrhythmia 
Asymptomatic, no 
intervention indicated  
Symptomatic, but not 
requiring treatment 
Symptomatic & 
incompletely controlled 
medically or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock 
Ventricular arrhythmia 
Asymptomatic, 
intervention not indicated 
Symptomatic, but not 
requiring treatment 
Symptomatic & 
incompletely controlled 
medically or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope shock 
Cardiac Arrhythmia – 
Other 
Asymptomatic, not 
requiring treatment 
Symptomatic, but not 
requiring treatment 
Symptomatic, and 
requiring treatment of 
underlying cause 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and 
testing suggests 
ischemia 
Asymptomatic ischemia 
(angina) or testing 
consistent with ischemia, 
intervention indicated 
Acute myocardial 
infarction 


Ion Channel Innovations                                                                         
Protocol I0N 04-ED 
 
 
Version 1.2 dated Mar 01, 2016  
 
 
  
38 
Appendix B.  Schedule of Events 
Test or Procedure 
Visit 1 
-2 Week 
Screening 
Visit 2 
Week 0 
Visit 3 
Week 1 
± 2 
days 
Visit 4 
Week 4 
± 3 
days 
Visit 5 
Week 8 
± 3 
days 
Visit 
6 
Week 
12 ± 3 
days 
Visit 
7 
Week 
24 ± 3 
days 
Informed Consent Process 
X 
 
 
 
 
 
 
Inclusion and Exclusion 
Criteria 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Medical History 
X 
X5 
X 
X 
X 
X 
X 
Physical Examination 
X 
X5 
X 
X 
X 
X 
X 
Physical Examination of 
Penis1    
X 
X5 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Blood Tests (Chemistry 
and Hematology)2 
X4 
 
X 
X 
 
X 
X 
Urine analysis3 
X 
X5 
X 
X 
 
X 
X 
ECG4 
X 
X4 
X 
X 
X 
X 
X 
IIEF5 
X 
X5 
X 
X 
X 
X 
X 
SEP5 
 
X5 
X 
X 
X 
X 
X 
Study drug administration 
 
X 
 
 
 
 
 
Conmomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Assay for  hSlo DNA6 
X6 
X 
X 
X 
X 
X 
X 
1PE of penis includes: inspection, palpation and neurosensory testing  
2Blood tests include: Hematology (CBC with differential, platelet count, PTT, PT, sedimentation rate, CRP), 
Chemistry (BUN, Cr, Na+, K+, Mg++, Ca++, CO2, Cl, albumin, alkaline phosphatase, ALT, AST, total bilirubin, total 
protein; Endocrine (testosterone, random cortisol, TSH, T4).  Hemoglobin A1c at Screening (V1) only. 
3Urine analysis includes: microscopic RBC and WBC, protein, glucose, and specific gravity. 
4ECG at V2 will be done prior to administration of study drug and at 1 and 2 hours following administration of study 
drug 
5Test will be done prior to administration of study drug. 
6 In all participants, plasma specimens will be collected to assay for the presence of hSlo DNA by PCR.  At Visit 2 
collect pre- dosing and 2 post dosing.


Ion Channel Innovations 
Protocol 0302 
                                                                                                                                                                39 
Appendix C. Sexual Encounter Profile (SEP) 
Sexual Encounter Profile DIARY 
Questions to be addressed 
after each attempt at 
intercourse 
1. Were you able to achieve at least  
some erection?  
2. Were you able to insert your penis  
into your partner’s vagina?  
3. Did your erection last long enough  
for you to have successful intercourse? 
4. Were you satisfied with the  
hardness of your erection?  
5. Overall, were you satisfied with the  
sexual experience?  
___/___/___ 
___/___/___ 
___/___/___ 
___/___/___  
MM/DD/YY 
MM/DD/YY 
MM/DD/YY 
MM/DD/YY 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 
N 
Y 


Ion Channel Innovations 
Protocol 0302 
 
 
                                                                                                                                                                40 
 
 
Appendix D. International Index Erectile Function 
INTERNATIONAL INDEX OF ERECTILE FUNCTION PAGE 1 OF 2 
PARTICIPANT 
(check the appropriate box – In the last month……….) 
1. How often were you able to get an erection 
4. 
during sexual activity?  
0. No sexual activity………………….  
1. Almost never / never………...........   
2. A few times (much less than half the  
time)………………… ...................   
3. Sometimes (about half the time)…..   
4. Most times (much more than half the  
time)………………………………   
5. Almost always/always………… ...   
2. When you had erections with sexual  
simulation, how often were your erections hard 
enough for penetration?  
0. No sexual activity………………….  
1. Almost never / never………...........   
2. A few times (much less than half the  
time)………………… ...................   
3. Sometimes (about half the time)…..   
4. Most times (much more than half the  
time)………………………………   
5. Almost always/always………… ...   
3. When you attempted sexual intercourse, how  
often were you able to penetrate (enter) your  
partner?  
0. No sexual activity………………….
1. Almost never / never………...........   
2. A few times (much less than half the  
time)………………… ...................   
3. Sometimes (about half the time)….. 
4. Most times (much more than half the  
time)………………………………   
5. Almost always/always………… ...   
 
 
 
 
 
 
 
 
 
During sexual intercourse, how often were you 
able to maintain your erection after you had  
penetrated (entered) your partner?  
0. Did not attempt intercourse….….  
1. Almost never / never…………....  
2. A few times (much less than half the  
time)………………....................   
3. Sometimes (about half the time)..  
4. Most times (much more than half the  
time)……………………………   
5. Almost always/always………....   
During sexual intercourse, how difficult was it 
to maintain your erection to completion of  
intercourse?  
0. Did not attempt intercourse……..  
1. Extremely difficult……………....  
2. Very difficult………....................   
3. Difficult………………………….  
4. Slightly difficult…………………  
5. Not difficult……………………...  
5. 
6. How many times have you attempted sexual 
intercourse?  
0. No attempts……………………..
1. One to two times………………..
2. Three to four times……………..  
3. Five to six times……………......  
4. Seven to ten times……………...  
5. Eleven + times………………….  
7. When you attempted sexual intercourse, how  
often was it satisfying for you?  
0. Did not attempt intercourse….…..  
1. Almost never / never…..…..........   
2. A few times (much less than half the  
time)……………….. ....................   
3. Sometimes (about half the time).… 
4. Most times (much more than half the  
time)……………..……………….   
5. Almost always/always…………....   


Ion Channel Innovations 
Protocol 0302 
 
 
                                                                                                                                                                41 
 
 
INTERNATIONAL INDEX OF ERECTILE FUNCTION PAGE 2 OF 2 
 
8. How much have you enjoyed sexual intercourse? 
0. No intercourse………………......  
1. No enjoyment……………….......  
2. Not very enjoyable……………...  
3. Fairly enjoyable………………....  
4. Highly enjoyable….………….....  
5. Very enjoyable……………..….  
9. When you had sexual stimulation or intercourse,  
how often did you ejaculate?  
0. No sexual stimulation/intercourse   
1. Almost never/never…………….….  
2. A few time (much less than half the  
time)…………………..………...   
3. Sometimes(about half the time)…  
4. Most times (much more than half the  
time)……………………………..  
5. Almost always/always……….....  
10. When you had sexual stimulation or intercourse, 
how often did you have the feeling or orgasm or  
climax?  
0. No sexual  
stimulation/intercourse……….…  
1. Almost never/never……………...  
2. A few time (much less than half the  
time)…………………………....   
3. Sometimes(about half the time)…  
4. Most times (much more than half the  
time)…………………………..  
5. Almost always/always……….....  
11. How often have you felt sexual desire?  
1. Almost never/never…………….  
2. A few times (much less than half the  
time)……………………………  
3. Sometimes (about half the time).  
4. Most times (much more than half the 
time)………………………..  
5. Almost always/always…………  
 
 
 
12. How would you rate your level of sexual  
desire?  
1. Very low/none at all………….…
2. Low……………………………..
3. Moderate………………………..
4. High…………………………….  
5. Very high……………………….
13. How satisfied have you been with your  
overall sex life?  
1. Very dissatisfied……..…….....
2. Moderately dissatisfied………...
3. About equally satisfied and  
dissatisfied……………………..  
4. Moderately satisfied…………...  
5. Very satisfied…………………..
14. How satisfied have you been with your  
sexual relationship with your partner?  
1. Very dissatisfied……………….  
2. Moderately dissatisfied………...
3. About equally satisfied and  
dissatisfied……………………..  
4. Moderately satisfied…………....
5. Very satisfied…………………..  
15. How do you rate your confidence that you  
could get and keep an erection?  
1. Very low………………………
2. Low……………………………
3. Moderate………………………
4. High…………………………...
5. Very high……………………...
 

SAP_001.pdf: 
67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
$XWKRU

5HYLHZHUV

$SSURYHGE\

$SSURYDO'DWH

'RFXPHQW1XPEHU
&13+,21('67$76$3
9HUVLRQ1XPEHU

7UHDWPHQW*URXSV
&RKRUW,QYHVWLJDWLRQDO0HGLFLQDO3URGXFWK0D[L.RU
ǋJ
&RKRUW3ODFHER3%6VXFURVH
3URWRFRO1XPEHU
,21('
3URWRFRO7LWOH
$'RXEOHEOLQG3ODFHERFRQWUROOHG3DUDOOHO'HVLJQ5DQGRPL]HG
3KDVH$7ULDO(YDOXDWLQJWKH3RWHQWLDO$FWLYLW\DQG6DIHW\RI
K0D[L.*HQH7UDQVIHULQ0DOHVZLWK(UHFWLOH'\VIXQFWLRQ
6SRQVRU
,RQ&KDQQHO,QQRYDWLRQV//&
&RQWUDFW5HVHDUFK
2UJDQL]DWLRQ

5HYLVLRQ&KURQRORJ\
9HUVLRQ
(IIHFWLYH'DWH
5HDVRQIRUFKDQJH

WK'HFHPEHU
,QLWLDO9HUVLRQ

WK'HFHPEHU
8SGDWHGZLWKLQSXWIURP&5)

WK-DQXDU\
8SGDWHGEDVHGRQFOLHQWFRPPHQWV

WK-XO\
8SGDWHGEDVHGRQFOLHQWFRPPHQWV

WK$XJXVW
,QFOXGHGOLVWRIRXWSXWV

WK1RYHPEHU
8SGDWHGOLVWRIRXWSXWV

WK'HFHPEHU
8SGDWHGSULPDU\DQDO\VLVVHFWLRQDQGOLVWRI
RXWSXWV

WK'HFHPEHU
,QFRUSRUDWHGFODULILFDWLRQVIURPFOLHQWVSRQVRU
$SSURYHG%\
6LJQDWXUH
'DWH


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
 7DEOHRI&RQWHQWV
 
7DEOHRI&RQWHQWV 
 
/LVWRI$EEUHYLDWLRQV  
 
,QWURGXFWLRQ 
 
6WXG\2EMHFWLYH  
 
$QDO\VLV6HWV 
 
'HILQLWLRQ 
 
'DWD+DQGOLQJ 
 
6DPSOH6L]H&DOFXODWLRQV 
 
6WDWLVWLFDO0HWKRGV 

$QDO\VLV&RQYHQWLRQV 

'HVFULSWLYH0HWKRGV 

3ULPDU\$QDO\VLV 

6DIHW\DQGRUIXUWKHUDQDO\VLV 
 
/LVWLQJV7DEOHVDQG)LJXUHV 
/LVWLQJV
7DEOHV  
 
6RIWZDUH 
 
5HIHUHQFH 


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
 /LVWRI$EEUHYLDWLRQV
7HUP
'HILQLWLRQ
$(
$GYHUVHHYHQW
'/7
'RVH/LPLWLQJ7R[LFLWLHV
('
(UHFWLOH'\VIXQFWLRQ
()
(UHFWLOH)XQFWLRQ
(&*
(OHFWURFDUGLRJUDP
%81
%ORRG8UHD1LWURJHQ
&%&
&RPSOHWH%ORRG&RXQW
&5)
&DVH5HSRUW)RUP
,,()
,QWHUQDWLRQDO,QGH[RI(UHFWLOH)XQFWLRQ
,8
,QWHUQDWLRQDO8QLW
,&
,QWUDFDYHUQRXV
,77
,QWHQWWRWUHDW
0RG,77
0RGLILHG,QWHQWWRWUHDW
33
3HUSURWRFRO
37
3URWKURPELQ7LPH
377
3DUWLDO7KURPERSODVWLQ
6(3
6H[XDO(QFRXQWHU3URILOH
6(3
$ELOLW\WRDFKLHYHYDJLQDOSHQHWUDWLRQ
6(3
$ELOLW\WRPDLQWDLQDQHUHFWLRQORQJHQRXJKIRUVXFFHVVIXOLQWHUFRXUVH
6HGUDWH
VHGLPHQWDWLRQUDWH
9('
9DFXXP(UHFWLRQ'HYLFHV


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
 ,QWURGXFWLRQ
(UHFWLOH '\VIXQFWLRQ (' LV D GLVHDVH GHILQHG DV WKH LQDELOLW\ WR DFKLHYH RU PDLQWDLQ DQ HUHFWLRQ
VXIILFLHQWIRUVDWLVIDFWRU\VH[XDOIXQFWLRQ7KHPRVWFRPPRQFDXVHRI('LVDGYDQFHGDJH3URSRVHG
FDXVHV RI DJHLQGXFHG (' LQFOXGH UHGXFWLRQ RI 12 SURGXFWLRQ LQFUHDVHG FRQWUDFWLOLW\ RI WKH VPRRWK
PXVFOH RI WKH SHQLOH FRUSRUD LQFUHDVHG P\RILODPHQW FDOFLXP VHQVLWLYLW\ GXH WR DOWHUHG 5KR NLQDVH
H[SUHVVLRQDFWLYLW\DQGUHGXFWLRQLQWKHUHODWLYHSHUFHQWDJHRIVPRRWKPXVFOHILEHUVDQGDQLQFUHDVH
LQFROODJHQFRQWHQWWKXVGHFUHDVLQJWKHFRPSOLDQFHRIWKHFDYHUQRXVWLVVXH7KHVHFRQGPRVWFRPPRQ
FDXVHLVGLPLQLVKHGEORRGIORZWRWKHSHQLVGXHWRFDUGLRYDVFXODUGLVHDVH

('FDQHLWKHUEHUHYHUVLEOHRUQRQUHYHUVLEOH0HQRYHU\HDUVWHQGWRKDYHSHUPDQHQWFDXVHVRI('
WKDW DUH GLVHDVHUHODWHG 7KH PRVW IUHTXHQWO\ DVVRFLDWHG GLVHDVHV LQFOXGH DWKHURVFOHURVLV
K\SHUWHQVLRQ DQWLK\SHUWHQVLYH PHGLFDWLRQV GLDEHWHV PHOOLWXV DQG SHOYLF VXUJHU\ DQG UDGLDWLRQ ,Q
\RXQJHUPHQDJHV±SV\FKRORJLFDOFDXVHVIRU('RIWHQSUHGRPLQDWHDQGWKLVUHYHUVLEOHIRUP
RI('FDQEHWUHDWHGZLWKVH[WKHUDS\DQGGUXJV

,RQ&KDQQHO,QQRYDWLRQVKDVGHYHORSHGK0D[L.WRWUHDW('XVLQJWKHVDPHSULQFLSDODVGUXJVWKDW
KDYH EHHQ XVHG VLQFH  LH WUHDWPHQW ZLWKPHGLFLQHV FDXVLQJ UHOD[DWLRQ RI WKH SHQLOH VPRRWK
PXVFOHUHVXOWLQJLQULJLGHUHFWLRQVK0D[L.FRQVLVWVRIWKHJHQHIRUWKHĮSRUHVXEXQLWRIWKHPD[L.
FKDQQHOK6ORLQVHUWHGLQWRDSODVPLGYHFWRU$GPLQLVWUDWLRQRIWKLVJHQHLQWRWKHFRUSRUDLQFUHDVHV
H[SUHVVLRQRIWKHPD[L.FKDQQHOLQWKHVPRRWKPXVFOHFHOOVDQGDQLQFUHDVHGHIIOX[RI.DFURVVWKH
FHOO PHPEUDQH UHVXOWLQJ LQ GHFUHDVHG HQWU\ RI &D LRQV 7KLV HIIHFW RQ LRQ H[FKDQJH DFURVV WKH
VPRRWKPXVFOHFHOOVDOORZVWKHVPRRWKPXVFOHRIWKHFRUSRUDWRUHOD[WKHFRUSRUDOVLQXVRLGVEHFRPH
HQJRUJHGZLWKEORRGDQGWKHSHQLVWRVWD\ULJLG)XUWKHUPRUHUHVXOWVIURPWKHVHSUHFOLQLFDOVWXGLHV
VXJJHVW WKDW H[SUHVVLRQ RI WKH ĮSRUH VXEXQLW IRU WKH PD[L. FKDQQHO IROORZLQJ DGPLQLVWUDWLRQ RI
K0D[L. PD\ KDYH D ORQJWHUP HIIHFW RQ WKH HUHFWLOH PHFKDQLVP 7KLV DFWLYLW\ RI K0D[L. PD\
UHSUHVHQW D GLVWLQFW DGYDQWDJH RYHU FXUUHQW GUXJ WKHUDS\ IRU (' ZKHUH WKH HIIHFW RI WUHDWPHQW LV
WHPSRUDU\

7KLVVWDWLVWLFDODQDO\VLVSODQGHVFULEHVLQGHWDLOWKHPHWKRGVDQGSUHVHQWDWLRQRIWKHGDWDDQDO\VHVIRU
WKHVWXG\,21('WRHYDOXDWHWKHVDIHW\DQGHIILFDF\RIDVLQJOHLQWUDFDYHUQRXVLQMHFWLRQRIK0D[L.
ǋJDQGǋJRUSODFHERXSRQSHQLOHULJLGLW\RUHUHFWLRQLQPDOHVZLWKHUHFWLOHG\VIXQFWLRQ
ORQJHUWKDQVL[PRQWKVWKDWLVDWWULEXWDEOHWRDQXQGHUO\LQJVWDEOHPHGLFDOFRQGLWLRQ

7KLV VWXG\ LV GRXEOHEOLQG SODFHER FRQWUROOHG SDUDOOHO GHVLJQ 3KDVH $ WULDO HYDOXDWLQJ WKH SRWHQWLDO
DFWLYLW\ DQG VDIHW\ RI WZR GLIIHUHQW GRVHV RI K0D[L.  ǋJ DQG ǋJ JLYHQ LQ D VLQJOH
DGPLQLVWUDWLRQ UHODWLYH WR SODFHER LQMHFWHG LQWR WKH FRUSXV FDYHUQRVXP RI WKH SHQLV 7KH SURSRVHG
VWXG\SHULRGLVDSSUR[LPDWHO\PRQWKVIROORZLQJWKHVLQJOHLQMHFWLRQRIVWXG\GUXJSHUSDUWLFLSDQW
7KLVVWXG\ZLOOHQUROOSDUWLFLSDQWVDWK0D[L.GRVHVRIǋJSDUWLFLSDQWVDWK0D[L.GRVHVRI
ǋJDQGRQSODFHER$PD[LPXPRISDUWLFLSDQWVZLOOEHHQUROOHG


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
6FKHGXOHRI(YHQWV



 6WXG\2EMHFWLYH
7KHREMHFWLYHRIWKHVWXG\LVWRHYDOXDWHWKHVDIHW\DQGHIILFDF\RIDVLQJOHLQWUDFDYHUQRXVLQMHFWLRQRI
K0D[L .  ǋJ DQG  ǋJ RU SODFHER XSRQ SHQLOH ULJLGLW\ RU HUHFWLRQ LQ PDOHV ZLWK HUHFWLOH
G\VIXQFWLRQORQJHUWKDQVL[PRQWKVWKDWLVDWWULEXWDEOHWRDQXQGHUO\LQJVWDEOHPHGLFDOFRQGLWLRQ

3ULPDU\REMHFWLYH

7KH SULPDU\ REMHFWLYH RI WKLV VWXG\ LV WR HYDOXDWH WKH SRWHQWLDO HIILFDF\ DQG VDIHW\ RI D VLQJOH
LQWUDFDYHUQRXV LQMHFWLRQ RI K0D[L.  ǋJ FRPSDUHG WR SODFHER LQ PDOHV ZLWK HUHFWLOH
G\VIXQFWLRQORQJHUWKDQVL[PRQWKVWKDWZDVDWWULEXWDEOHWRDQXQGHUO\LQJVWDEOHPHGLFDOFRQGLWLRQ
XSRQ SHQLOH ULJLGLW\ RU HUHFWLRQ LQ PDOHV ZLWK HUHFWLOH G\VIXQFWLRQ ORQJHU WKDQ VL[ PRQWKV WKDW LV
DWWULEXWDEOHWRXQGHUO\LQJVWDEOHPHGLFDOFRQGLWLRQ

6HFRQGDU\REMHFWLYH

7KH VHFRQGDU\ REMHFWLYH RI WKLV VWXG\ LV WR HYDOXDWH VDIHW\ RI D VLQJOH LQWUDFDYHUQRXV LQMHFWLRQ RI
K0D[L.HLWKHURUǋJFRPSDUHGWRSODFHER

6WXG\(QGSRLQWV

7KH SULPDU\ RXWFRPH PHDVXUHV WKDW ZLOO EH FRQVLGHUHG WR HYDOXDWH FKDQJH LQ HUHFWLOH VWDWXV IURP
EDVHOLQHIROORZLQJDGPLQLVWUDWLRQRIK0D[L.DUH

R
(UHFWLOH)XQFWLRQ()GRPDLQRIWKH,QWHUQDWLRQDO,QGH[RI(UHFWLOH)XQFWLRQ,,()


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
R
6H[XDO(QFRXQWHU3URILOH6(34XHVWLRQVDQG

7KHVDIHW\DQGWROHUDELOLW\RIWKHVWXG\GUXJZLOOEHHYDOXDWHGE\DQDO\VLVRI

R
$GYHUVHHYHQWV
R
&OLQLFDOODERUDWRU\WHVWV
R
(OHFWURFDUGLRJUDP
R
3K\VLFDOH[DPLQDWLRQVLQFOXGLQJYLWDOVLJQV
 $QDO\VLV6HWV

5DQGRPL]HGSRSXODWLRQ7KLVZLOOLQFOXGHDOOWKHVXEMHFWVZKRKDYHEHHQUDQGRPL]HGWRHLWKHU
RIWKHWUHDWPHQWJURXSV


,77 SRSXODWLRQ 7KLV ZLOO LQFOXGH DOO WKH VXEMHFWV ZKR KDYH EHHQ UDQGRPL]HG WR HLWKHU RI WKH
WUHDWPHQWJURXSVDQGZKRKDYHUHFHLYHGDWOHDVWRQHGRVHRIVWXG\WUHDWPHQW


0RGLILHG,77SRSXODWLRQ0RG,77SRSXODWLRQ7KLVSRSXODWLRQZLOOLQFOXGHDOOVXEMHFWVLQWKH
,77SRSXODWLRQZKRKDYHDWOHDVWRQHSRVWGRVHHIILFDF\DVVHVVPHQW


3HU 3URWRFRO 3RSXODWLRQ 33 3RSXODWLRQ7KLV ZLOOLQFOXGHDOOVXEMHFWVLQWKH,77SRSXODWLRQ
ZKRUHSRUWQRSURWRFROYLRODWLRQV

 6DIHW\3RSXODWLRQ7KLVZLOOLQFOXGHDOOVXEMHFWVZKRZHUHUDQGRPL]HGWRHLWKHURIWKHWUHDWPHQW
JURXSVDQGZKRKDYHUHFHLYHGDWOHDVWRQHGRVHRIVWXG\WUHDWPHQW
 'HILQLWLRQ
 $JH7KHDJHZLOOEHFDOFXODWHGDVWKHH[DFWQXPEHURIGD\VEHWZHHQWKHGDWHRIELUWKDQGGDWHRI
LQIRUPHGFRQVHQWFRQYHUWHGWR\HDUVLHGLIIHUHQFHLQGD\V$JHLVWKHLQWHJHUSDUWRI
WKLVYDOXH

 %DVHOLQH7KHWLPHSRLQWDWZKLFKUDQGRPL]DWLRQLVSHUIRUPHGZLOOEHWKHEDVHOLQHWLPHSRLQW7KH
ODVW LQVWDQFH RI GDWD FROOHFWHG EHIRUH DGPLQLVWUDWLRQ RI WUHDWPHQW ZLOO EH FRQVLGHUHG DV WKH
EDVHOLQHLQIRUPDWLRQIRUWKHUHVSHFWLYHSDUDPHWHU,IDSDWLHQWKDVUHSHDWHGDVVHVVPHQWVSULRUWR
WKHVWDUWRIGRXEOHEOLQGVWXG\GUXJWKHQWKHUHVXOWVIURPWKHILQDODVVHVVPHQWPDGHSULRUWRWKH
VWDUWRIGRXEOHEOLQGVWXG\GUXJZLOOEHXVHGDVEDVHOLQH

 %RG\0DVV,QGH[%0,%0,LVREWDLQHGE\GLYLGLQJWKHZHLJKWNJE\WKHVTXDUHRIKHLJKW
PLHZHLJKWNJKHLJKWAP
 &KDQJHEHWZHHQEDVHOLQHDQGSRVWGRVHYLVLWVIRUWKHSDUDPHWHUVZLOOEHFRQVLGHUHGDVWKH
GLIIHUHQFHEHWZHHQWKHSRVWEDVHOLQHYDOXHDQGWKHEDVHOLQHYDOXHSRVWEDVHOLQHYDOXH±EDVHOLQH
YDOXH7KLVZLOOEHDSSOLFDEOHWRODERUDWRU\GDWDDQGVDIHW\SDUDPHWHUV

 3ULRU&RQFRPLWDQW0HGLFDWLRQ7KHUDS\$OOPHGLFDWLRQVWKHUDSLHVZLWKHQGGDWHSULRUWRWKH
GDWHRIWUHDWPHQWZLOOEHFRQVLGHUHGDVSULRUPHGLFDWLRQV&RQFRPLWDQWPHGLFDWLRQZLOOEHGHILQHG
DVDQ\PHGLFDWLRQWDNHQEHWZHHQWKHGD\RIGRVLQJZLWKVWXG\GUXJDQGWKHHQGRIWKHPRQWK
VWXG\ IROORZXS SHULRG RU ILQDO YLVLW  $Q\ PHGLFDWLRQV VWDUWHG DIWHU WKH ILQDO YLVLW ZLOO QRW EH
FRQVLGHUHGFRQFRPLWDQWPHGLFDWLRQV

 7UHDWPHQW(PHUJHQW$GYHUVH(YHQWV7($(V$WUHDWPHQWHPHUJHQWDGYHUVHHYHQW7($(
ZLOO EH FRQVLGHUHG DV DQ HYHQW WKDW LV WHPSRUDOO\ DVVRFLDWHG ZLWK WKH XVH RI WKH VWXG\ GUXJ
ZKHWKHURUQRWFRQVLGHUHGUHODWHGWRWKHVWXG\GUXJ$OODGYHUVHHYHQWVZLWKVWDUWGDWHRQRUDIWHU
WKHGDWHRIWUHDWPHQWZLOOEHFRQVLGHUHGDV7($(V


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
 6HULRXV$GYHUVH(YHQWV6HULRXVDGYHUVHHYHQWVDUHGHILQHGDVWKHDGYHUVHHYHQWVZKLFKDUH
PHGLFDOO\ VLJQLILFDQW HYHQWV HJ LQWHQVLYH WUHDWPHQW LQ (5 RU DW KRPH IRU DOOHUJLF
EURQFKRVSDVPOLIHWKUHDWHQLQJUHTXLULQJKRVSLWDOL]DWLRQRUUHVXOWLQJLQGHDWKDGLVDELOLW\RUD
FRQJHQLWDODEQRUPDOLW\

 'DWD+DQGOLQJ
$QDO\VLV XVLQJ /DVW 2EVHUYDWLRQ &DUULHG )RUZDUG /2&) ZLOO EH XVHG IRU KDQGOLQJ PLVVLQJ GDWD
)XUWKHUZLWKUHJDUGWRPLVVLQJGDWDWKHDVVXPSWLRQRIPLVVLQJDWUDQGRPZLOOEHDVVHVVHGE\ORRNLQJ
IRUSDWWHUQVRYHUWLPHDQGE\FRPSDULQJWKRVHZLWKPLVVLQJYDOXHVWRDOORWKHUVXEMHFWVZLWKUHJDUG
WREDVHOLQHFKDUDFWHULVWLFV&KLVTXDUHRU([DFWWHVWVZLOOEHXVHGWRFRPSDUHLQFLGHQFHUDWHVDPRQJ
WKHWUHDWPHQWFRKRUWVZLWKUHVSHFWWRWKHEHORZEDVHOLQHFKDUDFWHULVWLFV

R
'HPRJUDSKLFVGDWHRIELUWKDJHUDFHZHLJKWKHLJKWDQGERG\PDVVLQGH[>%0,@
R
$VVHVVPHQWRISK\VLFDOH[DPLQDWLRQ
R
$EQRUPDOLWLHVLQ(&*SDUDPHWHUV
R
$EQRUPDOLWLHVLQYLWDOVLJQSDUDPHWHUV
R
(IILFDF\HQGSRLQWV
R
6DIHW\HQGSRLQWV
R
3ULRUDQGFRQFRPLWDQWPHGLFDWLRQ

 6DPSOH6L]H&DOFXODWLRQV
7KH VWXG\ SRSXODWLRQ LQFOXGHV PHQ ZLWK HUHFWLOH G\VIXQFWLRQ DWWULEXWDEOH WR DQ XQGHUO\LQJ VWDEOH
PHGLFDOFRQGLWLRQEXWZKRDUHRWKHUZLVHLQJRRGKHDOWK7KHPRVWFRPPRQVWDEOHPHGLFDOGLVHDVHV
WKDWFDXVHHUHFWLOHG\VIXQFWLRQLQFOXGHK\SHUWHQVLRQDQGDWKHURVFOHURVLVDQWLK\SHUWHQVLYHPHGLFDWLRQ
W\SH , DQG W\SH ,, GLDEHWHV PHOOLWXV SHOYLF VXUJHU\ DQG SHOYLF UDGLDWLRQ FHUHEURYDVFXODU DFFLGHQWV
VWURNHPXOWLSOHVFOHURVLVDQG3DUNLQVRQ¶VGLVHDVH0HQZLWKHUHFWLOHG\VIXQFWLRQVHFRQGDU\WRDJLQJ
DVDVROLWDU\FDXVHZLOOQRWEHLQFOXGHGLQWKHWULDO6HUXP3URODFWLQOHYHOVZLOOKDYHEHHQREWDLQHGRQ
WKHSDUWLFLSDQWVDVSDUWRIWKHLUZRUNXSIRUHUHFWLOHG\VIXQFWLRQ7KHWDUJHWSRSXODWLRQLVPHQZLWK
HUHFWLOH G\VIXQFWLRQ ZKR KDYH EHHQ XQDEOH WR WROHUDWH GR QRW ZLVK WR FRQWLQXH RU KDYH KDG
XQVXFFHVVIXOUHVXOWVZLWKSULRUWKHUDS\IRU('
7KHVDPSOHVL]HKDVEHHQHVWLPDWHGDVVXPLQJDVWDQGDUGGHYLDWLRQRIDQGDWZRVDPSOHWWHVWWR
KDYHSRZHU

6WDWLVWLFDO3RZHU
3RZHU
1
1
3ODFHER
5DWLR
$OSKDC

0HDQ

0HDQ

6'

6'










$OSKD
LVWKHDOSKDOHYHODGMXVWHGIRUWKUHHPXOWLSOHFRPSDULVRQVWKHWZRGRVHVFRPSDUHGZLWKHDFK
RWKHU HDFK GRVH FRPSDUHG ZLWK WKH SODFHER DQG WRWDO DFWLYH WUHDWPHQW WZR GRVHV FRPELQHG
FRPSDUHGWRSODFHER*LYHQWKHWKUHHFRPSDULVRQVWKDWLQFRUSRUDWHGD%RQIHUURQLPXOWLSOHFRPSDULVRQ
SURFHGXUHWKHRYHUDOODOSKDOHYHOLVSUHVHUYHGDW

$DWWULWLRQUDWHRYHUWKHZHHNVRIIROORZXSLVDQWLFLSDWHGZKLFKLQIODWHVWKHVDPSOHVL]HWR
DSSUR[LPDWHO\VXEMHFWVLQWRWDO

 6WDWLVWLFDO0HWKRGV
7KLVVHFWLRQGHVFULEHVWKHYDULRXVVWDWLVWLFDODQDO\VHVWKDWDUHSODQQHGWREHSHUIRUPHGIRUWKLVVWXG\
7KHSULPDU\DQDO\VLVZKLFKLQFOXGHVHIILFDF\DQDO\VLVZLOOEHSHUIRUPHGRQWKHPRG,77SRSXODWLRQDQG
VXSSRUWLYH DQDO\VLV RQ WKH 33 DQG ,77 SRSXODWLRQV 7KH VDIHW\ HQGSRLQWV ZLOO EH HYDOXDWHG RQ WKH
VDIHW\SRSXODWLRQ



67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
,IDSDWLHQWKDVUHSHDWHGDVVHVVPHQWVSULRUWRWKHVWDUWRIGRXEOHEOLQGVWXG\GUXJWKHQWKHUHVXOWV
IURPWKHILQDODVVHVVPHQWPDGHSULRUWRWKHVWDUWRIGRXEOHEOLQGVWXG\GUXJZLOOEHXVHGDVEDVHOLQH
,IHQGRIVWXG\DVVHVVPHQWVDUHUHSHDWHGRUXQVFKHGXOHGWKHODVWSRVWEDVHOLQHDVVHVVPHQWZLOOEH
XVHG DV WKH HQGRIVWXG\ DVVHVVPHQW IRU JHQHUDWLQJ VXPPDU\ VWDWLVWLFV +RZHYHU DOO SRVWEDVHOLQH
DVVHVVPHQWVZLOOEHSUHVHQWHGLQWKHGDWDOLVWLQJV

'RVHUHVSRQVHFRPSDULVRQVZLOOEHPDGHEHWZHHQPFJYVPFJYVSODFHERDVZHOODV
FRPSDULVRQVEHWZHHQWRWDODFWLYHSRSXODWLRQPFJDQGYVSODFHER2QVHWDQGGXUDWLRQ
RIHIIHFWZLOODOVREHDQDO\]HGDQGDGRVHUHVSRQVHHYDOXDWHG2QVHWDQGGXUDWLRQRIDFWLRQZLOODOVREH
DQDO\]HG

$OOWHVWVRIVLJQLILFDQFHZLWKUHJDUGWRHIILFDF\ZLOOEHRQHWDLOHGDQGSHUIRUPHGDWDQRYHUDOODOSKD
OHYHORI$OOHVWLPDWHVRIGLIIHUHQFHVZLOOEHSUHVHQWHGZLWKFRQILGHQFHOLPLWV


$QDO\VLV&RQYHQWLRQV
7KHIROORZLQJFRQYHQWLRQVZLOOEHDSSOLHGWRDOOGDWDSUHVHQWDWLRQVDQGDQDO\VHV
 7DEOHVDQGOLVWLQJVZLOOEHSUHVHQWHGLQODQGVFDSHRULHQWDWLRQ
 7DEOHVZLOOEHSUHVHQWHGIRUDQDO\VLVSRSXODWLRQVDVGHILQHGLQWKHWLWOHRIWKHWDEOHV

 /LVWLQJVZLOOEHSUHVHQWHGIRUWKHHQUROOHGSRSXODWLRQ

 $OOWKHGLVSOD\VZLOOEHLQ7DKRPDSWIRQW
 $OOWDEOHVDQGOLVWLQJVZLOOKDYHIRRWHUVHFWLRQVZKLFKZLOOFRQWDLQWKHQDPHRIWKHSURJUDP

 )RUDOOWDEOHVDQGOLVWLQJVWKHWLWOHVZLOODSSHDULQWKHERG\RIWKHGRFXPHQW7KHWLWOHZLOOLQFOXGH
WKH VSRQVRU QDPH SURWRFRO QDPH GDWH DQG WLPH RI JHQHUDWLRQ YHUVLRQ 'UDIW)LQDO SDJH
QXPEHULQWKHIRUPDW3DJH;RI<7DEOH/LVWLQJQXPEHUDQGQDPH
$QH[DPSOHLVJLYHQEHORZ

,RQ&KDQQHO,QQRYDWLRQV//&

'UDIW±''000<<<<++00
3URWRFRO,21('

3DJH[RI\
7DEOH;;;;
7DEOH7LWOH
3RSXODWLRQ
 6XPPDU\WDEOHVZLOOFRQWDLQIRRWQRWHVLQWKHERG\RIWKHWLWOHWKDWUHIHUHQFHDQ\GDWDOLVWLQJVRU
WDEOHVDVVRFLDWHGZLWKWKHWDEOHRUILJXUHHJ5HIHUHQFH/LVWLQJ;;;
 $GGLWLRQDOIRRWQRWHVPD\EHDGGHGDVSHUWKH67/VKHOOV

 7KHRXWSXWVKDYHWREHFUHDWHGDVSHUWKHVKHOOVWKDWZLOOEHSURYLGHGDORQJZLWKWKLVDQDO\VLV
SODQ

 *XLGHOLQHVSURYLGHGLQWKH67/VKHOOVXQGHU³3URJUDPPLQJQRWHV´VKRXOGEHUHIHUUHGWRE\WKH
SURJUDPPHUVIRUFODULW\RQVKHOOV

 $OOPHDQVDQGPHGLDQVZLOOEHIRUPDWWHGWRRQHPRUHGHFLPDOSODFHWKDQWKHPHDVXUHGYDOXH
&RQILGHQFHLQWHUYDOVDQGVWDQGDUGGHYLDWLRQYDOXHVZLOOEHIRUPDWWHGWRWZRPRUHGHFLPDOSODFHV
WKDQ WKH PHDVXUHG YDOXH 0LQLPXP DQG PD[LPXP YDOXHV ZLOO EH SUHVHQWHG ZLWK WKH VDPH
QXPEHURIGHFLPDOSODFHVDVWKHPHDVXUHGYDOXH

 7KHQXPEHUDQGSHUFHQWDJHRIUHVSRQVHVZLOOEHSUHVHQWHGLQWKHIRUP;;;;ZKHUHWKH
SHUFHQWDJHDVZKROHQXPEHUVZLOOEHLQSDUHQWKHVHV


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
 $OOSYDOXHVZLOOEHSUHVHQWHGZLWKDWOHDVWGHFLPDOSODFHVHQVXULQJPHDQLQJIXOUHSUHVHQWDWLRQ

 $OO VXPPDU\ WDEOHV ZLOO LQFOXGH WKH WRWDO QXPEHU RI VXEMHFWV LQ WKH SRSXODWLRQ WKDW LV EHLQJ
DQDO\]HG EDVHG RQ WUHDWPHQW UDQGRPL]HG DQG UHFHLYHG VWXG\ GUXJ 7KLV LQIRUPDWLRQ ZLOO EH
JLYHQLQWKHFROXPQKHDGLQJVLQHDFKWDEOH

 $OOOLVWLQJVZLOOEHRUGHUHGE\WUHDWPHQWFRKRUWVXEMHFWQXPEHUDQGYLVLWGDWHLIDSSOLFDEOH

 'DWHYDULDEOHVZLOOEHIRUPDWWHGDV''000<<<<IRUSUHVHQWDWLRQ
 6$69HUVLRQZLOOEHXVHGIRUDOOGDWDDQDO\VLV

 0HG'5$ YHUVLRQ  DQG :+2 YHUVLRQ UHOHDVHG RQ '(&   ZLOO EH XVHG IRU FRGLQJ
DGYHUVHHYHQWVDQGFRQFRPLWDQWPHGLFDWLRQVUHVSHFWLYHO\

'HVFULSWLYH0HWKRGV
7KHVWXG\FRPSULVHVRIWZRFRKRUWVFRPSULVLQJRIWKUHHWUHDWPHQWJURXSVQDPHO\
R
&RKRUW  K0D[L. FRPSULVLQJ RI WZR WUHDWPHQW JURXSV K0D[L. ǋJ DQG K0D[L.
ǋJ

R
&RKRUW3ODFHERZKLFKZDVDGPLQLVWUDWLRQRI3%6VXFURVH

$OO RXWSXWV ZLOO EH SUHVHQWHG ZLWK UHVSHFW WR WKH DERYH WZR FRKRUWV DQG RYHUDOO &RKRUW  ZLOO EH
IXUWKHUVXEFDWHJRUL]HGZLWKUHVSHFWWRWKHWZRWUHDWPHQWV

7KHYDULRXVEDVHOLQHDQGGHPRJUDSKLFFKDUDFWHULVWLFVZLOOEHDQDO\]HGIRUWKHUDQGRPL]HGSRSXODWLRQ
)RU TXDQWLWDWLYH YDULDEOHV WKH IROORZLQJ GHVFULSWLYH VWDWLVWLFV ZLOO EH FRPSXWHG QXPEHU RI VXEMHFWV
QQXPEHURIPLVVLQJYDOXHVVXEMHFWVPHDQVWDQGDUGGHYLDWLRQPLQLPXPPD[LPXPPHGLDQ4
DQG 4 )RU TXDOLWDWLYH YDULDEOHV WKH IUHTXHQF\ DQG SHUFHQWDJH RI VXEMHFWV DQGRU HYHQWV ZLOO EH
FDOFXODWHG$OOOLVWLQJVZLOOLQFOXGHWKHVXEMHFWLGHQWLILHUVWKHWUHDWPHQWJURXSFRKRUWWKDWWKHVXEMHFW
LV UDQGRPL]HG WR DQG WKH WDEOHV ZLOO EH SUHVHQWHG E\ WKH WUHDWPHQW FRKRUWV WR ZKLFK VXEMHFWV DUH
UDQGRPL]HG7KHFKDUDFWHULVWLFVWKDWZLOOEHDQDO\]HGDUHDVIROORZV


'HPRJUDSK\

$W VFUHHQLQJ GHPRJUDSKLF GDWD LQFOXGLQJ GDWH RI ELUWK DJH UDFH KHLJKW DQG ZHLJKW 7KH GDWH RI
ELUWK DJH KHLJKW ZHLJKW DQG %0, ZLOO EH OLVWHG LQ WKH GHPRJUDSK\ OLVWLQJ ,Q DGGLWLRQ WR WKLV WKH
LQIRUPDWLRQSHUWDLQLQJWRVXEMHFWEHLQJGLDEHWLFLQIRUPHGFRQVHQWDQGWKHDQDO\VLVSRSXODWLRQIODJZLOO
EHSUHVHQWHG
,QDGGLWLRQGHVFULSWLYHVWDWLVWLFVIRUUHOHYDQWYDULDEOHVZLOOEHSUHVHQWHGLQWDEXODUIRUPDW7KHDJH
DQG%0,ZLOOEHFDOFXODWHGDVPHQWLRQHGLQVHFWLRQRIWKLVGRFXPHQW$JHKHLJKWZHLJKWDQG%0,
ZLOOEHVXPPDUL]HGE\QXPEHURIVXEMHFWVQQXPEHURIPLVVLQJYDOXHVVXEMHFWVPHDQVWDQGDUG
GHYLDWLRQPLQLPXPPD[LPXPPHGLDQ4DQG4&DWHJRULFDOSDUDPHWHUVQDPHO\UDFHDQGVXEMHFW
EHLQJGLDEHWLFZLOOEHVXPPDUL]HGXVLQJFRXQWVDQGSHUFHQWDJHV7KHSHUFHQWDJHVZLOOEHFDOFXODWHG
EDVHGRQWKHQXPEHURIQRQPLVVLQJYDOXHV

 0HGLFDO+LVWRU\
0HGLFDO+LVWRU\WHUPVZLOOEHFRGHGXVLQJ0HG'5$YHUVLRQ$OLVWLQJZLOOEHFUHDWHGWRSUHVHQWWKH
PHGLFDO KLVWRU\ LQIRUPDWLRQ FROOHFWHG LQ WKH &5) $ WDEOH ZLOO EH FUHDWHG WR SUHVHQW WKH FRXQW DQG
SHUFHQWDJH RI VXEMHFWV ZLWK PHGLFDO FRQGLWLRQV IDOOLQJ XQGHU HDFK ERG\ V\VWHP DQG SUHIHUUHG WHUP
ZLWKLQHDFKERG\V\VWHP



67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
 3K\VLFDOH[DPLQDWLRQ
$FRPSOHWHUHYLHZRIERG\V\VWHPVZLOOEHSHUIRUPHGDWDOOYLVLWVDVSDUWRISK\VLFDOH[DPLQDWLRQ7KH
QXPEHUDQGSHUFHQWDJHRIVXEMHFWVKDYLQJQRUPDODEQRUPDORUQRWGRQHUHVSRQVHVDJDLQVWHDFKERG\
V\VWHP DW VFUHHQLQJ DQG SRVWGRVH YLVLWV  ZHHN    ZLOO EH WDEXODWHG  7KH FRUUHVSRQGLQJ
OLVWLQJZLOOSUHVHQWWKHERG\V\VWHPUHVSRQVHVDQGGHWDLOVRIDEQRUPDOLWLHVLIDSSOLFDEOH

 3K\VLFDO([DPLQDWLRQRI3HQLV

3K\VLFDOH[DPLQDWLRQRIWKHSHQLVZLOOEHGRQHDWDOOYLVLWVDQGZLOOLQFOXGHLQVSHFWLRQSDOSDWLRQDQG
QHXURVHQVRU\ WHVWLQJ 7KH SHUFHQWDJH RI VXEMHFWV KDYLQJ QRUPDO DEQRUPDO RU QRW GRQH UHVSRQVHV
DJDLQVW HDFK SDUDPHWHU ZLOO EH WDEXODWHG 7KH FRUUHVSRQGLQJ OLVWLQJ ZLOO SUHVHQW WKH SDUDPHWHU
UHVSRQVHVDQGGHWDLOVRIDEQRUPDOLWLHVLIDSSOLFDEOH

 (OHFWURFDUGLRJUDPV
$OHDG(&*ZLOOEHSHUIRUPHGDWVFUHHQLQJDQGSRVWGRVHYLVLWVZHHN7KHGHVFULSWLYH
VWDWLVWLFVIRUWKHIROORZLQJSDUDPHWHUVZLOOEHSUHVHQWHGKHDUWUDWH35LQWHUYDO47LQWHUYDO47F456
GXUDWLRQ456D[LV47F)47F%DQG55GXUDWLRQ7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVXQGHUHDFK
FDWHJRUL]DWLRQRIUK\WKPDQGRYHUDOOHYDOXDWLRQZLOOEHIXUWKHUSUHVHQWHG7KHFRUUHVSRQGLQJOLVWLQJZLOO
LQFOXGHWKHUHVXOWVDJDLQVWDERYHSDUDPHWHUVVLJQLILFDQFHGHWDLOVRIFOLQLFDOO\VLJQLILFDQWUHVXOWVDQG
GLIIHUHQFHV IURP SUHYLRXV DVVHVVPHQW %RWK WKH (&* RYHUUHDGHU¶V UHDGLQJ DQG VLWH UHDGLQJV ZLOO EH
HYDOXDWHG6KLIWWDEOHVZLOODOVREHSUHVHQWHGIRUWKHUHOHYDQWSDUDPHWHUV

 9LWDO6LJQV
9LWDOVLJQVZLOOEHFROOHFWHGDWDOOYLVLWV9LWDOVLJQVZLOOLQFOXGH

R
%UDFKLDOEORRGSUHVVXUH%3
R
3XOVHUDWH
R
2UDOWHPSHUDWXUH
R
:HLJKW

'HVFULSWLYHVWDWLVWLFVZLOOEHSUHVHQWHGIRUDOOWKHDERYHSDUDPHWHUVDWDOOWKHWLPHSRLQWVRIFROOHFWLRQ
ZLWKUHVSHFWWRWKHWUHDWPHQWFRKRUWV7KHFRUUHVSRQGLQJOLVWLQJZLOOSUHVHQWWKHUHVXOWV

 3ULRUDQG&RQFRPLWDQW0HGLFDWLRQ

3ULRUDQGFRQFRPLWDQWPHGLFDWLRQVZLOOEHOLVWHGDQGWDEXODWHG/LVWLQJVZLOOSUHVHQWWKHLQIRUPDWLRQ
FROOHFWHGDJDLQVWWKHVHWHUPVDQGDIODJWRLGHQWLI\SULRUDQGFRQFRPLWDQWPHGLFDWLRQV6HSDUDWHWDEOHV
ZLOO EH JHQHUDWHG WR SUHVHQW WKH FRXQWV DQG SHUFHQWDJHV RI VXEMHFWV ZLWK SULRU DQG FRQFRPLWDQW
PHGLFDWLRQV IDOOLQJ LQ HDFK WKHUDSHXWLF FODVV DQG FKHPLFDO VXEJURXS REWDLQHG DV SDUW RI :+2''
FRGLQJ

 ,QFOXVLRQ([FOXVLRQFULWHULD
7KHLQIRUPDWLRQSHUWDLQLQJWRWKHLQFOXVLRQDQGH[FOXVLRQFULWHULDZLOOEHOLVWHG
 &RPSOLDQFHWRVWXG\PHGLFDWLRQ
7KHVXEMHFWVDUHSODQQHGWREHDVVLJQHGWRRQHRIWKHEHORZWUHDWPHQWFRKRUWV

R
&RKRUW  K0D[L. FRPSULVLQJ RI WZR WUHDWPHQW JURXSV K0D[L. ǋJ DQG K0D[L.
ǋJ

R
&RKRUW3ODFHERZKLFKZDVDGPLQLVWUDWLRQRI3%6VXFURVH



67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
&RPSOLDQFH WR VWXG\ PHGLFDWLRQ ZLOO EH VXPPDUL]HG DQG OLVWHG 7KH VXPPDU\ WDEOH ZLOO LQFOXGH WKH
QXPEHUDQGSHUFHQWDJHRIVXEMHFWVUDQGRPL]HGWRWKHWZRWUHDWPHQWFRKRUWV)XUWKHUFDWHJRUL]DWLRQ
RQWKHWUHDWPHQWVDGPLQLVWHUHGZLWKLQHDFKFRKRUWZLOOEHSURYLGHG,WZLOODOVRLQFOXGHWKHQXPEHU
DQG SHUFHQWDJH RI VXEMHFWV ZKR ZHUH DGPLQLVWHUHG WUHDWPHQW 7KH OLVWLQJ ZLOO LQFOXGH WKH GHWDLOV
SHUWDLQLQJWRWUHDWPHQWFRKRUWWUHDWPHQWUDQGRPL]DWLRQQXPEHUGDWHRIDGPLQLVWUDWLRQDQGZKHWKHU
WUHDWPHQWZDVDGPLQLVWHUHG

 5DQGRPL]DWLRQ
7KHGDWDSHUWDLQLQJWRWKHWUHDWPHQWWRZKLFKVXEMHFWKDVEHHQUDQGRPL]DWLRQZLOOEHOLVWHG
 3URWRFRO'HYLDWLRQV
/LVWRISURWRFROGHYLDWLRQVZLOOEHSURYLGHGE\WKH&52DQGWKLVZLOOEHFODVVLILHGLQWRPLQRURUPDMRU
EDVHGRQLQSXWVIURPWKHVSRQVRU7KHVXEMHFWVUHSRUWLQJSURWRFROGHYLDWLRQVZLOOEHOLVWHGDORQJZLWK
WKHGHYLDWLRQDQGLWVFODVVLILFDWLRQ
 6WXG\7HUPLQDWLRQ
7KHVWXG\FRPSOHWLRQOLVWLQJZLOOEHGHYHORSHGEDVHGRQWKHGDWDREWDLQHGLQWKHVWXG\WHUPLQDWLRQ
IRUP  7KH OLVWLQJ ZLOO LQFOXGH WKH GDWH RI FRPSOHWLRQZLWKGUDZDO VWDWXV DW WKH HQG RI VWXG\ PDLQ
UHDVRQ IRU QRW FRPSOHWLQJ GDWH RI ODVW FRQWDFW DQG GDWH RI GHDWK LI DSSOLFDEOH $OO SDWLHQWV ZKR
SUHPDWXUHO\GLVFRQWLQXHGGXULQJWKHVWXG\ZLOOEHOLVWHGE\GLVFRQWLQXDWLRQUHDVRQIRUWKHUDQGRPL]HG
,773RSXODWLRQ
 6XEMHFW'LVSRVLWLRQ

$ WDEOH UHSUHVHQWLQJWKH FRXQWV DQG SHUFHQWDJHV RI VXEMHFWV DWWDLQLQJ WKH YDULRXV VWXG\ PLOHVWRQHV
QDPHO\HQUROPHQWUDQGRPL]DWLRQPHHWLQJDQDO\VLVSRSXODWLRQFULWHULDSURWRFROGHYLDWLRQVDQGVWXG\
FRPSOHWLRQRUZLWKGUDZDO ZLOOEHSUHVHQWHG7KHUHDVRQIRUGLVFRQWLQXDWLRQ ZLOODOVREHVXPPDUL]HG
ZLWKLQWKHWDEOH

 (IILFDF\HQGSRLQWV

7KH,QWHUQDWLRQDO,QGH[RI(UHFWLOH)XQFWLRQ,,()LVDYDOLGDWHGVHOIDGPLQLVWHUHGTXHVWLRQQDLUHWKDW
KDV EHHQ VKRZQ WR EH D FURVVFXOWXUDOO\ DQG SV\FKRPHWULFDOO\ YDOLG PHDVXUH RI PDOH HUHFWLOH
G\VIXQFWLRQ

7KHWHVWFRQWDLQVTXHVWLRQVLQILYHGRPDLQV

D HUHFWLOHGXUDWLRQIXQFWLRQVL[LWHPV
E RUJDVPLFIXQFWLRQWZRLWHPV
F VH[XDOGHVLUHWZRLWHPV
G LQWHUFRXUVHVDWLVIDFWLRQWKUHHLWHPV
H RYHUDOOVH[XDOVDWLVIDFWLRQWZRLWHPV

7KHVXPPDU\WDEOHVDJDLQVWWKHGDWDFROOHFWHGWKURXJKWKH,,()ZLOOLQFOXGHWKHGHVFULSWLYHVWDWLVWLFV
DJDLQVWWKHWRWDODQGGRPDLQVSHFLILFVFRUHE\YLVLW7KHGRPDLQVSHFLILFVFRUHVZLOOEHWKHVXPRIWKH
VFRUHVDJDLQVWTXHVWLRQVXQGHUWKHUHVSHFWLYHGRPDLQ7KHWRWDOVFRUHZLOOEHWKHVXPRIVFRUHVRIDOO
WKHTXHVWLRQV7KHOLVWLQJVZLOODOVREHSUHVHQWHGDJDLQVWDOOWKHGDWDWKDWLVFROOHFWHG

6(3 LV D GLDU\ LQ ZKLFK VXEMHFWV UHFRUG HDFK VH[XDO DWWHPSW PDGH WKURXJKRXW WKH VWXG\ DQG LV
FRPSRVHGRITXHVWLRQVDVVHVVLQJVH[XDOIXQFWLRQ6(3HYDOXDWHVWKHSHQHWUDELOLW\RIWKHHUHFWLRQ
DQG6(3WKHPDLQWHQDQFHRIWKHHUHFWLRQ

7KHVXPPDU\WDEOHVDJDLQVW6(3ZLOOLQFOXGHWKHQXPEHUDQGSHUFHQWDJHVRIVXEMHFWVUHSRUWLQJ\HVQR
DJDLQVWHDFKRIWKHTXHVWLRQV&RUUHVSRQGLQJOLVWLQJZLOODOVREHSUHVHQWHG


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
,Q DGGLWLRQ WR WKH VXPPDU\ WDEOHV WDEOHV ZLOO EH SUHVHQWHG DJDLQVW WKH DQDO\VLV PHQWLRQHG LQ WKH
EHORZVHFWLRQ

3ULPDU\$QDO\VLV
7KH SULPDU\ RXWFRPH PHDVXUHV WKDW ZLOO EH FRQVLGHUHG WR HYDOXDWH FKDQJH LQ HUHFWLOH VWDWXV IURP
EDVHOLQHIROORZLQJDGPLQLVWUDWLRQRIK0D[L.DUH

 (UHFWLOH)XQFWLRQ()GRPDLQRIWKH,QWHUQDWLRQDO,QGH[RI(UHFWLOH)XQFWLRQ,,()
 6H[XDO(QFRXQWHU3URILOH6(34XHVWLRQVDQG


(UHFWLOH)XQFWLRQ()GRPDLQRIWKH,QWHUQDWLRQDO,QGH[RI(UHFWLOH)XQFWLRQ,,()
7KHHUHFWLOHIXQFWLRQGRPDLQTXHVWLRQVDQGRIWKH,,()KDVEHHQYDOLGDWHGWRDVVHVVHUHFWLOH
FKDQJHV RQO\ 7KH ,,() () GRPDLQ KDV D SRLQW WRWDO VFRUH ZKHUH KLJKHU VFRUHV UHIOHFW EHWWHU
HUHFWLOHIXQFWLRQ7KH()GRPDLQRIWKH,,()ZLOOEHFRPSOHWHGDW9LVLWVFUHHQLQJDQG99ZHHN


7KH WRWDO VFRUH IRU D VXEMHFW IRU WKH () GRPDLQ ZLOO EH FRPSXWHG DV WKH VXP RI WKH VL[ TXHVWLRQV
'HVFULSWLYH VWDWLVWLFV RI WKH GRPDLQ VFRUH ZLOO EH SUHVHQWHG ZLWK UHVSHFW WR WKH VXEMHFWV UHFHLYLQJ
K0D[L.ǋJDQGSODFHERDWDOOYLVLWV7KHFKDQJHLQVFRUHVIURPEDVHOLQHDWHDFKYLVLWZLOOEH
HYDOXDWHGXVLQJRQHVLGHGSDLUHGWWHVWDWVLJQLILFDQFHOHYHOWRDVVHVVLPSURYHPHQWLQVFRUHVSRVW
WUHDWPHQWZKHQFRPSDUHGWREDVHOLQHIRUWKHWZRWUHDWPHQWJURXSVVHSDUDWHO\)XUWKHUDRQHVLGHG
WZRVDPSOHWWHVWZLOOEHDSSOLHGWRFRPSDUHWKHFKDQJHVIURPEDVHOLQHLQVFRUHVEHWZHHQWKHWZR
WUHDWPHQWJURXSV7KHVFRUHVIRUWKHRWKHUGRPDLQVRQWKH,,()ZLOODOVREHFRPSXWHGDQGDQDO\]HG
DVVHFRQGDU\DQDO\VHV

5HSHDWHGPHDVXUHV$129$ZLOOEHSHUIRUPHGWRDVVHVVWKHHIIHFWRIYLVLWRQWKHWRWDOVFRUHIRUHDFK
WUHDWPHQW JURXSV )XUWKHU D WZRVDPSOH W WHVW ZLOO EH SHUIRUPHG WR VWXG\ WKH HIIHFW RI WUHDWPHQW
JURXSVDQGWLPHSRLQWVRQWKHGRPDLQVFRUHV

7KHDERYHDQDO\VLVZLOOEHUHSHDWHGIRUFRPSDULVRQEHWZHHQWKHWZRWUHDWPHQWFRKRUWVDQGEHWZHHQ
K0D[L.ǋJDQGSODFHERWUHDWPHQWJURXSV

$QDO\VLVZLOOEHSHUIRUPHGLQFOXGLQJDOOVXEMHFWVDQGWKHILQDOVXEMHFWVVHSDUDWHO\


6H[XDO(QFRXQWHU3URILOH6(34XHVWLRQVDQG
7KH WZR TXHVWLRQV IURP WKH 6H[XDO (QFRXQWHU 3URILOH 6(3 GHDO ZLWK WKH DELOLW\ WR DFKLHYH YDJLQDO
SHQHWUDWLRQ 6(3 DQG WKH DELOLW\ WR PDLQWDLQ DQ HUHFWLRQ ORQJ HQRXJK IRU VXFFHVVIXO LQWHUFRXUVH
6(3ZLOOEHDQDO\]HGDVSDUWRIWKLVVWXG\7KLVTXHVWLRQQDLUHZLOOEHFRPSOHWHGDW99ZHHN


&KLVTXDUHDQDO\VLVZLOOEHSHUIRUPHGWRFRPSDUHWKHUHVSRQVHVDWHDFKSRVWGRVHYLVLWZLWKEDVHOLQH
UHVSRQVH IRU WKH WZR WUHDWPHQW JURXSV QDPHO\ K0D[L.  ǋJ DQG SODFHER ,Q DGGLWLRQ
UHSHDWHGPHDVXUHVORJLVWLFUHJUHVVLRQZLOOEHSHUIRUPHGWRDQDO\]HWKHHIIHFWRIWUHDWPHQWJURXSVDQG
WLPHSRLQWVRQWKHUHVSRQVHWRWKH6(3TXHVWLRQV7KHEDVHOLQHDQGSRVWEDVHOLQHVFRUHIRUHDFK6(3
TXHVWLRQ ZLOO EH D SDWLHQW
V SHUFHQWDJHRI \HV UHVSRQVHV WRWKDW TXHVWLRQ GXULQJ WKH EDVHOLQH DQG
SRVWEDVHOLQHSHULRGUHVSHFWLYHO\

$1&29$ ZLOO EH XVHG WR DQDO\]H WKH PHDQ FKDQJH LQ 6(3 UHVSRQVH IURP EDVHOLQH WR SRVW EDVHOLQH
YLVLWVEHWZHHQK0D[L.ǋJDQGSODFHER

7KHDERYHDQDO\VLVZLOOEHUHSHDWHGIRUFRPSDULVRQEHWZHHQWKHWZRWUHDWPHQWFRKRUWVDQGEHWZHHQ
K0D[L.ǋJDQGSODFHERWUHDWPHQWJURXSV



67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&

6DIHW\DQGRUIXUWKHUDQDO\VLV
7KHEHORZSDUDPHWHUVZLOOEHDQDO\]HGDJDLQVWWKHVDIHW\SRSXODWLRQDVSDUWRIWKHVDIHW\DQDO\VLV

 $GYHUVHHYHQWV
 6HULRXV$GYHUVH(YHQWV
 &OLQLFDOODERUDWRU\WHVWV
 (OHFWURFDUGLRJUDP
 3K\VLFDOH[DPLQDWLRQVDQG9LWDOVLJQV
 3KDUPDFRNLQHWLFV(YDOXDWLRQV$VVD\VIRUKVOR0D[L.


$GYHUVH(YHQWV

$OOWKHDGYHUVHHYHQWVZLOOEHFRGHGXVLQJWKH0HG'5$9HUVLRQ$OOWKHLQIRUPDWLRQFROOHFWHGLQ
WKH $( IRUP LQ WKH &5) DQG WKH SUHIHUUHG WHUP DQG V\VWHP RUJDQ FODVV FRUUHVSRQGLQJ WR HDFK
UHSRUWHGWHUPZLOOEHSUHVHQWHGDVDOLVWLQJ,QDGGLWLRQWRWKLV6$(VZLOOEHSUHVHQWHGDVDVHSDUDWH
OLVWLQJ

$Q RYHUDOO VXPPDU\ WDEOH IRU WKH DGYHUVH HYHQWV ZLOO EH SUHVHQWHG $OO 7($(V UHFRUGHG GXULQJ WKH
VWXG\ ZLOO EH IXUWKHU VXPPDUL]HG LQ GHWDLO 7KH LQFLGHQFH RI DGYHUVH HYHQWV ZLOO EH VXPPDUL]HG E\
V\VWHPRUJDQFODVVDQGSUHIHUUHGWHUPZLWKLQV\VWHPRUJDQFODVVRYHUDOODQGE\VHYHULW\UHODWLRQVKLS
RXWFRPHDFWLRQWDNHQVHSDUDWHO\DQG'/7

6XPPDU\WDEOHVFRUUHVSRQGLQJWRWKH$(VZLOOFRQWDLQWKHLQFLGHQFHRIHYHQWVDQGWKHQXPEHUDQG
SHUFHQWDJHRIVXEMHFWVH[SHULHQFLQJDQDGYHUVHHYHQW7KHSHUFHQWDJHVZLOOEHFDOFXODWHGZLWKUHVSHFW
WR WKH WRWDO QXPEHU RI VXEMHFWV LQ WKH VDIHW\ SRSXODWLRQ :KLOH FRXQWLQJ WKH QXPEHU RI VXEMHFWV D
VXEMHFWZLWKPRUHWKDQRQHDGYHUVHHYHQWZLWKWKHVDPHSUHIHUUHGWHUPZLOOEHFRXQWHGRQO\RQFH
XVLQJ WKH LQFLGHQFH ZLWK KLJKHVW VHYHULW\ VHYHULW\ DFWLRQ WDNHQ DQG '/7 WDEOHV RU VWURQJHVW
UHODWLRQVKLSWRVWXG\WUHDWPHQWDQGPRVWVHYHUHRXWFRPHIRUWKHUHVSHFWLYHWDEOHV7KHGHVFHQGLQJ
RUGHURIWKHDERYHFKDUDFWHULVWLFVZLOOEHFRQVLGHUHGDVEHORZ

x
6HYHULW\ 7R[LFLW\JUDGH

R6HYHUH
R0RGHUDWH
R0LOG

x
5HODWLRQVKLS

R'HILQLWHO\5HODWHG
R3UREDEOH
R3RVVLEOH
R8QUHODWHG

x
2XWFRPH

R&RQGLWLRQ'HWHULRUDWHG
R6WLOO3UHVHQW
R,PSURYLQJ
R5HFRYHUHGZLWK6HTXHOD
R5HFRYHUHG
R2WKHU

6HULRXV$(DUHGHILQHGDVWKHIROORZLQJ

R 0HGLFDOO\VLJQLILFDQWHYHQWVHJLQWHQVLYHWUHDWPHQWLQ(5RUDWKRPHIRUDOOHUJLF
EURQFKRVSDVP


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
R OLIHWKUHDWHQLQJ
R UHTXLULQJKRVSLWDOL]DWLRQ
R UHVXOWLQJLQGHDWK
R UHVXOWLQJLQDGLVDELOLW\
R UHVXOWLQJLQDFRQJHQLWDODEQRUPDOLW\

6LPLODUWDEOHVZLOOEHSUHVHQWHGIRUVHULRXVDGYHUVHHYHQWV'HDWKVZLOOEHUHSRUWHGDV$(WHUPLQWKH
&5)'HDWKVDQGRWKHUVHULRXVDGYHUVHHYHQWVZLOOEHOLVWHG

 &OLQLFDOODERUDWRU\WHVWV
7KH IROORZLQJ ODERUDWRU\ WHVWV ZLOO EH SHUIRUPHG DW GLIIHUHQW YLVLWV DV LQGLFDWHG LQ WKH IORZ FKDUW LQ
VHFWLRQDERYH
R
+HPDWRORJ\LQFOXGLQJFRPSOHWHEORRGFRXQW&%&ZLWKGLIIHUHQWLDO
R
&KHPLVWU\
R
8ULQH$QDO\VLV
R
(QGRFULQH7HVWV

$OOUHVXOWVFRUUHVSRQGLQJWRODERUDWRU\HYDOXDWLRQVZLOOEHSUHVHQWHGLQ,8XQLWV7KHODERUDWRU\UHVXOWV
ZLOOEHOLVWHGE\WUHDWPHQWFRKRUWVVXEMHFWDQGYLVLW$EQRUPDOUHVXOWVZLOOEHIODJJHGDV+RU/EDVHG
RQYDOXHVEHLQJDERYHRUEHORZWKHQRUPDOUDQJHUHVSHFWLYHO\9DOXHVZLWKLQWKHQRUPDOUDQJHVZLOOEH
IODJJHGDV1

7KHIUHTXHQF\RIQXPEHURILQFLGHQFHVRIODERUDWRU\DEQRUPDOLWLHVZLOOEHGLVSOD\HGE\SDUDPHWHUDQG
WUHDWPHQWFRKRUWZLWKUHVSHFWWRWKHFODVVLILFDWLRQRIYDOXHVEDVHGRQWKHQRUPDOUDQJH'HVFULSWLYH
VWDWLVWLFVZLOOEHSUHVHQWHGIRUODERUDWRU\UHVXOWVZLWKUHVSHFWWRWUHDWPHQWFRKRUWDQGYLVLW)XUWKHU
WKHFKDQJHIURPEDVHOLQHDWHDFKSRVWGRVHYLVLWZLOOEHSUHVHQWHGGHVFULSWLYHO\LQDFFRUGDQFHWRWKH
SODQ RI GDWD FROOHFWLRQ  'HVFULSWLYH VWDWLVWLFV IRU WKH FKDQJH IURP EDVHOLQH WR WKH ODVW DYDLODEOH RQ
WUHDWPHQW YLVLW ZLOO DOVR EH SUHVHQWHG 6KLIW WDEOHV ZLOO EH SUHVHQWHG IRU HDFK DQDO\WH WR DVVHVV WKH
FKDQJHLQDEQRUPDOLWLHVRYHUYLVLWV

 (OHFWURFDUGLRJUDP

$VSDUWRIWKHDQDO\VLVIRUWKLVVDIHW\HQGSRLQWLQDGGLWLRQWRWKHDQDO\VLVVXJJHVWHGLQVHFWLRQ
DERYHFKDQJHVIURPEDVHOLQHDWHDFKSRVWGRVHYLVLWZLOOEHSUHVHQWHG1XPEHUDQGSHUFHQWDJHRI
VXEMHFWVUHSRUWLQJDEQRUPDOLWLHVZLOOIXUWKHUEHWDEXODWHGZLWKUHVSHFWWRWUHDWPHQWFRKRUWDQGYLVLWV
IRUERWKWKHRYHUUHDGHUDQGVLWHHYDOXDWLRQV6KLIWWDEOHVZLOODOVREHSUHVHQWHGWRVWXG\WKHFKDQJHLQ
DEQRUPDOLWLHVRYHUWKHYLVLWV

 3K\VLFDOH[DPLQDWLRQVDQGYLWDOVLJQV
,QDGGLWLRQWRWKHDQDO\VLVPHQWLRQHGLQVHFWLRQWKHGHVFULSWLYHVWDWLVWLFVIRUFKDQJHIURPEDVHOLQH
DWSRVWGRVHYLVLWVZLOOEHSUHVHQWHGIRUWKHEHORZSDUDPHWHUV
x
+HDUWUDWH
x
%ORRGSUHVVXUH
x
:HLJKW
x
2UDO7HPSHUDWXUH
)XUWKHU WKH QXPEHU DQG SHUFHQWDJH RI VXEMHFWV UHSRUWLQJ DEQRUPDOLWLHV IRU DERYH SDUDPHWHUV DQG
GXULQJSK\VLFDOH[DPLQDWLRQRIWKHSHQLVZLOOEHWDEXODWHGZLWKUHVSHFWWRWUHDWPHQWFRKRUWDQGYLVLWV


3KDUPDFRNLQHWLFV(YDOXDWLRQV


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
$W9±9SODVPDVSHFLPHQVZLOOEHFROOHFWHGWRDVVD\IRUWKHSUHVHQFHRIK6OR'1$E\3&57KLV
GDWDZLOOEHOLVWHGDQGSUHVHQWHGGHVFULSWLYHO\1R3.DQDO\VLVZLOOEHSHUIRUPHG

/LVWLQJV7DEOHVDQG)LJXUHV


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&


67$7,67,&$/$1$/<6,63/$1
,21('
&13+,21('67$76$3
9HUVLRQ
3DJHRI
'(&
6RIWZDUH
6$69HUVLRQRUKLJKHUZLOOEHXVHGIRUDOOGDWDDQDO\VLV

5HIHUHQFH
x
)LQDO.XZDLWSURWRFRO$'RXEOHEOLQG3ODFHERFRQWUROOHG3DUDOOHO'HVLJQ
5DQGRPL]HG3KDVH$&OLQLFDO7ULDO(YDOXDWLQJWKH3RWHQWLDO$FWLYLW\DQG6DIHW\RIK0D[L.
*HQH7UDQVIHULQ0DOHVZLWK(UHFWLOH'\VIXQFWLRQ
x
)LQDO,21SURWRFRO0DUYHUVLRQSGI