Phase 1 Double Blind, Placebo Controlled Study Assessing Safety and Activity Of 2 Escalating Doses of hMaxi-K Gene Transfer By Direct Injection Into the Bladder Wall In Female Subjects With OAB
Phase: PHASE1
Conditions: Overactive Bladder
Sponsor: Urovant Sciences GmbH

Ion Channel Innovations 
Protocol I0N 03 –OAB 
Amendment 5: October 1, 2015 
1 
 
 
 
 
 
 
 
A Phase 1 Multicenter Study Evaluating the 
Safety and Potential Activity Of Two Escalating 
Doses of hMaxi-K Gene Transfer By Direct 
Injection into the Bladder Wall In Female 
Participants With Idiopathic (Non-neurogenic) 
Overactive Bladder Syndrome and Detrusor 
Overactivity: Double Blind, Imbalanced Placebo 
Controlled Design Within 2 Sequential Active 
Treatment Groups 
 
Protocol No. ION 03 – OAB 
IND No: 13208 
 
 
 
 
Sponsor 
Ion Channel Innovations, LLC 
969 Park Ave., 1G 
New York, NY 10028 
Tel: 212-639-1561 
 
 
 
July 30, 2012 
Amendment 1-February 5,  2013 
Amendment 2- July 29, 2013 
Amendment 3- December 7,  2013 
Amendment 4 – October 8,  2014 
Amendment 5- October 1,  2015 

Ion Channel Innovations 
Protocol I0N 03 –OAB 
Amendment 5: October 1, 2015 
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A Phase 1 Multicenter Study Evaluating the Safety and Potential Activity Of Two Escalating 
Doses of hMaxi-K Gene Transfer By Direct Injection into the Bladder Wall In Female 
Participants With Idiopathic (Non-neurogenic) Overactive Bladder Syndrome and Detrusor 
Overactivity: Double Blind, Imbalanced Placebo Controlled Design Within 2 Sequential Active 
Treatment Groups 
Protocol ION 03-OAB 
 
 
 
 
Sponsor Representative 
Arnold Melman, MD 
Directing Member 
Ion Channel Innovations 
 
Signature:   
 
Date: October 1, 2015 
Principal Investigator 
I agree to perform this study in accordance with the 
protocol and Good Clinical Practice (GCP)  Guidelines. 
Signature:    
 
Date:    
 

Ion Channel Innovations 
Protocol I0N 03 –OAB 
Amendment 5: October 1, 2015 
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Table of Contents 
Table of Contents .................................................................................................................................3 
List of Figures ......................................................................................................................................5 
List of Tables ........................................................................................................................................5 
List of Abbreviations ...........................................................................................................................6 
Protocol Synopsis .................................................................................................................................8 
1.0 
Introduction ..............................................................................................................................13 
1.1 
Overview ............................................................................................................................13 
1.2 Preclinical Data on Urinary Incontinence and pVAX/hSlo...................................................15 
1.3 Preclinical Toxicology of pVAX/hSlo following Intravesical Administration .....................22 
1.4 
Clinical Data .......................................................................................................................24 
2.0 
3.0 
1.4. 1 Erectile Dysfunction ...........................................................................................................24 
1.4. 2 Overactive Bladder .............................................................................................................26 
Objectives ..................................................................................................................................28 
Study Design .............................................................................................................................28 
3.1 
Duration of study participation ...........................................................................................29 
4.0 
Study Population ......................................................................................................................29 
4.1 
Inclusion Criteria ................................................................................................................29 
4.2 
Exclusion criteria ................................................................................................................30 
5.0 
Test Material and Administration ..........................................................................................32 
5.1 
Study Medication ...............................................................................................................32 
5.2 
Dose Selection and Administration ....................................................................................34 
5.2.1 
Stopping Rules ...........................................................................................................36 
5.2.2 
Dose Escalation ..........................................................................................................36 
5.3 
Randomization and description of blinding methods .........................................................37 
5.3.1 Assigning participants to treatment group ........................................................................37 
5.3.2 
Packaging and labeling ...............................................................................................38 
5.4 
Concomitant Medications/Therapies ..................................................................................38 
6.0 
Outcome Assessments and Procedures ..................................................................................38 
6.1 
OAB / DO Objective Assessment: Cystometry .................................................................38 
6.2 
Clinical Evaluation of OAB / DO ......................................................................................41 
6.2.1 Voiding Diary .................................................................................................................41 
6.2.2 
Pad Test ......................................................................................................................41 
6.2.3 King Health Questionnaire and Assessment of Disease State/Treatment ......................42 
6.2.4 International Consultation on Incontinence Questionnaire-Short From ........................42 
6.2. 5 
SF-12 ..........................................................................................................................42 
6.3 
Bladder Scan .......................................................................................................................42 
6.4 
Physical Evaluation ............................................................................................................42 

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Amendment 5: October 1, 2015 
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6.4.1 
Physical Examination .................................................................................................42 
6.4.2 
ECG ............................................................................................................................43 
6.4.3 
Vital Signs ..................................................................................................................43 
6.5 
Laboratory Safety Tests ......................................................................................................43 
6.6 
Concomitant Medication ....................................................................................................44 
6.7 
Pharmacokinetics ................................................................................................................44 
6.8 
Laboratory Evaluations ......................................................................................................44 
7.0 
Schedule of Evaluations ...........................................................................................................47 
7.1 
Visit 1 (Study Week - 2: Screening) ..................................................................................47 
7.2 
Visit 1A (Study Day - 14 to -8): Screening Cystometry ....................................................48 
7.3 
Visit 2 (Study Week 0: Baseline - Administration of study drug) .....................................49 
7.4 
1-Day and 3-Day Post Visit 2 Telephone Contact .............................................................51 
7.5 
Visit 3 (Study Week 1 +2 days) .........................................................................................51 
7.6 
Visit 4 (Study Week 2 +2 days) .........................................................................................52 
7.7 
Visit 5 (Study Week 4) .......................................................................................................52 
7.8 
Visit 6 (Study Week 8) .......................................................................................................53 
7.9 
Visit 7 (Study Week 12) .....................................................................................................54 
7.10 Visit 8 (Study Week 24) or Exit Visit: ..............................................................................55 
7.11 Visit schedule and Visit Windows .....................................................................................55 
7.12 Definition of source data ....................................................................................................56 
7.13 Access to the randomization code during the study ...........................................................56 
7.14 Long-term follow-up ..........................................................................................................57 
8.0   Participant Withdrawal ............................................................................................................57 
8.1 
List of withdrawal criteria ..................................................................................................57 
8.2 
Reasons for withdrawal ......................................................................................................58 
8.3 
Replacement of participants ...............................................................................................58 
8.4 
Withdrawal follow-up procedure .......................................................................................58 
9.0 
Adverse Events Definitions and Monitoring ..........................................................................59 
9.1 
Adverse Event ....................................................................................................................59 
9.2 
Serious Adverse Event .......................................................................................................59 
9.3 
Assessment of Causality .....................................................................................................59 
9.4 
Severity of Adverse Event ..................................................................................................60 
9.5 
Monitoring of Adverse Events ...........................................................................................60 
10.0 
 
 
 
 
11.0 
 
 
 
12.0 
Assessment of Endpoints .........................................................................................................62 
10.1 Safety .................................................................................................................................62 
10.2 Efficacy ..............................................................................................................................62 
10.3 Analysis of Endpoints ........................................................................................................63 
Monitoring of Participant Safety ............................................................................................63 
11.1 Informed Consent ...............................................................................................................63 
11.2 Data Safety Monitoring Board (DSMB) .............................................................................63 
Regulatory Standards ..............................................................................................................64 
12.1 Electronic case report forms ..............................................................................................64 

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12.2 Clinical and Regulatory Monitoring ...................................................................................64 
12.2.1 
Study Conduct (Site) ...............................................................................................64 
12.2.2 Adherence to Reporting Requirements ........................................................................65 
12.3 Participant Confidentiality..................................................................................................65 
12.4 Records ..............................................................................................................................66 
13.0 References ..................................................................................................................................67 
APPENDIX A  Grading of Adverse Events ....................................................................................70 
APPENDIX B.  King’s Health Questionnaire .................................................................................72 
APPENDIX C. Participant Assessment of Disease and Response to Treatment ........................76 
APPENDIX D. Cystometry Procedure Guidance ..........................................................................77 
APPENDIX E. International Consultation on Incontinence Questionnaire: Short  Form ........80 
APPENDIX F. Participant Daily Diary ...........................................................................................81 
APPENDIX G. Components and Guidelines for Health Status Questionnaire  (SF-12) ............82 
 
List of Figures 
Figure 1. Maxi-K channel effect on smooth  muscle ....................................................................... 15 
Figure 2. Graphical depiction of the impact of 2 weeks of obstruction on the relevant micturition 
parameters in the two treatment groups, relative to the Sham-operated, Age-Matched 
Control rats. Panels A-D represent the data summarized in Table   3. ................................ 18 
Figure 3. Graphs A-C are representative examples of approximately 1 hour of cystometric 
recordings from distinct rats in each treatment group. ....................................................... 19 
Figure 4. Representative tracing of a cystometric recording in a rat given vector alone (pVAX), 
and 300 and 1000 µg of pVAX/hSLO.   Note the regular, periodic emptying and  the 
virtual absence of intermicturition pressure fluctuations in the treated animals.  ............... 20 
Figure 5.  Biodistribution Data ......................................................................................................... 24 
Figure 6.  Bladder Injection Sites ..................................................................................................... 50 
 
List of Tables 
Table 1.  Procedures By Visit ..........................................................................................................12 
Table 2. Summary of treatment effects on mean micturition parameters in 6 week obstructed 
female rats and sham-operated  controls ..............................................................................16 
Table  3.  Summary of treatment effects on mean micturition parameters in 2 week obstructed 
male rats and sham-operated controls.  ............................................................................... 17 
Table 4. Summary of treatment effects on mean micturition parameters in 2 week obstructed 
female rats  .......................................................................................................................... 21 
Table 5. Rabbit Intravesicular Injection Protocol............................................................................. 22 
Table 6. Final Dose-hMaxi-k ........................................................................................................... 33 
Table 8.  Procedure Flow Guidance on Cystometry Visit Days (and Cystoscopy) ......................... 40 
Table 9.  Blood collection (minimum amount of blood that should be taken) ................................ 45 
Table 10.  Summary of Laboratory Tests By Visit .......................................................................... 46 
Table 11;. Powering .......................................................................................................................... 62 

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Amendment 5: October 1, 2015 
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List of Abbreviations 
 
AE: adverse event 
LOCF: last observation carried  forward 
ALP: alkaline phosphatase 
Mg++: magnesium 
ALT: alanine aminotransferase  (SGPT) 
mg: milligram 
ANCOVA: analysis of covariance 
Min: minute 
ANOVA: analysis of variance 
mL: milliliter 
aPTT: activated partial thromboplastin  time µg: microgram 
ARF: acute renal failure 
µL: microliter 
AST: aspartate aminotransferase  (SGOT) 
Mm Hg: millimeters of mercury 
BMI: body mass index 
NIH: National Institutes of Health 
BP: blood pressure 
Mm or mmol: millimole 
BUN: Blood Urea Nitrogen 
µmol: micromole 
Ca++: Calcium 
mEq: milliEquivalents 
CBER: Center for Biologics Evaluation 
and Research 
Na+: sodium 
CBC: Complete blood count 
ng: nanogram 
CFR: Code of Federal  Regulations 
OAB: Overactive Bladder  Syndrome 
Cl: chloride 
OBA: Office of Biotechnical Activities,  NIH 
cm: centimeter 
OHSR: Office of Human Subject Research,  NIH 
CO2: Carbon Dioxide 
PT: Prothrombin time 
CRO: Clinical Research  Organization 
PTT: Partial thromboplastin  time 
CPK: creatine phosphokinase 
PUO: Partial Urethral  Obstruction 
E-CRF: electronic case report  form 
QoL: Quality of Life 
CRP: C- reactive protein 
QTcF: QTc Fridericia / QTcB: QTc  Bazett 
CSR: clinical study report 
RBC: red blood cell 
DBP: diastolic blood pressure 
SAE: serious adverse event 
DO or DH: Detrusor  overactivity 
SAP: statistical analysis plan 
dL: deciliters 
SBP: systolic blood pressure 
DLT: Dose limiting toxicity 
SD: standard deviation 
DRF: discrepancy resolution  form 
SF-12:  Health Status Questionnaire 

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List of Abbreviations 
 
DSMB: Data Safety Monitoring  Board 
SGOT: serum glutamic-oxaloacetic  transaminase 
ECG: electrocardiogram 
SGPT: serum glutamic-pyruvic  transaminase 
FDA: Food and Drug  Administration 
TEAE: treatment-emergent adverse  event 
FSH: Follicular stimulating  hormone 
ULN: upper limit of normal 
g: gram 
NOBLE: National Overactive BLadder  Evaluation 
GCP: good clinical practices 
UUI: urge urinary incontinence 
GeMCRIS: Genetic Modification Clinical 
Research Information System, NIH 
GGT:  gamma glutamyltransferase 
KHQ: King’s Health  Questionnaire 
K+: potassium 
LDH: lactate dehydrogenase 
LLN: lower limit of normal 
h: hour 
HR: heart rate 
hpf: high powered field 
ICH: International Conference on 
Harmonization 
ICIQ-SF: International Consultation on 
Incontinence Questionnaire- Short  Form) 
IEC: independent ethics  committee 
IRB: institutional review board 
ITT: intent-to-treat 
kg: kilogram 
L: liter 

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Protocol I0N 03 –OAB 
Amendment 5: October 1, 2015 
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Protocol Synopsis 
 
 
Title 
A Phase 1 Multicenter Study Evaluating the Safety and Potential Activity Of Two 
Escalating Doses of hMaxi-K Gene Transfer By Direct Injection into the Bladder 
Wall In Female Participants With Idiopathic (Non-neurogenic) Overactive Bladder 
Syndrome and Detrusor Overactivity: Double Blind, Imbalanced Placebo Controlled 
Design Within 2 Sequential Active Treatment  Groups 
Study No. 
ION 03-OAB 
Study Phase Phase 1 
No. of Sites Up to six clinical sites in USA 
Study 
Objectives 
The primary objective of this study is to evaluate occurrence of Adverse Events and 
their relationship to hMaxi-K following multiple intramuscular (IM) injections into 
the bladder wall.  Two dose levels (16000 µg and 24000 µg by IM injection into 
the bladder wall) in females with moderate OAB/DO of ≥ six months duration are 
initially planned. Pending safety and efficacy results for the 2 doses that are 
planned, the protocol may be amended to investigate additional doses in this 
study. 
The secondary objectives of this study are to evaluate the following safety 
parameters: 
• Clinical laboratory tests- changes from baseline 
• Electrocardiogram change from baseline 
• Physical Examination- changes from baseline 
These changes will be evaluated primarily at the individual level, through clinical 
assessment of outliers supported by descriptive  statistics. 
In addition efficacy parameters will be evaluated (change from baseline compared 
to placebo), including number of micturitions per day, volume per micturition, 
incontinence episodes, pad weight, uninhibited contractions during cystoscopy, and 
general and bladder specific quality of life  assessments. 
Study 
Design 
This study is a double blind, placebo-controlled, multicenter, sequential   active 
dose, phase 1 study in females with moderate OAB/DO of ≥ six months duration. 
The proposed study period is approximately 6 months following a single 
administration of study drug by multiple IM injections into the bladder wall per 
participant.  The protocol sample size of this phase I study is not intended   to 
support the statistical significance of the primary endpoint as outlined in the study 
objectives. Rather, the sample size takes into account clinical safety considerations. 
Nine participants per dose level are planned: [6 assigned active treatment and 3 
assigned placebo (PBS-20% sucrose only control group)]. Therefore a total of up to 
9 participants will be enrolled in each dose group. Each arm of participants will be 
enrolled sequentially and enrollment into the next higher dose level will be  
dependent on assessment of safety. The participants chosen will be assigned in   a 

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randomized fashion to either placebo or an active treatment group within each 
group. 
 
Study 
Population 
The study population is women ≥ 18 years old of non-child bearing potential1 with 
overactive bladder (OAB) and detrusor overactivity who are otherwise in good 
health. 
The target population is women with idiopathic (non-neurogenic) OAB   and 
detrusor overactivity (DO) who have been unable to tolerate, do not wish to 
continue, or have had unsuccessful results with, prior therapy for OAB/DO. OAB is 
characterized by a decreased bladder capacity, frequent voiding,    frequent  
sensations of a strong urge to void, and in some patients, episodes of incontinence. 
DO is one or more uncontrolled phasic contraction(s) of the detrusor of at least 5 
cm/H20 pressure that are observed during urodynamic testing with or without  
urinary leakage. 
Inclusion criteria will include clinical symptoms of overactive bladder of  ≥  6 
months duration including at least one of the  following: 
a. Frequent micturition (≥ 8/24hrs) 
b. Symptoms of urinary urgency (the complaint of sudden compelling 
desire to pass urine, which is difficult to defer) or nocturia (the 
complaint of waking at night two or more times to void) 
c. Urge urinary incontinence (average of 5 per week – Urge urinary 
incontinence is defined as: the complaint of involuntary leakage 
accompanied by or immediately preceded by urgency) 
Participants must also have a bladder scan at screening demonstrating a residual 
volume of ≤ 200 ml and detrusor overactivity documented during baseline 
urodynamic testing of ≥1 uncontrolled contraction(s) of the detrusor of at least 5 
cm/ H20. 
1 All female participants must be of non-childbearing potential (e.g., hysterectomy, tubal ligation or post 
menopausal defined as last menstrual cycle >12 months prior to study enrollment, or serum FSH >40 mIU/L). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study 
Procedures 
There will be a total of 9 visits (V) and a 1 and 3 day post dosing telephone 
contact with the patient to evaluate for any new complaints. Following screening 
(V1, V1A) and study drug administration at week 0 (V2), eligible participants 
will be evaluated for safety post dosing with study drug at weeks 1 (V3), 2 (V4), 
4 (V5), 8 (V6), 12 (V7), and 24  (V8). 
At Screening (V1), Baseline (prior to dosing) and 1 (V3), 2 (V4), 4 (V5), 8 (V6), 
12 (V7) and 24 (V8) weeks post dosing participants will have a   complete 
physical exam including urogenital examination. (ECG) will be performed at 
Screening (V1), at Baseline (V2 prior to dosing and at 2 hours post dosing), at 
one week post dosing (V3), 4 weeks post dosing (V5),  and at the final visit   (V8). 
Laboratory evaluations including chemistry, hematology, and urinalysis will be 
performed at Screening (Week -2 (V1), Baseline (prior to dosing; V2) and  Weeks 
1 (V3), 2(V4), 4 (V5), 12 (V7) and 24 (V8) weeks post dosing. At Baseline (V2) 
no chemistries required.  At V1A and prior to dosing at V2, urinalysis will be 
done by Dipstick. No chemistry or hematology required at V1A. No chemistry, 
hematology, urinalysis or urine culture required at V6. Urine cultures will   be 
done at V1 (by catheterization with a urodynamic catheter), at V3 (clean void), at 
V1A, V2, V5 and V8 prior to cystometry or cystoscopy (by catheterization with 
the urodynamic catheter) and before discharge by clean void to insure    the 
absence of infection (at V2 it will be the first clean voided urine after study drug 
dosing). 
At Screening (V1) and at 2 (V4), 8 (V6), and 24 (V8) weeks post dosing 
participants will have a bladder scan to evaluate for residual volume. Participants 
will be assessed for study drug effects on incontinence at Screening (V1A),   and 
at Week 4 (V5) and Week 24 (V8) by cystometry. Participants will complete a 
daily diary at home for 7 days prior to the baseline (prior to V2). Prior to V1A 
they should complete diaries as well which may be less than 7 days, but can be 
used to evaluate for compliance and inclusion criteria such as   incontinence. 
Diaries will capture number of micturitions, volume of micturitions, number of 
urge incontinence episodes, and rating of episode, and the number of pads used 
every 72 hours. The participants will continue to complete this daily diary during 
the course of the trial and the diary will be evaluated at each follow-up   visit. 
Diaries will be assessed at 1, 2, 4, 8, 12, and 24 weeks after treatment. 
Micturition diaries will be completed daily for 7 days prior to treatment and 7 
days prior to each visit after treatment. Pads will collected for up to 72 hours 
prior to V1A, prior to V2 and prior to all visits  thereafter. 
The participants' perception of their bladder condition will be rated at Baseline 
(prior to dosing) and at weeks 1, 2, 4, 8, 12, and 24  post dosing and their   opinion 
of response to treatment assessed after 1, 2, 4, 8, 12, and 24 weeks following the 
study drug administration. QoL will be assessed with the Kings Health 
Questionnaire (KHQ) and SF-12 at Baseline (prior to dosing) and thereafter at 
weeks 4, 8, 12, and 24 weeks post  dosing.1 
All participants will be administered the International Consultation  on 

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Incontinence Questionnaire – Short Form (ICIQ-SF) at Baseline and at 4, 8, 12, 
and 24 weeks following administration of study  drug. 
 
In all participants, urine and blood specimens will be collected to assay for the 
presence of hSlo DNA by PCR. If they are positive, for the hSlo after 6 months, 
urine and/or blood specimens will be collected monthly thereafter (post study)  
until 2 consecutive specimens are negative. On the day of dosing, blood and urine 
will be collected pre-dosing and 2 hours  post-dosing. 
Primary 
Outcome 
Safety will be assessed by analysis of adverse experiences, clinical laboratory 
tests, electrocardiogram, and physical  examinations. 
Secondary 
Outcomes 
The mean number of micturitions per 24 hours will be evaluated at all visits and 
changes compared to baseline and  placebo. 
The mean volume per micturition will be evaluated at all visits and changes 
compared to baseline and  placebo. 
The change in the mean number of urge incontinence episodes per 7 day 
collection period and the urgency episodes per 24 hours will be evaluated at all 
visits and compared to baseline and  placebo. 
The change in detrusor overactivity at week 4 and 24 will be evaluated and 
compared to baseline and  placebo. 
Urgency will be rated with a 4 point validated urgency scale included in the 
voiding diary. 
Participants will rate their perceived bladder condition severity using a validated 
6-point scale and assess their response to treatment. Improvement will be defined 
as a decrease of 1 point or more from baseline. Participants' assessment of 
Quality of Life (QoL) will be evaluated using the Kings Health Questionnaire 
algorithm and changes compared to baseline and  placebo. 
Changes from baseline at the final visit (24 weeks) in bladder capacity will be 
evaluated and compared to baseline and  placebo. 
Study 
Duration 
6 months (24 weeks) per participant with an additional 18 month safety follow- 
up. 
Study Start November, 2013 
Sample Size Maximum of 18 participants. 
Statistical 
Analysis 
Both the safety data and data to assess activity will be analyzed using summary 
descriptive statistics for the four cohorts and the total study population. The 
group sample sizes of 6 per arm achieve 80% power to detect a 30% reduction in 
frequency of voiding to placebo assuming a standard deviation of 2.5 with a 
significance level of 0.05 using a two-sided, two sample t-test. A comparison to 
baseline will also be done using a two-sided t- test. Total number of active 
treatment participants (N=12) will also be compared to total number of placebo 
participants (N=6). 

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Table 1. Procedures By Visit 
Phase 
Screening Phase 
Post-Treatment Follow up Visits 
Visit/Period 
Visit 1 Visit 1An 
Visit 2 
Telephone 
Follow-up j 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Day 
-14 
-14 to -8 
0 (Baseline) 
Day 1 & 3 
8 
15 
29 
57 
85 
169 (Final) 
Week 
-2 
0 
0 
1 
2 
4 
8 
12 
24 
Visit Window (days) 
+2 
+2 
Day 3±1 
+2 
+2 
±2 
±3 
±5 
±5 
Signed Informed Consent 
▲ 
Evaluation of Inclusion / Exclusion 
Criteria 
▲ 
▲ 
▲f 
Demographics and Medical / 
Surgical History 
▲ 
Physical Examination 
▲ 
▲ f 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
ECG 
▲ 
▲a 
▲ 
▲ 
▲ 
Previous / Concomitant 
Medication Assessment 
▲ 
▲ 
▲ f 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
Vital Signs h 
▲ 
▲f, l 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
Objective OAB /DO Evaluation 
(Cystometry) b 
▲d 
▲ 
▲ 
Bladder  scan c 
▲ 
▲ 
▲ 
▲ 
Dispense Daily Voiding 
Diary/Urgency questionnaire i 
▲ 
▲ 
▲ f 
▲ 
▲ 
▲ 
▲ 
▲ 
Pad Test m 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
QoL (King’s Health 
Questionnaire) and SF-12 
▲ f 
▲ 
▲ 
▲ 
▲ 
Subjective Evaluation of Disease 
State k 
▲ f 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
Subjective Evaluation of Response 
to Treatment k 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
ICIQ-SF 
▲ f 
▲ 
▲ 
▲ 
▲ 
Urinalysis and Urine Cultures d 
▲ 
▲ 
▲ f 
▲ 
▲ 
▲ 
▲ 
▲ 
Hematology Laboratory Tests e 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
Chemistry Laboratory Tests e 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
Pharmacokinetic Assessment 
(urine and blood hSlo cDNA) 
▲ f, g 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ g 
Adverse Event Assessment 
▲ 
▲f 
▲j 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
Study Drug administered 
▲ 
a. ECG will be done prior to administration of study drug and at 2 hours post dosing. 
b. Cystometry includes: volume at first desire to void, detrusor pressure, abdominal pressure, detrusor pressure at beginning of voiding, detrusor pressure at maximum flow, 
maximum detrusor pressure, volume at strong urge to void, peak flow rate during voiding, voided volume, volume at DO, post-void residual volume, total bladder volume 
(voided volume + residual volume), number of detrusor contractions during procedure and duration of DO 
c. Inclusion criteria specify residual volume ≤200 ml. Bladder scans at V1 and V8 to be done before catheterization. 
d. Urinalysis with microscopic RBC and WBC, protein, glucose, nitrites, pH, and specific gravity at V 1, 3-5 and V7 and V8. At V1A and V2, urinalysis by Dipstick will be 
done. Urine cultures at V1 (by catheterization with the urodynamic catheter), V3 (clean void); at V1A, V2, V5 and V8 prior to cystometry or cystoscopy (by catheterization 
with the urodynamic catheter) and before discharge by clean void (at V2 use first voided urine after drug administration).  Visit 2 urinalysis by Dipstick will be done prior 
to dosing and urine culture will be performed both prior to study drug administration and prior to discharge 
e. Lab tests to be done at V1, V2 - 5, V7 and V8 include: Hematology- CBC with differential, platelet count, sedimentation rate, PTT, PT (no PT and PTT at V2 and V4), 
CRP, Antinuclear antibody; Fasting chemistry- BUN, creatinine, Na+, K+, Mg++, Ca++ , CO2, Cl-, albumin, alkaline phosphatase, ALT, AST, GGT, total bilirubin, total 
protein, CPK, LDH, glucose; Serum Pregnancy Test for beta-HCG required for women of child bearing age who have not had hysterectomy at Screening V1 and on as 
need basis. In addition, FSH> 40 IU/L if last menstrual cycle not > 12 months prior to study enrollment. HbA1c will be done at screening Visit 1 only. No chemistries will 
be done at 2 (Week 0). At V4, chemistries will include only BUN, creatinine, electrolytes (Na+, K+), CRP, glucose, and ANA. No lab tests will be done at Visit 1A or V6. 
Lab tests should be taken at the same time of day at all study visits. 
f. Test or procedure will be done prior to administration of study drug at Visit 2 . At V2 there is also a urine culture after dosing. 
g. At V2, blood and urine pre-dosing and at 2 hour post-dosing. If specimen is still positive at week 24, participant must return monthly until two successive specimens are 
negative for hSlo DNA. 
h. Vital signs will include height at V1 only; weight at V1 and V8; oral body temperature at all visits (except V1A). Same arm should be used for all BP measurements and 
specified. 
i. Diaries are to be completed prior to V1A (to test for compliance and inclusion criteria), for 7 days prior to Visit 2 and 7 days prior to each visit, thereafter. 
j. Participants will be contacted by telephone on Study Day 1 and 3 (1 day and 3 days ±1, following drug administration at Visit 2) for assessment of adverse events. 
k. Subjective assessments are based on the following questions in Appendix C: “How bothersome do you consider your bladder problem?” and “Has the treatment been of 
benefit to you?” 
l. BP will be taken every 15 minutes for 2 hour post administration of study drug. 
m. Participants will bring in pads/diapers worn for 3 days prior to Visit 1A & 2 (if V1A after screening V1) and 3 days prior to all subsequent visits (Visit 3 to Visit 8); also 
bring in clean pad/diapers to use as baseline. 
n. Visit 1A may occur on same day as V1. In this case all V1A procedures not already to be done at V1 should be completed. Cystoscopy should be performed after all other 
V1 procedures and post cystoscopy urine culture obtained using clean void. If V1A coincides with V1, then since pad collection and diaries will not be completed prior to 
V1, these must be checked for compliance at V2. 

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1.1 
Introduction 
 
1.2 
Overview 
 
Overactive Bladder Syndrome (OAB) resulting in urinary incontinence is a common and 
significant problem that affects millions of men and women in the United   States. 
Although both age and disease (e.g., benign prostatic hyperplasia, stroke, and diabetes mellitus) 
contribute to the multifactorial nature of urinary incontinence, bladder overactivity, or 
involuntary, uncontrolled, spontaneous detrusor contractions, often leading to urge urinary 
incontinence (UUI) is a particularly prominent manifestation.2, 3 Incontinence affects all ages, 
both sexes, and people of every social and economic level. It is estimated that over 17 million 
men and women in the United States have OAB4. It is also estimated that 15 to 30 percent of 
people over the age of 60 who live at home have incontinence.  In addition, at least half of the 
1.5 million Americans who reside in nursing homes are incontinent. Nevertheless, while OAB is 
often perceived as a condition of older people, about half of the people who suffer from this 
condition are between the ages of 35 and 64 years old.5 Also, in the past it had been postulated 
that women were twice as likely as men to have this condition. However, OAB affects men and 
women at approximately the same rate (prevalence is 16.9% for women and 16.0% for men6), 
although the symptoms of urge incontinence are more prevalent among women (9.3%) than men 
(2.6%).4 Men tend to have higher rates of “dry” OAB including symptoms of frequency and 
urgency. The National Overactive Bladder Evaluation (NOBLE) Program, a survey in over 5000 
patients, supports these findings. In this study the overall prevalence of OAB did not differ by 
sex; however, the severity and nature of symptom expression did differ. Sex-specific anatomic 
differences may increase the probability that OAB is expressed as urge incontinence among 
women compared with men. Even so, OAB, with and without incontinence, has a clinically 
significant impact on quality of life, quality of sleep, and mental health, in both men and women. 
Despite this effect on quality of life, as many as 40% of the people with OAB do not discuss it 
with their physician or healthcare professional. Of those that do mention it, only 25% may 
receive pharmacological therapy.7 
 
OAB is characterized by a decreased bladder capacity, frequent voiding, frequent sensations of a 
strong urge to void, and in some patients, episodes of urge incontinence or UUI which is often 
used interchangeably with OAB. According to the International Continence Society these 
symptoms are defined as  follows8: 
 Urgency: the sudden, compelling desire to urinate. This symptom can occur with and 
without urge incontinence (leakage). Sufferers experience strong, sudden urges to urinate, 
even if their bladder is not full. 
 Frequency: urinating 8 or more times per 24-hour period. 
 Urge Incontinence: an involuntary, accidental loss of urine, also called “leakage” or 
“incontinence.” 
Standardization of terminology in lower urinary tract function based on the report from the 
standardization sub-committee of the International Continence Society states that the term 
"overactive bladder" has replaced the previously used term "unstable bladder". "Detrusor 
overactivity" is the corresponding urodynamic term, replacing "detrusor instability"   and 

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"detrusor hyperreflexia". Knowledge regarding the epidemiology of the overactive bladder is 
limited. The myogenic and neurogenic theories of pathophysiology require further   evidence.9 
The parasympathetic nervous system provides the major control of bladder contractility mainly 
through muscarinic receptors (M2 and M3) and is a key target for presently administered 
pharmacological therapy for patients with OAB/UUI and detrusor   overactivity. 
The current treatment of choice for OAB/UUI remains the non-selective muscarinic receptor 
antagonists (e.g. oxybutynin, tolterodine) that are associated with an increased incidence of dry 
mouth and other side effects. Newer more selective agents also display these adverse events. It is 
also established that 5-HT4 receptors at prejunctional parasympathetic terminals can mediate the 
neurogenic potentiation of cholinergic transmission of human isolated bladder. 10 Mirebegron, a 
β3-agonist and smooth muscle relaxer, was approved by the FDA in 2012. The reported adverse 
effects were similar to antimuscarinics, but with a lower incidence of dry mouth compared with 
tolterodine.11. 
Overall, the mechanistic basis for increased detrusor overactivity is not fully understood, but the 
general importance of ion channel activity to bladder smooth muscle function is well established 
2, 3,  12,  13, 14   The loss of smooth muscle control is likely to be a basic cause of urge   incontinence. 
 
pVAX/hSlo (hMaxi-K is the name we have established for theGMP product) consists of the gene 
for the α−pore subunit of 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. A single instillation of 100 µg of pVAX/hSlo into the bladder has 
been shown to restore normal bladder function in rats with documented overactivity in an 
obstructed female rat model. 15 Decreased bladder spasms were observed in rats transfected with 
Maxi-K channel DNA and the restoration of smooth muscle demonstrated. As described below, 
more recent data in male and female rat models of obstruction-induced bladder overactivity also 
documents the efficacy of hSlo gene transfer. Consistent with these observations, Nelson and 
colleagues16  have observed robust bladder overactivity in the Maxi-K α-subunit KO   mouse. 
Moreover, this mouse Maxi-K α-subunit KO mouse appears to recapitulate relevant aspects of 
the corresponding clinical conditions in affected patients. The effect(s) on smooth muscle for 
OAB/UUI are likely to be very similar to those previously proposed mechanisms that  
ameliorated erectile dysfunction in the rat model. (See Figure 1 below depicting mechanism of 
action.) 
 
Smooth Muscle Relaxation 
KATP,  KV 
Gene Transfer 
 
Smooth Muscle Cell Hyperpolarization 
Lower cytosolic Ca++ 
Vasodilation or bladder  relaxation 
Maxi-K 

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Figure 1. Maxi-K channel effect on smooth muscle 
 
However efficacy over time may vary in different tissues, and moreover, in the bladder, it is 
conceivable that different cell types (urothelium and perhaps nerves, etc.) may participate in the 
therapeutic effect.15 It is proposed that intravesical injections of Maxi-K channel DNA into the 
bladder of incontinent patients could reduce painful bladder spasm and improve bladder   control. 
 
 
1.2 Preclinical Data on Urinary Incontinence and pVAX/hSlo 
 
The pathophysiology of partial urinary outlet obstruction in the rat model recapitulates many 
relevant aspects of the corresponding lower urinary tract symptoms observed in humans. 17, 18, 19 
The noted physiological and pathophysiological similarities make it reasonable to assume that 
studies on the rat bladder will provide insight into at least some aspects of human bladder 
physiology and dysfunction. 
Because the physiology of the rat bladder parallels many aspects of the human bladder20, 21 
studies examined the potential utility of bladder instilled K channel gene therapy with   hSlo 
cDNA (i.e., the maxi-K channel) to ameliorate bladder overactivity in a rat model of partial  
urinary outlet obstruction.  In one study twenty-two female Sprague-Dawley rats were subjected 
to partial urethral (i.e., outlet, PUO) obstruction, with 17 sham-operated control rats run in  
parallel. After 6 weeks of obstruction, suprapubic catheters were surgically placed in the dome of 
the bladder in all rats. Twelve obstructed rats received bladder instillation of 100 µg of 
hSlo/pcDNA in 1 ml PBS-20% sucrose during catheterization and another 10 obstructed rats 
received 1 ml PBS-20% sucrose (7 rats) or 1 ml PBS-20% sucrose containing pcDNA only (3 
rats). Two days after surgery cystometry was performed on all animals to examine the 
characteristics of the micturition reflex in conscious and unrestrained rats. Obstruction was 
associated with a three to fourfold increase in bladder weight and alterations in virtually every 
micturition parameter estimate (see Table 2 below). Obstructed rats injected with PBS-20% 
sucrose routinely displayed spontaneous bladder contractions between micturitions. In contrast, 
hSlo injection eliminated the obstruction-associated bladder hyperactivity, without detectably 
affecting any other cystometric parameter. Presumably, expression of hSlo in rat bladder 
functionally antagonizes the increased contractility normally observed in obstructed animals and 
thereby ameliorates bladder overactivity. These initial observations indicate a potential utility of 
gene therapy for urinary incontinence. In fact, the dramatic bladder hypertrophy and detrusor 
overactivity associated with this in vivo rat model recapitulates many relevant aspects of human 
lower urinary tract symptoms 18, 22, 23, 24 and thus provides an excellent opportunity to further 
explore the utility of K channel gene therapy for the treatment of this condition and other smooth 
muscle disorders (i.e., erectile dysfunction, irritable bowel syndrome, and   asthma). 

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Table 2. Summary of treatment effects on mean micturition parameters in 6 week obstructed female rats 
and sham-operated controls 
 
WT 
(mg) 
MP 
THP 
BP 
BC 
MV 
RV 
MIP 
(IP-BP) 
Control: 
unobstructed 
(n=17) 
171 
± 
15.0 
73.9 
± 
4.99 
22.3 
± 
2.1 
12.6 
± 
1.09 
1.2 
± 
0.1 
1.13 
± 
0.10 
0.13 
± 
0.04 
3.49 
± 
0.79 
aObstructed: 
pVAX/hSlo 
injected (n=12) 
*547.6 
± 
55.4 
*128.9 
± 
16.1 
*36.3 
± 
4.30 
*22.1 
± 
43.9 
*3.44 
± 
0.41 
*3.22 
± 
0.39 
*,**0.3 
± 
0.10 
**5.59 
± 
1.05 
bObstructed: 
untreated (n=10) 
*473.1 
± 
56.6 
*132.7 
± 
17.9 
*39.3 
± 
3.6 
*18.8 
± 
1.9 
*2.91 
± 
0.62 
*2.94 
± 
0.65 
0.09 
± 
0.05 
9.37 
± 
1.79 
a 
100 µg pVAX/hSlo in 200 µl PBS-20% sucrose 
b 3 of these rats received 1000 µg pcDNA in PBS-20% sucrose. Control: Sham operated, unobstructed age-matched control 
animals, WT: bladder weight (mg), MP: micturition pressure (cm H2 O), THP: threshold pressure (cm H2 O), BP: basal pressure 
(cm H2 O), BC: bladder capacity (ml), MV: micturition volume (ml), RV: residual volume (ml), MIP: mean inter-micturition 
pressure ((cm H2 O; the mean pressure over the entire inter-micturition interval minus the basal pressure on the same animal). 
* 
Significantly different from sham-op; p<0.05. 
** Significantly different from control (obstructed but not treated); p<0.05, One-Way ANOVA, with Newman Keuls post hoc 
pairwise comparisons. 
 
Another study examined the ability of hSlo gene transfer to alter and/or ameliorate the 
intermicturition pressure fluctuations observed in an obstructed male rat model. For these studies 
rats were obstructed for 2 weeks using a perineal approach.25 Following 2 weeks of obstruction, 
the rats were catheterized for cystometric investigations as previously described15, 25 and placed 
into 1 of 2 treatment groups. Age-Matched Control rats were subjected to a sham obstruction and 
run in parallel. 
 
The mean values for the micturition parameters in all experimental animals are summarized in 
Table 3, and the salient features of these findings are graphically depicted in Figures 2 and 3. 
Importantly, as with the study in the 6-week obstructed female rat, a single intravesical  
instillation of 100 µg hSlo/pVAX was associated with statistically significant changes in several 
micturition parameters of major physiological  relevance. 

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Table 3. Summary of treatment effects on mean micturition parameters in 2 week obstructed male rats and 
sham-operated  controls. 
 
Bcap 
MV 
RV 
BP 
TP 
MP 
IMP 
SA 
Bcom 
BW 
pVAX 
(n = 8)b 
2.36 ± 
0.48 
1.84 
±0.31 
0.53 ± 0.21 18.65 ± 
5.38 
47.21 ± 
8.61c 
91.28 ± 
18.52c 
32.49 ± 
7.5c 
13.84 ± 
2.57c 
0.12 ± 
0.04 
348.3 ± 
105.3 
hSlo 
(n = 16)b 
2.48 ± 
0.30c 
2.22 ± 
0.26c 
0.27 ±0.12 
7.66 ± 
1.35d 
27.26 ± 
3.7d 
54.05 ± 
6.28d 
18.13 ± 
2.8d 
10.47 ± 
1.89c 
0.17 ± 
0.03 
352.3 ± 
42.99 
Sham 
(n = 10)a 
1.35 ± 
0.14 
1.32 ± 
0.12 
0.03 ±0.02 
10.6 
±0.81 
18.47 ± 
0.79 
46.58 ± 
3.34 
13.96 ± 
1.09 
3.39 ± 
0.61 
0.18 ± 
0.018 
274.4 ± 
24.5 
Bcap, bladder capacity (ml); MV, micturition volume (ml); RV, residual volume (ml); BP, basal pressure (cm H2 O); TP, threshold pressure (cm 
H2 O); MP, micturition pressure (cm H2 O); IMP, mean intermicturition pressure (cm H2 O; the mean pressure over the entire intermicturition 
interval minus the basal pressure on the same animal); SA, spontaneous activity (cm H2 O); Bcom, bladder compliance (ml/cm H2 O); BW, bladder 
weight (mg). 
a5 of these animals are 2-week sham controls, the other 5 are 1 month older (or 6-week sham controls). However, statistical analysis revealed that 
there were no significant differences in any of the micturition parameters, and thus, these 2 populations were considered to be homogeneous for 
the purposes of this analysis. 
bAll treated rats were given 1000 µg pVAX alone or 100 µg hSlo/pVAX in 1 ml PBS with 20% sucrose. All data represent the mean ± S.E.M. and 
were analyzed using a one-way analysis of variance, with a post hoc Tukey’s test for all pairwise (multiple) comparisons. 
cSignificant difference from the corresponding sham control value. 
dSignificant difference from the corresponding pVAX value. 
 
 
 
As illustrated, 2 weeks of obstruction produces a general increase in bladder pressure.  
Specifically, BP, TP, MP, IMP and SA are all increased in the 2-week obstructed male rat, 
relative to the Age-Matched Control Sham-operated rat. The elevated bladder pressures observed 
in this rat model may well represent the clinical correlates of symptomatic urgency, and 
furthermore, if left unabated, may well predispose one to urge incontinence. More importantly, a 
single intravesical injection of 100 µg of hSlo/pVAX was associated with a statistically 
significant decline in the mean BP, TP, MP and IMP observed in pVAX-treated obstructed rats. 
Of note, the micturition pressure values observed after gene transfer were indistinguishable from 
those observed in the Sham rats. This is a clear indication of the potentially beneficial effect such 
therapy might be expected to have on patients experiencing urgency as a result of similar 
elevations in bladder pressure. 
 
Interestingly, the pathophysiological manifestations observed in the 2-week male rat model of 
bladder overactivity (as judged by the differences in the measured micturition parameters) are 
apparently more severe than, and thus, at least in some respects, differ from our previous 
observations in the 6-week obstructed female rat model. Nonetheless, both models produce a 
consistent increase in inter-micturition pressures, which are the presumptive clinical correlates of 
urgency. As such, these data may indicate that hSlo gene transfer has therapeutic utility in more 
than one “type” of urgency and/or urge  incontinence. 

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Figure 2. Graphical depiction of the impact of 2 weeks of obstruction on the relevant micturition 
parameters in the two treatment groups, relative to the Sham-operated, Age-Matched Control rats. Panels A- 
D represent the data summarized in Table 3. 
 
Below, Figure 3 shows representative examples of cystometric recordings from distinct 
rats in each treatment group (Graphs  A-C). 
 
Graph A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time (mins) 
2-week Sham control male rat 
Volume(ml) 
Pressure(cmH2O) 

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Graph B 
 
 
Time (mins) 
 
Graph C 
 
 
 
 
Time (mins) 
 
Figure 3. Graphs A-C are representative examples of approximately 1 hour of cystometric recordings from 
distinct rats in each treatment group. 
2-week obstructed male rat: treated with hSlo 
2-week  obstructed male rat: treated  with pVAX (vector  only) 
Volume (ml) 
Pressure (cmH2O) 
Volume(ml) 
Pressure(cmH2O) 

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A third study evaluated the effects of hSlo gene transfer following 2 weeks of partial urethral 
outlet obstruction in female rats. In order to create a partial urethral outlet obstruction (PUO), a 
ligature was placed on the urethra of female Sprague-Dawley rats weighing 200-250g (Christ et 
al., 2001) as described above. Two weeks after placement of the ligature, the rats were subjected 
to surgery for placement of a suprapubic catheter. Two days later, bladder function studies (i.e., 
cystometry) were performed on conscious, unrestrained rats in metabolic cages. As illustrated in 
Table 4 and Figure 4 following the 2 weeks of partial urethral outlet obstruction, female rats 
exhibit significant changes in bladder function, as evidenced by the more than 2-fold increase in 
bladder capacity and the appearance of significant spontaneous bladder  contractions.  The 
increased spontaneous bladder contractions were observed as pressure fluctuations between 
micturitions (see Figure 4), and can be quantified as shown in Table 4 by the corresponding 
increases observed in the SA and IMP values. A single intraluminal bladder injection of 300 µg 
and 1000 µg of pVAX/hSlo (in 1 ml PBS-20% sucrose) resulted in a nearly complete ablation of 
detrusor overactivity. This effect is reflected by the significant decrease in IMP and SA in the 
hSlo-treated, obstructed rats when compared with the rats treated with pVAX vector only (see 
Table 4). Although, a true DO effect relationship for hSlo gene transfer was not shown in this 
model, this study did demonstrate that over a 1-log unit variation in DO (from 100 to 1000 µg), 
there is a statistically significant, and moreover, physiologically relevant, diminution in DO, in 
the absence of any detectable effect on the ability of the bladder to empty. That is, in this animal 
model, pVAX/hSlo is able to ameliorate the pathophysiological effects of outflow obstruction- 
related DO, without having any detrimental effect on bladder function. Similar effects were 
observed after instillation of 100 µg pVAX/hSlo in the 6-week obstructed female Sprague Dawley 
rats, which are shown below. 
 
 
 
 
 
Figure 4. Representative tracing of a cystometric recording in a rat given vector alone (pVAX), and 300 and 
1000 µg of pVAX/hSLO. Note the regular, periodic emptying and the virtual absence of intermicturition 
pressure fluctuations in the treated animals. 

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Table 4. Summary of treatment effects on mean micturition parameters in 2 week obstructed female rats 
 
MP 
TP 
BP 
BC 
MV 
RV 
MIP 
(IP-BP) 
MF 
SA 
BC
O 
Control: 
pVAX 
(n=10) 
68.1±8.1 34.2±4.9 
9.1±1.9 2.3±0.3 2.2±0.3 1.1±0.0 
24.0±4.6 
4.6±0.5 
14.9± 
3.4 
0.1±0.0 
2 
aObstructed: 
10 µg 
pVAX/hSlo 
injected (n=7) 
65.3 
± 
10.5 
30.3 
± 
3.6 
7.2 
± 
1.0 
2.5 
± 
0.3 
2.4 
± 
0.3 
0.2 
± 
0.1 
20.0 
± 
3.5 
4.4 
± 
0.5 
12.8 
± 
3.0 
0.1 
± 
0.02 
bObstructed: 
30 µg 
pVAX/hSlo 
injected 
(n=9) 
81.1 
± 
7.3 
36.6 
± 
4.4 
11.8 
± 
2.6 
3.2 
± 
1.0 
2.7 
± 
0.4 
0.4 
± 
0.2 
27.1 
± 
3.5 
4.3 
± 
0.4 
15.3 
± 
1.5 
0.1 
± 
0.02 
bObstructed: 
300 µg 
pVAX/hSlo 
injected 
(n=10) 
47.8 
± 
3.7 
17.7*,** 
± 
1.6 
6.3 
± 
1.1 
2.3 
± 
0.4 
2.2 
± 
0.3 
0.3 
± 
0.2 
10.3*,** 
± 
1.2 
5.3 
± 
0.6 
4.1*,* 
* 
± 
0.4 
0.2*,** 
± 
0.02 
bObstructed: 
1000 µg 
pVAX/hSlo 
injected 
(n=12) 
57.2 
± 
6.2 
21.4*,** 
± 
1.8 
5.7 
± 
1.1 
2.1 
± 
0.1 
2.0 
± 
0.1 
0.1 
± 
0.04 
11.6*,** 
± 
1.3 
5.2 
± 
0.3 
5.9*,* 
* 
± 
0.5 
0.1*,** 
± 
0.01 
a 
10, 30, 300, 1000 µg pVAX/hSlo in 200 µl PBS-20% sucrose 
b 
Control: Obstructed age-matched control animals that received 1000µg of pVAX only, WT: bladder weight (mg), MP: 
micturition pressure (cm H2 O), 
TP: threshold pressure (cm H2 O), BP: basal pressure (cm H2 O), BC: bladder capacity (ml), MV: micturition volume (ml), RV: 
residual volume (ml), 
MIP: mean inter-micturition pressure ((cm H2 O; the mean pressure over the entire inter-micturition interval minus the basal 
pressure on the same animal); 
SA spontaneous activity (MIP-BP); BCOM Bladder compliance (bladder capacity/TP-BP) 
* 
Significantly different from control; p<0.05. All pairwise multiple comparison procedures (Holm-Sidak method) 
** 
Significantly different from control; p<0.05, One-Way ANOVA. 
 
A rabbit study to evaluate the distribution of different volumes of gene transfer injected into the 
bladder wall was performed prior to initiation of the clinical trial in women with OAB using 
direct intravesicular injections. Nine female Adult New Zealand white rabbits weighing an 
average of 6 pounds were used. The animals were anesthetized and  pVAX-lacz  was  to be 
injected into the detrusor in 0.05, 0.1, and 0.15 ml aliquots into 4, 8, and 10 sites in the bladder 
wall. An additional set of 3 animals was to be injected with carrier alone at only the highest 
volume of carrier (4, 8, or 10 sites x 0.15 ml). The plasmids were in solution at a concentration 
of 4000 µg/ml. One week later the animals were euthanized and the bladders  excised  and 
weighed. Areas with blue color were prepared for histological examination and molecular 
analysis. Molecular analysis of hslo expression tissue was done with RNA extraction and real 
time PCR. In addition, histopathology was performed on the various rabbit   tissues. 

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Table 5. Rabbit Intravesicular Injection Protocol 
 
N=12 
rabbits 
50-50 mixture of p- 
VAXhslo (ml) 
sites/ 
rabbi
sites/ 
rabbi
sites/ 
rabbi
0.05 
4 
8 
10 
0.1 
4 
8 
10 
0.15 
4 
8 
10 
 
Due to difficulty with direct bladder injections in this animal model, only one rabbit was given 
the 0.05 ml injection. Six rabbits had 0.1 ml at 4, 8, and 10 sites (3 from inside the bladder; 3 
from outside the bladder). Three rabbits had 0.15 ml at 4, 8, and 10 sites. Results indicated that 
those rabbits with a greater number of injections (8-10 injections) had less expression than some 
animals with the smallest number of injections (4 injections). The overall conclusion is that the 
direct injection into the bladder wall results in expression of the gene, however, it seems to work 
best with wider dispersion of the injections perhaps 1 cm apart. The gene was detected in the 
blood up until 30 minutes post treatment. There were granulomatous lesions observed due to the 
sutures (a common artifact in the rabbit  model). 
 
1.3 Preclinical Toxicology of pVAX/hSlo following Intravesical 
Administration 
 
Tolerance and biodistribution data were evaluated after intracavernous (i.e.,   intravenous) 
injection of 1000 µg of pVAX/hSlo in a Sprague-Dawley retired breeder rat model of erectile 
dysfunction. Importantly, signal was not detected in either the testis or the heart beyond the 24 
hour time point. A positive signal in the heart was never detected after the 1-hour time point; a 
time that surmised to be related to plasmid in the blood, since the kinetics of disappearance of the 
plasmid from the plasma was previously determined to be less than 0.5 hours for transition from 
supercoiled to nicked circular, and less than 2 hours for total DNA. Thus, even following an 
intracavernous administration, which is really equivalent to an intravenous injection, these data 
support the supposition that the gene transfer would not be expected to elicit any untoward 
systemic, in particular, cardiac  effects. 
 
For the OAB indication it is not technically possible to simulate the same transurethral route of 
intravesical administration of pVAX/hSlo in rats as will be used in the human trials. Therefore, in 
the toxicology and biodistribution studies evaluating intravesical injection of pVAX/hSlo, animals 
underwent surgical exposure of the bladder and study material was injected directly into the 
bladder using a needle. 
 
The effect of pVAX/hSlo on hematological and chemical parameters were assessed in fifteen 275- 
300 gm normal female Sprague- Dawley rats.   1000 µg of either pVAX/hSlo  (8 animals) or  
pVAX vector (7 animals) was injected directly into the lumen of the bladder following surgical 
exposure. Blood samples were collected via a heart stick immediately after the animals were 
euthanized by CO2 anesthesia at 4, 8, and 24 hours and at 1 week following injection of test 
material.  Samples were analyzed for glucose, urea nitrogen, creatinine, total protein,   total 

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bilirubin, alkaline phosphatase. ALT, AST, cholesterol, sodium, potassium, chloride, A/G ratio, 
BUN/creatinine ratio, globulin, lipase, amylase, triglycerides, CPK, GTP, magnesium and 
osmolality. The laboratory parameters were similar between pVAX/hSlo and controls at the four 
timepoints. 
 
The effect of pVAX/hSlo on the histopathology in female Sprague-Dawley rats (275 to 300 gm) 
was evaluated in two studies. In the first study, four rats underwent partial bladder obstruction 
surgery and 2 weeks later 100 µg pVAX/hSlo in 1000 µL PBS-20% sucrose was administered 
directly into the lumen of the bladder with surgical exposure of the bladder. A single animal was 
euthanized at 1, 8, and 24 hours, and at one week after injection of pVAX/hSlo. The tissues of 47 
organs were immediately fixed in 10% formalin and processed for routine histopathological 
examination. Histopathological changes were noted only in  the  bladder  and  consisted  of 
serositis, edema, hemorrhage, and fibrosis. These changes were consistent with those expected 
with partial urethral obstruction and were not considered related to injection of   pVAX/hSlo. 
 
Because of the histopathological changes in the bladder of rats with PUO administered 
pVAX/hSlo, the effect of pVAX/hSlo compared to vector (pVAX) and PBS-20% sucrose on 
histology of the bladder was evaluated in normal rats.  Following  surgical  exposure,  the 
following test material was injected directly into the bladder lumen: 1) 0.6 ml PBS–20% sucrose, 
2) 1000 µg pVAX in 0.6 ml PBS–20% sucrose, or 3) 1000 µg pVAX/hSlo in 0.6 ml PBS–20% 
sucrose. Animals were euthanized with CO2 72 hours after instillation and the bladders removed 
and immediately fixed in 10% formalin solution. The 72 hour time point was chosen to limit the 
mechanical effects of the needle puncture on the bladder wall and minimize any potential effects 
of inflammation that might be caused by the pVAX/hSlo , vector, or   diluent. 
 
There were no gross findings on examination of the bladder. Overall, there were no treatment- 
related differences between pVAX/hSlo and either the vehicle or pVAX. No treatment-related 
alterations in the urothelium were noted. The lesions seen on histological examination were 
consistent with trauma from the needle used for injection since they  were  focal  rather  than 
diffuse or multifocal in  distribution. 
 
In the biodistribution study, test material was injected directly into the lumen of  exposed 
bladders in 275-300 g normal Sprague-Dawley rats. 1000 µg pVAX/hSlo in 0.6 ml of PBS-20% 
sucrose was administered to 12 animals and 0.6 ml PBS-20% sucrose administered to 5 animals. 
Four animals each were sacrificed at 24 hours, 1 week, and 1 month following injection of test 
material. Tissue samples were collected in the specified order as follows: heart, liver, brain, 
kidney, spleen, lung, aorta, trachea, lymph node, eye, biceps, colon, vagina, and   uterus. 
 
Genomic DNA samples were analyzed for the kanamycin gene with a validated QPCR method. 
The results indicate that after injection of 1000 µg pVAX/hSlo, the plasmid could be detected 
after 24 hours in the aorta, uterus, bladder, and urethra. At 1 week, approximately 13 million 
copies/µg total DNA were measured in the bladder and pVAX/hSlo could also be detected 
slightly in the biceps. The results are displayed in graphical format in Figure 5   (below). 
 
Although these results differ from findings after intracavernous injection, the detection of 13 
million copies/µg total DNA is still lower than the <30 copies plasmid/105 host cells that persist 
at the site of DNA vaccine injections after 60 days in clinical Investigational New Drug   (IND) 

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trials for these vaccines. These DNA vaccine studies have demonstrated that intramuscular, 
subcutaneous, intradermal, or particle-mediated delivery did not result in long-term persistence 
of plasmid at ectopic sites.26 In addition, the procedure to inject pVAX/hSlo directly into the 
surgically exposed bladder in animals may explain the ability to detect plasmid in tissue other 
than the bladder. In humans, hMaxi-K will be instilled directly into the bladder using a using a 
transurethral catheter and the risk of plasmid distribution due to tissue damage or trauma is 
obviously markedly reduced. 
 
 
Biodistribution: Average copies of plasmid/µg total DNA in tissues 
of female animals after injection of 1000 µg of pVAX-hSLO at 24h and 1 week 
(N=4 animals per time point/ measured in duplicate). 
15x10+06 
 
 
12x10+06 
 
 
9x10+06 
 
 
6x10+06 
 
 
3x10+06 
 
 
 
 
 
Heart 
Liver 
Brain 
Kidney 
Spleen 
Lung 
Aorta 
Trachea 
Vagina 
Uterus 
L.N. 
Biceps 
Eye 
Colon 
Ovary 
Bladder 
Urethra 
Ureter 
 
 
0 
24 h. 
 
1 week 
 
1 month 
 
Note- the background value for control tissue (animals that were not injected with pVAX-hSLO, average of 39 tissues) was 8.9 x10-3 ng plasmid/ µg total 
DNA, with an upper value of 8x 10-2 ng/µg total DNA. Therefore, only values greater than 9.6 x105 copies/µg total DNA were considered to be above 
control animal values (shown by the red line). 
 
Figure 5.   Biodistribution Data 
 
Lastly, the half-life of the plasmid in human urine has been determined to be approximately 3.5 
minutes, as compared to about a 30 minute half-life in  blood. 
 
 
1.4 
Clinical Data 
 
1.4. 1 Erectile Dysfunction 
 
In humans, the safety and tolerability of hMaxi-K administered intracorporally has been assessed 
in an open-label single-escalating dose study that evaluated the safety and efficacy of   doses 
Plasmid (copies/µg total DNA) 
Aorta 
Uterus 
Bladder 
Urethra 
Bladder 

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ranging from 500 µg up to 7500 µg (Stage 1 of study) and 8000 µg to 16000 µg (Stage 2 of 
study) in men with recalcitrant ED. Eleven participants received study drug in Stage 1 of the 
study and 9 participants received study drug in Stage 2 of the study. All participants were 
followed for 6 months during the conduction of the study and up to an additional 18 months 
thereafter.  All doses were well tolerated. No dose limiting toxicities or significant adverse  
events occurred to prevent escalation to the next higher dose during this trial as determined by 
the Data Safety Monitoring Board. In Stage 1 of the study three men received the 500 µg dose, 
three men received the 1000 µg dose, three men received the 5000µg dose, and two men  
received the 7500 µg dose. In Stage 2 of the study, three men received 8000 µg, three men 
received 12000 µg and three men received 16000  µg). 
 
In Stage 1, none of the reported adverse events occurred sooner than 29 days after the gene  
transfer and none of the events were considered related to the gene transfer product by the 
investigators. All three participants in the 500 µg dose group reported adverse experiences. One 
of these subjects had knee arthroscopy. The second participant had atrial flutter with ablation 
considered unrelated to study drug.  This participant had a 25 year history of atrial arrhythmia 
prior to study entry and had been cardioverted to normal sinus rhythm before receiving hMaxi-K. 
He reverted to atrial flutter approximately 29 days after receiving the hMaxi-K. He was 
successfully cardioverted after this episode. The third participant in the 500 µg dose group had 
kidney stones removed by lithotripsy and was subsequently hospitalized with an infection 
following the lithotripsy.  These last 2 events were reported as severe and serious adverse   events. 
 
One patient given 1000 µg hMaxi-K reported acid reflux, sciatic pain and an upper respiratory 
infection and one patient who received 1000 µg had a parasitic intestinal infection and foot 
edema. One patient given 5000 µg had bladder stone removal and neither patient given 7500 µg 
reported any adverse experiences. 
 
There were no statistically or clinically significant changes from normal to abnormal in any 
blood chemistry, endocrine, hematology or urinalysis values seen at any visit for any subject. No 
patients reported any discomfort from the injection and no local physical events related to the 
injections were observed. No clinically significant changes were seen in the general or 
genitourinary physical examinations during the study. ECGs were monitored at one and three 
hours immediately following gene transfer and at one, 2, 4, 8, 12, and 24 weeks thereafter. No 
gene transfer related cardiac events were noted or reported during the study and no significant 
changes in electrocardiograms as determined by shift analysis (no normal to abnormal  
occurrences) were observed with the exception of the reoccurrence of atrial flutter in the one 
patient with the prior history of intermittent spontaneous atrial flutter. As noted above, this event 
was considered unrelated to treatment.  In addition, the two unrelated serious adverse events in 
this trial were reported at the lowest dose of 500 µg dose.  No serious adverse events were  
reported at the higher doses evaluated (1000, 5000, and 7500 µg) suggesting no increased risk 
for serious adverse events with increasing doses of hMaxi-K administered intracorporally. No 
residual hSlo DNA has been detected in  semen.27 
In Stage 2 of the study only 7 of the 9 men completed the trial.28 Two participants had early 
discontinuation; one was a voluntary withdrawal in 8000 µg group and one was for lack of 
efficacy in the 12000 µg group. In Stage 2 of the study there was only one possibly related 
adverse event in one man in the 12000 µg dose group who reported tingling in the glans   penis. 

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Other adverse events were considered unrelated to study drug. They included borderline QTc 
prolongation in one participant in the 8000 µg group, flu like symptoms in one participant in the 
8000 µg group, allergic reaction in one participant in the 12000 µg group, right hand pain, penile 
pain and platelets =570 in one participant in the 16000 µg, and common cold in another  
participant in the 16000 µg  group. 
 
Although the primary objective of the study was evaluation of safety in participants with 
overall severe recalcitrant ED, efficacy was assessed using change from baseline in the 
International Index of Erectile Function (IIEF score – Erectile Function [EF] Domain). In 
this study, positive changes from baseline for most individual subjects were small and did 
not indicate improvement by IIEF. However descriptive analysis showed the following 
efficacy conclusions from a very small number of participants at each dose (without 
placebo control). 
• Mean IIEF-EF domain scores for the two lower dose groups (500 and 1000 μg) 
fluctuated around the baseline score throughout the 24 weeks of the study. 
• Improvements in the mean IIEF-EF domain scores observed for the 5000, 7500 and 
12000 μg higher dose groups beginning two weeks after transfer. 
• Improvements were maintained in the 3 groups throughout the 24 weeks of study. 
• Individual subjects given the 5000, 7500 and 12000 μg hMaxi-K doses had apparent 
sustained improvements in IIEF-EF domain over the length of the study which was 
corroborated by their partner assessments. 
• Improvements in the mean IIEF-EF sub domain scores (items 3 and 4) observed for the 
5000 and 7500 μg dose groups beginning two weeks after transfer 
• Improvements were maintained in the 3 groups through the 24 weeks of study 
• Individual subjects given the 5000 and 7500 μg hMaxi-K doses had apparent sustained 
improvements of the IIEF-EF sub-domain over the length of the study 
• Partner responses to Items 3 and 4 of the IIEF were consistent and validated the 
responses of each subject at each visit. 
• Rigiscan also improved in one subject given 7500 μg. 
 
 
1.4. 2 Overactive Bladder 
 
Female patients with moderate OAB and detrusor overactivity (DO) were evaluated for safety 
following administration of a single intravesical instillation of hMaxi-K at three dose levels 
compared to placebo in a double blind increasing dose tolerance study. In this study hMaxi-K 
5000 µg/90 ml, 10000 µg/90 ml, and 15000 µg/ 90 ml were to be evaluated, however only the 
5000 and 10000 µg/90 ml doses groups were administered. The study was discontinued due to 
financial issues prior to administration of the 15000 µg/90 ml dose. There were 13 participants 
per dose level: 10 assigned to active treatment and 3 assigned to placebo (PBS saline = control 
group).  Participants included women ≥ 18 years old of non-child bearing potential with OAB 
and detrusor overactivity who were otherwise in good health but unable to tolerate, did not wish 
to continue, or had unsuccessful results with, prior therapy for OAB/DH. They were to have 
clinical symptoms of overactive bladder of ≥ 6 months duration including at least one of the 
following: 
• Frequent micturition (≥ 8/24hrs) 

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• Symptoms of urinary urgency 
• Complaint of sudden compelling desire to pass urine, which is difficult to defer or 
nocturia (the complaint of waking > 2 x at night to void) 
• Urge urinary incontinence (average of 5 per week) 
• Urge urinary incontinence is defined as involuntary leakage accompanied by or 
immediately preceded by urgency 
• Residual volume of ≤ 200 ml by transabdominal bladder ultrasound at Screening 
• DH [detrusor overactivity] during baseline urodynamic testing of ≥1 uncontrolled 
contraction(s) of the detrusor of at least 5 cm/ H20. 
 
Participants completed cystometry testing at baseline (prior to dosing) and at Week 4   after 
dosing, a daily diary at home for 7 days prior to baseline to capture the number of incontinence 
episodes per week, number of micturitions every 24 hours, volume voided, number of pads used 
every 24 hours. Micturition diaries were completed daily for 3 days prior to each visit after 
instillation and quality of life assessments done.   Ten participants received the 5000 µg/90 ml 
dose (7 in this group completed the study; 3 discontinued early seeking other treatment for their 
OAB), 6 participants received the 10000 µg/90 ml dose and 5 participants received placebo (all 
participants completed in the 10000 µg/90 ml and placebo groups). There were no   serious 
adverse events reported or a withdrawal for an adverse event.  In the 5000 µg/90 ml dose, 
possibly related adverse events reported in one subject each, included urinary tract infection  
(UTI); AV block Mobitz type II (possibly related; mild severity, 170 days post treatment); fatigue, 
headache, shaking chills, and insomnia (all possibly related; mild-moderate severity; 13- 76 days 
post treatment).  Unrelated events in one subject each (unless otherwise specified)  included 
headache; rash (2 subjects); fractured left (big) toe; infection left (big) toe; worsening of labial 
adipose lipoma; knee tendonitis; right kidney cyst benign; worsening of depression; worsening of 
GERD; elevated creatinine; diffuse loss of renal parenchyma; hypertensive renal disease; atypical 
chest pain; CK elevated (possibly secondary to hypertensive renal disease); CK- MB elevated 
((possibly secondary to hypertensive renal disease); diarrhea; vomit, hiatal hernia; bacteriuria, 
asymptomatic; constipation; fatigue; fall;  upper lip abrasion secondary to fall; acne on face; 
reflux; and UTI (2 subjects).   In the 10000 µg/90 ml dose group, adverse events were all 
considered unrelated and included  in one subject each, common cold; elevated   blood pressure; 
worsening of urge incontinence; tension headache; low back pain; fall; dysuria; UTI, elevated 
LFTs; and hepatitis C. In the placebo group heart palpitations were reported in one participant, 
which were considered possibly related, mild severity, and occurred 6 days post treatment.  
Unrelated events for placebo that were reported in one participant each included slight irritation 
at vulva, fractured pelvis (left side) and wrist fracture (left); 4 unrelated   UTIs were reported in 2 
participants. 
 
The study was designed as a safety study in a moderate to severe OAB patient population; 
however secondary efficacy endpoints were evaluated in the small number of subjects enrolled 
per dose. Overall findings showed no significant changes for the mean number of voids or urge 
incontinence episodes at any time point. However, despite the severity of the OAB population 
and the small number of subjects, there were some positive findings. There was a trend of mean 
treatment effect at Week 8 (p = 0.0812) with >40 % mean decrease for 5000 µg/90 ml for urge 
incontinence episodes. In addition, there was a significant mean treatment effect of reduced 
detrusor contractions at Week 24 (p<0.0508) (>80% reduction vs. baseline in contractions in the 
5000 µg group at Week 24).  There was also a decrease in mean pad weight indicative of   less 

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incontinence in the 10,000 µg/90 ml group vs. placebo which was a significant mean change 
from baseline (p = 0.0089) at Week 24. Quality of life parameters (King Health Questionnaire) 
showed some clinically significant mean changes for active treatment vs. placebo and across 
treatment groups at Week 24; this included the General Health Perception (p = 0.0272, 5000 µg 
vs. placebo) and Impact on Life (p = 0.0032, 5000 µg vs.   placebo). 
 
 
2.1 
Objectives 
 
The primary objective of this study is to evaluate occurrence of adverse events and their 
relationship to a single treatment of approximately 20 to 30 bladder wall intramuscular injections 
of hMaxi-K compared to placebo (PBS-20% sucrose).  Two dose levels (16000 µg and   24000 
µg) in females with moderate OAB/DO of ≥ six months duration are initially planned. In each 
dose level, 6 participants will receive hMaxi-K and 3 will receive placebo. Pending safety and 
efficacy results for the 2 doses that are planned, the protocol may be amended to  
investigate additional doses in this  study. 
 
The secondary objectives of this study are to evaluate the following safety   parameters: 
• Clinical laboratory tests- changes from baseline 
• Electrocardiogram change from baseline 
• Physical Examination- changes from baseline 
These changes will be evaluated primarily at the individual level, through clinical assessment of 
outliers supported by descriptive  statistics. 
Additional secondary efficacy objectives focus on the potential activity of intramuscular 
injections into the bladder wall of hMaxi-K compared to placebo. Two dose levels (16000 µg, 
and 24000µg) in female participants with moderate OAB/DO of ≥ six months duration are 
initially planned. Individual efficacy parameters that will be evaluated as secondary endpoints 
are: 
• Mean number of micturitions per 24 hours –change from baseline 
• Mean volume per micturition – change from baseline 
• Mean number of Urge Incontinence episodes –change from baseline 
• Overall bladder capacity – change from baseline (as defined in section 6.1) 
 
3.1 
Study Design 
 
This study is a double blind, placebo-controlled, multicenter, sequential active dose, phase 1 
study in females with moderate OAB/DO of ≥ six months  duration. 
The proposed study period is approximately 6 months following a single administration of study 
drug per participant. The protocol sample size of this phase I trial is not intended to find 
statistically significant differences between placebo and treatment for the primary endpoint as 
outlined in 2.0. Rather, the sample size takes into account clinical safety   considerations. 
However, the study is designed to observe a 30% reduction in the number of voids following 
gene transfer using the following calculations with NCSS/PASS program (NCSS, Kaysville, 
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Power29,30, 31 
N1 
N2 
Ratio 
Alpha 
Beta 
Mean1 Mean2 S1 
S2 
0.80251 
9 10 
1.111 
0.05000 0.19749 
10.0 
6.6 
2.5 2.5 
 
Up to 9 female participants (6 participants on active treatment and 3 on placebo) will be enrolled 
per dose level “arm”. The 2 active doses to be evaluated sequentially are 16000 µg and 24000µg 
compared to intramuscular injections into the bladder wall of PBS-20% sucrose (control group). 
Additional participants may be enrolled for evaluating the tolerability to a given dose. Each arm 
of 9 participants per dose level will be enrolled sequentially, beginning with the lowest   dose. 
Enrollment of the first 5 participants in each cohort will be managed directly by the sponsor (or 
their designee) with a 2-day waiting period following each participants dosing. The next 
participant will be enrolled only after the site has contacted the previously dosed participant on 
day 3 following transfer to determine if a clinically significant adverse event occurred. The site 
will contact the clinical monitor with the result of that contact.  In the event that no   event 
occurred the next participant will be enrolled. The DSMB will review eligibility and all available 
safety data after the 5th  participant has been administered study drug in the first dosing   cohort. 
This first review will occur as soon as possible after the 5th participant’s 3-Day Post-visit 2 
telephone contact.  Following their review of the safety data, the DSMB will recommend 
whether enrollment into the first dosing cohort may proceed. This process will be repeated  
through the 5th  participant in each cohort before the balance of the cohort (4 additional 
participants) is enrolled. 
If a clinically serious sign or symptom is reported the medical   monitor 
will contact all the sites and no further enrollment will be done until the medical monitor or 
sponsor gives permission. In addition, enrollment into the next cohort or arm in the series (at the 
next highest dose) will be dependent on safety dose-limiting toxicity assessments as per Section 
5.2. 
 
3.2 
Duration of study participation 
 
The study will consist of up to a 14-day screening period prior to the single administration 
hMaxi-K or PBS-20% sucrose placebo on Day 0 (V2). A 6 month period for follow-up will 
complete the study for each participant. The total participation duration will be approximately 
184 days; however each participant on active treatment will be required to be followed for an 
additional 18 months (every 6 months) for safety evaluations only (see Section   7.12). 
 
4.1 
Study Population 
 
The study population includes women (of non-childbearing potential) with OAB/DO who are 
otherwise in good health. 
 
The study population, if they meet the criteria for eligibility, will be selected from the urology 
practice of 1 to 6 participating sites. 
 
4.2 
Inclusion Criteria 
 
1. Healthy women of 18 years of age or older and non-childbearing potential (i.e., prior 
hysterectomy or bilateral tubal ligation; last menstrual cycle more than 12 months prior to 

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study enrollment or serum FSH >40 IU/L if woman has not had a bilateral tubal ligation 
or hysterectomy). 
2. Clinical symptoms of overactive bladder for 6 months or longer including at least one of 
the following: 
a. Frequent micturition ≥8 times per 24 hrs 
b. Symptoms of urinary urgency (the complaint of sudden compelling desire to pass 
urine, which is difficult to defer) or nocturia (the complaint of waking at night two 
or more times to void) 
 
c. Urge urinary incontinence five or more incontinence episodes per week based on 
7-day voiding diary. Urge urinary incontinence is defined as: the complaint of 
involuntary leakage accompanied by or immediately preceded by urgency. 
 
3. Detrusor overactivity with ≥1 uncontrolled phasic contraction(s) of the detrusor of at  least 
5 cm/ H20 pressure documented on cystometry at Screening Visit 1A (i.e., prior to study 
drug administration at Visit 2). 
4. Bladder scan or direct catheter drainage demonstrating a residual volume of ≤200 ml 
5. Non-response or response but poor tolerance to a previous treatment for symptoms of 
overactive bladder/urinary incontinence (e.g., anti-muscarinic/ anticholinergic agents, or 
Botox) or do not wish to continue these treatments. 
6. Able to understand study requirements (i.e., literate in English), give written informed 
consent, and comply with all study procedures and requirements. 
 
4.3 
Exclusion criteria 
 
1. A woman with a positive serum (HCG) pregnancy test or lactating. (All women of child 
bearing years who have not had a hysterectomy will have a serum HCG.) 
2. History of three or more culture documented recurrent urinary tract infections per year. 
3. Current history of bladder outlet obstruction secondary to urethral stenosis, third degree 
cystocele, or obstruction from prior urethral sling surgery documented by cystoscopy, 
urothelial cancer, or other significant genitourinary disorders except incontinence (previous 
vesicle lithiasis or bladder stones that have been successfully removed are not an exclusion). 
4. Current history or previous diagnosis of painful bladder syndrome (interstitial cystitis) with 
pain in the region of the pelvis, perineum, or lower abdomen relieved by voiding. 
5. A urine culture (≥ 1000 colonies/ml) of a urinary pathogen from a catheterized urine obtained 
at screening. 
6. Current history of neurological bladder dysfunction. 
7. A life expectancy of less than 12 months. 
8. Current history of Grade 2 or greater cystocele. 

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9. Stress urinary incontinence as determined by observation of the participant coughing while 
standing with a full bladder and/or response of 2 or 3 on the following Stress Urinary 
Incontinence question: 
Do you experience leakage when laughing, coughing, lifting heavy objects or other types 
of discreet, moderately intense  activities? 
 
0= NONE: No leakage 
1= MILD: Minimal leakage on rare occasions during these types of activities; easily 
tolerated; do not use pads for  this. 
2=MODERATE: Enough leakage that it requires occasional use of pads and may 
interfere with usual activity &  tasks 
3 =SEVERE: Extreme leakage & discomfort that stops all activity &/tasks and requires 
use of pads on all occasions 
 
10. An indwelling urethral catheter or need for clean intermittent self-catheterization. 
11. Any screening laboratory values outside of the normal laboratory range, as defined by the 
laboratory normal ranges and in the judgment of the investigator is considered clinically 
significant (hepatic biochemical markers ≤ twice the upper limit of the normal reference 
range may be accepted with written consent of sponsor). 
12. A hemoglobin A1c >7% in a person with diabetes. 
13. A history of sickle-cell disease, sickle cell trait, or any other medical condition that, in the 
judgment of the investigator, would produce significant risk to the patient. 
14. 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 (e.g, potentially 
poor compliance in completion of diaries). 
15. A current malignancy (basal cell carcinoma is not an exclusion). 
16. 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) 
• Unstable angina (chest pain greater than three times weekly while on therapy) 
• Required treatment with calcium channel, beta-blocker medication, nitrates, or anti- 
epileptic drugs 
17. Latex allergy (unless the facility can treat the participant with all latex free supplies). 
18. Allergy to lidocaine, xylocaine or other local anesthetics. 
19. Known current drug addiction and/or alcohol abuse. 

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20. Mental or legal incapacity. 
21. Abnormal screening ECG as defined by the over reader (some abnormalities considered 
benign may be acceptable with the written consent of the Sponsor). 
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). 
 
22. QTc of ≥ 450 ms (via 12-lead resting ECG using  both Fridericia’s and Bazett’s  formula) 
and/or family history of sudden death or participants with a family history of long-QT 
Syndrome. 
23. Any current treatment or treatment within the last 14 days for OAB including herbal 
preparations. Botox within the last 6 months. 
24. If the participant has used a bladder-training program, she must still fulfill inclusion criteria 
for symptoms, and exercise/training program must be continued without change. 
25. History of urinary retention, or residual bladder volume > 200 ml) (evaluated by bladder 
scan). 
26. Treatment with any compound likely to increase urine production  rate,  or  any compound 
likely to affect detrusor mechanics or voiding habits (see section 5.4 for full listing of 
prohibited medication classes). Thiazide diuretics alone or in combination 
with 
antihypertensive medications are acceptable if the dose and dose regimen is kept constant 
throughout the study and symptoms of OAB preceded these treatments. 
27. Participation in any other interventional or investigational clinical study during the last two 
months before inclusion, or during the study period. 
 
5.1 
Test Material and Administration 
 
5.2 
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. 
 
hMaxi-K is manufactured by Althea Technologies, Inc under GMP conditions. Sterile 
borosilicate vials of hMaxi-K, 2 ml, will be shipped to Sharp Clinical Services, Inc. 
(Phoenixville, PA) and stored at -20oC. Identical vials of 2 ml sterile PBS-20% sucrose 
manufactured by Olympia Compounding Pharmacy (Orlando, FL) will be shipped to   Sharp 
Clinical Services, Inc. and stored at  –20°C. 
 
The table below provides information on the 16,000 μg and 24,000 μg doses of hMaxi-K. Each 2 
mL vial contains 4000 μg per mL, so multiple vials will be used for each dosing event. The sites 
will store the vials in a locked freezer until use. Participant vials will be retained at the site until 

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the drug accounting processes have been completed, when they will either be returned to the 
Sponsor or destroyed with Sponsor  approval. 
 
Table 6. Final  Dose-hMaxi-k 
 
hMaxi-K Dose 
16,000mcg 
PBS-20% sucrose 
24,000 mcg 
PBS-20% sucrose 
Volume 
4 mL 
6 mL 
Number of Vials 
2 
3 
Final Volume 
4 mL 
6 mL 
Number of IM 
injections 
20 injections of 0.2 ml at specified sites 
in bladder wall approx. 1 cm  apart 
30 injections of 0.2 ml at specified sites 
in bladder wall approx. 1 cm  apart 
Note: In each dose cohort 6 participants will receive hMaxi-K and 3 will receive PBS-20% sucrose (placebo). 
 
Sharp Clinical Services, Inc. will maintain a randomization schedule generated by a Statistical 
Group (Section 5.3.1). Following notification by the site that an eligible participant is to be 
randomized, Sharp Clinical Services. Inc. will ship a sequentially labeled study drug participant 
kit following the central randomization schedule by overnight mail on ice within one to seven 
days prior to the planned treatment date. The sites will store the participant kit at -20oC in a 
locked freezer prior to use. Vials can be kept at -20oC for up to 360 days. Participant kits will be 
retained at the site until study completion when they will either be returned to the sponsor or 
destroyed. 
If there is a single site, then Sharp will be allowed to ship all kits to that site to be distributed by 
the site’s local pharmacy in a sequential fashion. Prior to dosing each participant, the site will 
confirm which kit number they will be using with the clinical research monitor to minimize 
errors. 
If a kit is damaged, a replacement kit will be made available. Prior to using a replacement kit 
(which will be shipped to the site from Einstein where will it be stored), the site will contact the 
clinical research monitor for directive as to which replacement kit they can use as a substitute for 
a damaged kit. The replacement kit number will be provided by the unblinded statistician. If 
there is an additional site included, then the drug supply may be shipped to Einstein from the 
single site, where it will be stored and distributed in a sequential and blinded fashion to the sites 
by overnight mail on ice within one to seven days prior to the planned treatment   date. 
 
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 sites 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. 
The double-blind patient drug kit is to be given to the participant will be supplied as indicated 
above and labeled with tear-off labels containing the following   information: 
 
• 
Study ION-03 OAB 
• 
Subject identification number (kit number) 

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• 
Contains two or three 2 mL sterile borosilicate vials (each vial contains either 4000 
μg per mL hMaxi-K or PBS-20% sucrose  placebo) 
• 
INSTRUCTIONS: Inject 0.2 mL of study drug into the bladder wall (as directed at 20 
sites for Cohort 1 and at 30 sites for Cohort 2) approximately 1 cm apart. 
• 
Store kit at -20o C in a locked freezer prior to use. Store at controlled room 
temperature once thawed: 15º C to 30º C (59º F to 86º  F). 
• 
CAUTION: New Drug – Limited by Federal Law (or United States) to investigational 
use. 
Ion Channel Innovations, LLC 
969 Park Avenue, Suite 1G 
New York, NY 10028 
 
The lot # for hMaxi-K used in this study is FIN0400 and the lot # for PBS-20% sucrose is FP- 
012-092906. 
 
The gene product or PBS-20% sucrose will be prepared and administered in the same manner as 
Botox® is administered in the office. The participant kit will be taken from the freezer and the 
vials warmed to room temperature and the cap of the vial will be wiped with alcohol. The 2 or 3 
vials in the kit will be administered sequentially.  This sequential administration of vials for a 
total of 4 ml or 6 ml volume maintains the study blind while minimizing the risk for bacterial 
contamination that could occur if the vials were mixed prior to   administration. 
 
To minimize the possibility of dehydration and/or a vasovagal response after required blood 
collections or the hMaxi-K administration, participants will be instructed to eat breakfast and 
abstain from any alcohol products on that  morning. 
 
The investigator (or designee) should administer the drug and must remain blinded. 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. 
 
5.3 
Dose Selection and Administration 
 
Two doses of hMaxi-K will be evaluated: 16000 µg and 24000  µg. 
Up to 9 female participants (6 participants on active treatment and 3 on placebo) will be enrolled 
per dose level “arm”. The 2 active doses to be evaluated sequentially are 16000µg and 24000µg 
compared to direct intramuscular injection into the bladder wall of PBS-20% sucrose (control 
group).  Additional participants may be enrolled for evaluating the tolerability to a given   dose. 

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Each arm of 9 participants per dose level will be enrolled sequentially, beginning with the lowest 
dose.  Enrollment of the first 4 participants in each cohort will be managed directly by the 
sponsor (or their designee) with a 2-day waiting period following each participants dosing. The 
next participant will be enrolled only after the site has contacted the previously dosed participant 
on day 3 following transfer to determine if a clinically significant adverse event occurred. The 
site will contact the clinical monitor with the result of that contact. In the event that no event 
occurred the next participant will be enrolled. The DSMB will review eligibility and all available 
safety data after the 5th  participant has been administered study drug in the first dosing   cohort. 
This first review will occur as soon as possible after the 5th participant’s 3-Day Post-visit 2 
telephone contact. Following their review of the safety data, the DSMB will recommend 
whether enrollment into the first dosing cohort may proceed. This process will be repeated 
through the 5th participant in each cohort before the balance of the cohort (4 additional 
participants) is enrolled. 
If a clinically serious sign or symptom is reported the medical monitor will contact all the sites 
and no further enrollment will be done until the medical monitor or sponsor gives permission. In 
addition, enrollment into the next cohort or arm in the series (at the next highest dose) will be 
dependent on safety dose-limiting toxicity assessments as per Section 5.2 There has been no 
toxicity observed at any dose level in any of the preclinical or clinical trials at any dose to date, 
including multiple dosing in the ED rat model. In the completed clinical study evaluating 
intracorporal administration of up to 16000 µg hMaxi-K in participants with ED, there was only 
one adverse event considered possibly related to hMaxi-K (“tingling warmth in the   glans”). 
In the previous OAB trial there were several events considered possibly related: UTI; AV block 
Mobitz type II (possibly related; mild severity, 170 days post treatment); fatigue, headache, 
shaking chills, and insomnia (all possibly related; mild-moderate severity; 13-76 days post 
treatment). In the placebo group heart palpitations were reported (possibly related, mild severity, 
occurred 6 days post treatment). 
The obstructed bladder pre-clinical studies in the rat evaluated single doses of up to 1000 µg 
based on surface area of the bladder. In the rat ED model, doses of up to 1000 µg were 
administered by intracavernous injection. In men with ED, doses of up to 16000 µg were 
administered by injection into the corpus cavernosum (similar to iv). For ease of administration 
(based upon manufacture and storage of the hMaxi-K), during this OAB trial 16,000 and   24,000 
µg of hMaxi-K have been chosen for bladder wall injection. These concentrations of drug are 
well within the doses used in the preclinical studies. The doses evaluated in this trial will be 
equivalent to 240 and 480 µg used in the rat  studies. 
In addition to preclinical toxicology data, selection of dose was also based upon activity seen in 
the preclinical pharmacology studies. In the Partial  Urethral  Obstruction  (PUO)  studies  in 
female rats, 100 µg in one ml bladder instillation demonstrated highly significant changes. The 
100µg dose also corrects detrusor overactivity in the male PUO model. Therefore, based upon 
preclinical results one would expect to observe an effect in the lowest dose. A rabbit study to 
evaluate the distribution of different volumes of gene transfer injected into the bladder wall was 
performed prior to initiation of the clinical trial using direct intravesicular injections in women 
with OAB. Nine female Adult New Zealand white rabbits weighing an average of 6 pounds were 
used. The animals were anesthetized and pVAX-lacz was to be injected into the detrusor in 0.05, 
0.1, and 0.15 ml aliquots into 4, 8, and 10 sites in the bladder wall. An additional set of 3 animals 
was to be injected with carrier alone at only the highest volume of carrier (4, 8, or 10 sites x 0.15 

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ml). The plasmids were in solution at a concentration of 4000 microgr/ml. One week later the 
animals were euthanized and the bladders excised and weighed. Areas with blue color were 
prepared for histological examination and molecular analysis. Molecular analysis of hslo 
expression tissue was done with RNA extraction and real time  PCR. 
One rabbit was given the 0.05 ml injection. Six rabbits had 0.1 ml at 4, 8, and 10 sites (3 from 
inside the bladder; 3 from outside the bladder). Three rabbits had 0.15 ml at 4, 8, and 10 sites. 
Results indicated that those rabbits with a greater number of injections (8-10 injections) had less 
expression than some animals with the smallest number of injections (4 injections). The overall 
conclusion is that the direct injection into the bladder wall results in expression of the gene 
however, it seems to work best with wider dispersion of the injections perhaps 1 cm   apart. 
 
 
5.2.1 Stopping Rules 
 
No acute toxicity was seen in the preclinical studies in rats with administered intravenous doses 
up to 1000 µg (approximately 1500 µg/kg in the rat). Potential toxicities would be those that 
could occur  (1) because of enhanced efflux of K+  with resultant decreased intracellular   Ca++ 
concentration, thus altering smooth muscle function in diverse organ systems; (2) reaction to the 
naked DNA. 
 
In the event that any participant experiences one of the following events, no additional 
participants will be accrued and no further doses of hMaxi-K will be administered until the 
DSMB and FDA have reviewed the case and have provided their recommendation to the 
sponsor. 
 
1) Urinary retention, i.e., the inability to micturate for more than 12 hours with a urine 
bladder volume (greater than 400 ml established by bladder scan) that requires placement 
of a bladder drainage catheter. 
2) Any adverse event of Grade 2 that last longer than 96 hours or Grade 3 or higher in the 
blood chemistry, completed blood count or urine categories of  adverse  event  criteria 
listed in Appendix A. 
3) In the event of a clinically significant sign or symptom reported by the site PI to the 
medical monitor in any of the first four participants of each cohort unless permission is 
given by the medical monitor. 
4) Bladder pain and /or irritation that persists for four hours or more after gene transfer that 
is thought by the Principal Investigator not to be related to acute trauma from the 
cystoscopy, direct bladder muscle injections, and catheterization. 
 
Clinical data regarding the event will be collected, reviewed, and discussed with DSMB and 
FDA. After review of these data with FDA the clinical study may resume only with concurrence 
of FDA. 
 
5.2.2 Dose Escalation 
 
The DSMB will review participant’s eligibility data and all unblinded safety data at 4   weeks 
following administration of study drug for the last participant enrolled into each dose cohort,   in 

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order to assess the need for modifications in safety monitoring and/or dosing. Following their 
review of the safety data for the last participant in the cohort at the 4th week post-dosing, the 
DSMB will recommend whether or not enrollment into the next dosing cohort may proceed 
(Section 11.2). 
 
The DSMB will inform the sponsor or designee of their decision to dose escalate in   writing. 
The DSMB will also review all safety data following the occurrence of any event throughout the 
study that would stop the clinical study (section 5.2.1) within a reasonable period of time 
following the occurrence of the event. Additional meetings may be schedule if requested by the 
DSMB. 
The DSMB will review the unblinded safety data from the participants in all the cohorts at the 
six month timepoint following the final  dose. 
 
5.3 
Randomization and description of blinding methods 
 
Sites will be provided blinded treatment code identities. For each participant there is supplied a 
tear off label which should be kept in the participant’s source records, affixed to a study 
treatment label page. This removable panel contains a scratch off laminate which would serve to 
unblind the treatment if necessary. The DSMB will receive the blinded codes from unblinded 
statistician. 
 
The treatment code must not be broken by the site unless there is an emergency situation where 
the appropriate management of the participant necessitates knowledge of the treatment  
allocation. Every attempt must be made to contact appropriate sponsor personnel prior to 
breaking any participant’s treatment  code. 
 
5.3.1 Assigning participants to treatment group 
 
The study is a randomized study with an imbalanced-block design (e.g., 6 active and 3 placebo 
participants per treatment group). As each participant signs a consent form, they will receive a 
sequential participant number according to their chronological order of screening within each 
site.  This will be their Screening number.  The schedule of randomization numbers and  
sequence will be generated centrally by the CE3 Inc. Statistical group. This code will be  
provided to the packaging group (Sharp Clinical Services Inc.) who will package the study drug 
and blind the random number with a corresponding kit  number. 
 
When a participant is qualified for randomization and meets all of the inclusion criteria and none 
of the exclusion criteria, the site requests a shipment of a study kit from the Clinical Supplies 
Manager who assigns and ships the next available numbered kit as per the assignment schedule 
to the site.  The kit number allocated will be documented in the participant’s electronic case  
report form (E-CRF) and source notes. This will be the participant’s assigned kit number which 
will be their random number provided by CE3 Inc. Statistical  group. 

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5.3.2 Packaging and labeling 
 
Each participant’s assigned kit will contain a two-part (tear-off), label. The label will contain 
appropriate information including the study number, contents, dosing directions, name of 
sponsor, storage conditions, packaging lot number, treatment number, visit number. The 
duplicate portion of this label will be detached and affixed to a page in the source documents as 
outlined in section 5.1. 
 
5.4 
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 2 months of study entry (including over-the-counter preparations) will be 
recorded on the Concomitant Medication Form. Any changes in concomitant medication,  
including additions, discontinuations, and dose changes, occurring during the study will be 
recorded on the concomitant medication form. If participants are receiving hormone replacement 
therapy, dosing should be stable for at least 2 months prior to enrollment and remain stable 
throughout the study. 
 
Participants are not allowed to concomitantly use any approved, unapproved, or investigational 
medications or therapies intended to treat OAB/UUI. Anticholinergic or antimuscarinic agents 
are not permitted.  These medications/therapies include, but are not exclusively limited to  
Detrol (tolterodine), Ditropan (oxybutynin), Enablex (darifenacin), 
VESicare  (solifenacin), SancturaTM  (trospium), ddAVP.   In addition, Botox® (Botulinium 
Toxin A)  or 
related products are not permitted.  Use of Myrbetriq®  (mirebegron) is also an exclusion.    Agents 
known to affect urine production output or detrusor function should also be avoided or kept 
constant throughout the study (if permitted by Sponsor), including: adrenoreceptor (alpha1a 
subtype) antagonists; adrenoreceptor agonists (beta2 and beta3 subtypes); phosphodiesterase-1 
inhibitors; adenyl cyclase stimulators; neurokinin receptor antagonists (NK-1, NK-2 subtypes); 
potassium channel activators; calcium channel blockers; serotonin reuptake inhibitors (serotonin- 
noradrenalin uptake inhibitors); cyclooxygenase-2 inhibitors. Thiazide diuretics alone or in 
combination with antihypertensive medications are acceptable if the dose and dose regimen is  
kept constant throughout the study. All other diuretics will be excluded, unless approved by the 
Sponsor or their designee prior to the participant’s entry into the study. The investigator should 
consult the Trial Monitor for any specific questions related to concomitant medication initiation 
or change.   Participants should not take any antiplatelet including over the counter NSAIDs  
and/or anticoagulant drugs for at least 10 days prior to the treatment   visit. 
 
6.1 
Outcome Assessments and Procedures 
 
6.2 
OAB / DO Objective Assessment: Cystometry 
 
Clinical assessment of the efficacy hypothesis that hMaxi-K will reduce detrusor overactivity. 
Detrusor overactivity will be assessed with two standardized, sitting position, saline cystometries 
followed by pressure flow studies (see Appendix D). Every attempt should be made to perform 
the studies at the same time of day and in the same way for each participant. Studies are to be 
completed at V1A (screening), V5 (4 weeks post dosing with study drug) and V8 (or Final   Visit). 

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An over-reader will interpret the results as well as the investigator. If there is a discrepancy 
between the reads, then the central over reader’s interpretation will take   priority. 
 
 
 
 
Table 7: Cystometry Parameters and  Definitions 
Parameter 
Description 
Definition 
DO; Yes/No 
Detrusor overactivity ≥ 5 cm H2 O 
Any involuntary contraction that has a pressure 
>/= 5 cm H2 O (INCLUSION CRITERIA) 
VFirst des 
(mL) 
Volume at first desire to void 
The volume attained during filling cystometry that 
would lead the patient to pass urine at the next 
convenient moment but voiding can be delayed if 
necessary (ICS definition). 
Pdet. open (cm 
H2 O) 
Detrusor pressure at beginning of 
voiding (prior to onset of first 
contraction (either volitional or 
involuntary) 
Detrusor pressure at onset of the first detrusor 
contraction (either volitional or involuntary). 
V1st (mL) 
Volume at first involuntary contraction; 
if detrusor overactivity (DO) present. 
Not applicable if no DO present. 
Volume infused at the point of maximum detrusor 
pressure during the 1st contraction. 1 
Detfrq 
Total number of detrusor contractions 
during procedure (voluntary AND 
involuntary) 
Total number of detrusor contractions including 
voluntary AND involuntary 
Leak 
(Yes/no) 
Was there a leak with overactivity 
Involuntary detrusor contractions resulting in leak 
(NOT counting voluntary voids). 
DO Leak freq 
Number of involuntary detrusor 
contractions resulting in leak (if DO 
present) 
Number of involuntary detrusor contractions 
resulting in leak (if DO present).1 
Vleak  (mL) 
If yes, Volume of each leak 
Volume of each leak for each episode of leak2 
Vleak cum 
(mL) 
If yes, cumulative volume of ALL 
leaks during procedure 
Cumulative volume of leaks (calculated by 
computer from individual volumes) 2 
DO No Leak freq 
Number of involuntary detrusor 
contractions NOT resulting in leak. 
Total number of involuntary detrusor contractions 
that do not have an associated leak. 1 
Pdet  Max 
(cm H2 O) 
Maximum detrusor pressure at 
involuntary contraction 
Maximum amplitude of detrusor contraction 
during an involuntary contraction (if present) 3 
Pdet 1st 
(cm H2 O) 
Maximum detrusor pressure at FIRST 
contraction 
Max detrusor pressure at FIRST contraction 
(voluntary or involuntary). 1 
PDet Any 
(cm H2 O) 
Maximum detrusor pressure at ANY 
contraction 
MAXIMUM detrusor pressure attained during the 
entire study (voluntary or involuntary). 4 
Cys Cap 
(mL) 
Cystometric Capacity: Volume at 
strong urge to void 
The volume at which the patient feels that he/she 
can no longer delay micturition (has a strong 
desire to void). (ICS definition) 
Qmax 
(mL / sec) 
Peak flow rate during voiding (for both 
leaks and voluntary voids) 
The Maximum rate of flow during any void (for 
both involuntary and voluntary voids) 
V voided (mL) 
Total voided volume (leaks and 
voluntary) 
Total volume voided for leak and volitional voids 
during the procedure 
PVR (mL) 
Post Void Residual Volume (PVR) 
(from  catheterization) 
Volume left in bladder after voiding at the 
conclusion of the study. This is measured by 
urodynamic catheterization. 
(Vtotal bladder) 
(mL) 
Total Bladder Volume 
(Total voided 
volume +catheterized PVR) 
Post void residual volume + total voided volume 
(will be calculated) 

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DO dur 
(seconds) 
Duration of detrusor overactivity 
Duration of MAXIMUM detrusor activity. 2 

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C 
 
 
 
Digitized recordings should be captured and stored for each patient. Waveforms from filling 
cystometries and pressure flow studies will be interpreted by a trained professional for each 
parameter noted above in table. Printed waveforms should be kept with the patient’s source 
records, with items such as artifacts and peak pressure measurements clearly identified (see 
details in Appendix D). 
 
Table 7.   Procedure Flow Guidance on Cystometry Visit Days (and  Cystoscopy) 
 
Review diaries, pads, con meds, and AEs; 
ECG, physical exam, vital signs, QoL 
assessments, questionnaires 
Prior to cystometry 
Bladder Scan 
Bladder scan at V8 to be done 
before catheterization for urine 
culture. 
Urinalysis 
Prior to cystometry (by Dipstick at Visit 
1A) 
Urine culture 
Prior to cystometry by catheterization 
and repeat prior to discharge by clean 
void 
Urine/blood for hSlo cDNA  detection 
Prior to cystometry (not at Visit 1A  ) 
Phlebotomy 
Prior to cystometry (not at Visit 1A  ) 
Cystometry 
Should be done exactly the same way at 
each visit 
Cystoscopy: Visit 2 Only 
 
 
 
PDet, Q Max 
(cm H2 O) 
Detrusor pressure at maximum flow 
during an involuntary contraction 
Maximum detrusor pressure during terminal void 
(voluntary or involuntary). 2 
Vbladder  DO 
(mL) 
Bladder volume at each involuntary 
detrusor contraction 
Infused bladder volume at the peak pressure of 
each involuntary contraction minus the amount 
leaked at each point for each involuntary 
contraction; Total will be calculated by the 
computer. 2 
Pabd   (cm 
H2 O) 
Maximum abdominal pressure during 
any contraction 
MAXIMUM abdominal pressure during ANY 
contraction. This will assess the abdominal 
straining component to voiding. 2 
1. 
This i
2. 
Done
3. Detru
4. Maxi 
on e 
s done by overreader, but not the sites 
by site only 
sor pressure at first involuntary contractio 
mum detrusor pressure at ANY contraction
RF. 
n is called “Detrusor Pressure” for sites on eCRF. 
is called “Maximum Detrusor Pressure” for sites 

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Table 7.   Procedure Flow Guidance on Cystometry Visit Days (and  Cystoscopy) 
 
Review diaries, pads, con meds, and AEs; 
ECG, physical exam, vital signs, QoL 
assessments, questionnaires 
Prior to cystoscopy and drug 
administration 
Urine/blood for hSlo cDNA  detection 
Prior to cystoscopy and drug 
administration 
Urinalysis 
Prior to cystoscopy (by Dipstick at Visit 
2 prior to drug administration) 
Urine culture 
Prior to cystoscopy by catheterization 
and repeat prior to discharge by clean 
void (first clean void after study drug 
administered) 
Phlebotomy 
Prior to cystoscopy 
Administer the local anesthesia through a 
catheter 
At Visit 2 only; after all required 
Baseline procedures completed 
Cystoscopy 
At Visit 2 only, insert cystoscope 10-20 
minutes after local anesthesia  given 
Study drug administration through a 
cystoscope 
At Visit 2 only, 20-30 injections in 
bladder wall depending on dose 
Blood pressure 
BP will be taken every 15 minutes for 2 
hour post administration of study  drug. 
Urine/blood for hSlo cDNA detection;  ECG 
2-hours post-dosing 
 
 
6.3 
Clinical Evaluation of OAB / DO 
 
6.3.1 Voiding Diary 
Clinical signs and symptoms of OAB / DO will be determined by a daily voiding diary. The 
participants must complete the diaries for the 7 days prior to the Baseline visit (visit 2), and for 7 
days prior to visits 3-8. The participants will also complete the diaries prior to visit 1A to test for 
compliance and evaluate for some inclusion criteria. The site will contact the participant 7-8 days 
prior to the scheduled visit (V2-8) to remind the participant to complete the diary. The daily 
voiding diary will collect standard bladder function and frequency parameters including frequency 
of micturitions, volume voided and urgency episodes. The urgency questionnaire is a 4 point 
scale.   See Appendix F. 
 
6.3.2 Pad Test 
Each participant will record their use of any pads/panty liners (e.g., Poise pads or Depends, 
etc.) in their diary. The participant will bring in pads/diapers worn prior to Visit 1A and for the 
three days prior to Visit 2 (as well as a new pad/diaper to use as a baseline) and for the 3 days 
prior to all subsequent visits (V3 to V8).  Used pads/diapers will be stored in a plastic   bag 

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provided by the site and weighed upon receipt and compared to the clean pad. All pads/diapers 
used by the participants for the 7 days prior to each visit, will be counted by the participants and 
entered in the voiding diary by  themselves. 
 
6.3.3 King Health Questionnaire and Assessment of Disease State/Treatment 
 
Patients will also complete a disease-specific quality of life tool, the King’s Health Questionnaire 
(KHQ) at Baseline (V2 prior to dosing), V5, V6, V7, and end of study (V8). See Appendix B. 
Patients will also be queried on subjective assessment of their disease state at Baseline (V2), and 
subsequent visits. Participants will also be asked to evaluate their response to treatment at Visits 
3 to 8. Participants will rate their perceived bladder condition severity at Baseline (V2) and 
Visits 3 to 8 using a 6-validated point rating scale (1, no problems; 2, very minor problems; 3, 
minor problems; 4, moderate problems; 5, severe problems; and 6, many severe   problems). 
Participants' assessment of their response to treatment will be measured by asking "Has the 
treatment been of benefit to you?" with possible responses of no benefit; yes, a little benefit; and 
yes, very much benefit. See Appendix  C. 
 
6.3.4 International Consultation on Incontinence Questionnaire-Short From 
 
The International Consultation on Incontinence Questionnaire- Short Form will be completed in 
this study by all participants at V2, 5, 6, 7, and 8.  Please refer to Appendix   E. 
 
6.2. 5  SF-12 
 
The SF-12 which includes 12 questions evaluating general quality of life will be completed in 
this study by all participants at V2, 5, 6, 7, and 8.  Please refer to Appendix   G. 
 
6.4 
Bladder Scan 
 
Residual volume will be measured using a scan of the bladder. This examination will be carried 
out at the Screening visit (V1) and V4, 6, and 8. At Visit 1 and Visit 8 urine cultures by 
catheterization should be done after bladder scans are performed. Copies of the bladder scan 
figures supplied by the device or a report of the examination must be appended to the patients’ 
source documents. 
 
6.5 
Physical Evaluation 
 
6.5.1 Physical Examination 
A complete physical examination, including a complete urogenital exam, and review of body 
systems will be performed at V1 to V8 (excluding V1A). Vital signs (pulse, respiratory rate, oral 
body temperature, and blood pressure) will be performed at all visits as below (except V1A). 
Height will be obtained at Screening V1 only. Weight will be obtained at Screening V1 and V8. 
Any untoward clinically significant change from Screening will be recorded on the E-CRF as an 
adverse event. 

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6.5.2 ECG 
A 12-lead ECG will be performed at Screening (V1) Baseline (V2 -prior to treatment and 2 hours 
post treatment), V3, V5 and V8. These ECGs obtained at the study centers, will be forwarded to 
a central reader for final interpretation by a board-certified cardiologist or physician board  
certified in ECG interpretation. The over reader will return the results to the study center within 
48 hours. This does not negate the responsibility of the staff conducting the study to initially 
review the ECG and to take appropriate clinical actions. The following parameters will be 
assessed: heart rate, rhythm, PR interval, RR interval, QT interval, QTcF, QTcB, QRS duration, 
and overall evaluation. For the Visit 2 pre-dose ECG, if abnormalities or clinically significant 
changes are noted from V1 screening ECG, then the investigator in conversation with    the 
Sponsor and/or designee will determine the participant’s eligibility to proceed with   dosing. 
 
6.5.3 Vital Signs 
 
Vital signs will be performed at all visits as above (excluding V1A).  Vital signs should include 
an apical pulse measurement and brachial blood pressure both taken after 5 minutes resting in the 
sitting position (standard sphygmomanometry). For all blood pressure measurements, the same 
arm should be used throughout the study and whether the right or left arm is used should be 
specified. Oral body temperature will be obtained at all visits (except V1A). Any clinically 
significant changes from screening will be recorded on the E-CRF as an adverse   event. 
Following administration of study drug at V2, BP and pulse will be measured and recorded every 
15 minutes for 2 hours. 
 
6.6 
Laboratory Safety Tests 
 
Laboratory safety tests will be performed at Screening (V1), Baseline (V2) and 1 (V3), 2 (V4), 4 
(V5), 12 (V7), and 24 (V8) weeks post dosing with study  drug. 
 
The laboratory safety tests  include: 
• Hematology: V1, V2-V5, V7-V8; Complete blood count (CBC) with differential, platelet 
count, sedimentation rate (sed. rate), PT and PTT (no PT and PTT at V2 and V4). 
 
• Fasting chemistry: V1,V3-V5, V7-V8; Blood Urea Nitrogen (BUN), creatinine, 
electrolytes (Na+, K+, Mg++ , Ca++, CO2, Cl), albumin, alkaline phosphatase, ALT, AST, 
GGT, LDH, CPK, total bilirubin, total protein, C-reactive protein (CRP), antinuclear 
antibody (ANA), and glucose. V4 chemistry testing: Blood Urea Nitrogen (BUN), 
creatinine, electrolytes (Na+, K+), C-reactive protein (CRP), glucose, and ANA only. 
• At screening, participants of child bearing years must have a serum pregnancy test for 
beta- HCG if they have not had a hysterectomy.  In addition, they must have either a 
serum FSH >40 IU/L or a history of no menses for more than 12 months to confirm post- 
menopausal status if a hysterectomy or bilateral tubal ligation has not been done. 
• At screening only, participants must have a serum hemoglobin A1c performed 

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• Urine analysis; Conducted at V1, V1A (by dipstick), V2 (by dipstick), V3-V5, V7-V8; 
microscopic RBC and WBC, protein, glucose, nitrites, pH, and specific gravity. Dipstick 
will measure blood, leukocyte esterase and nitrites. 
 
• Urine culture: At Screening Visit 1 and 1A (collect by catheterization) and at V3. At Visit 
1A, Visit 5 and Visit 8, prior to cystometry (collect using urodynamic catheter) and 
repeated with clean void prior to discharge. At Visit 2, collect using urodynamic catheter 
prior to cystoscopy and first clean voided urine after study drug dosing. If V1A 
cystometry performed at V1 then urine cultures pre-and post-cystometry should be done 
using urodynamic catheter before cystometry and repeated with clean void prior to 
discharge. 
 
6.7 
Concomitant Medication 
 
At baseline, a history of concomitant medications taken within the past 2 months with special 
attention given to treatment with anticholinergics, antispasmodics or antimuscarinic medications 
(including mirebegron and Botox) will be completed. At subsequent visits, assessments of any 
changes in medication for all prescription or nonprescription medications will be   performed. 
 
6.8 
Pharmacokinetics 
 
Urine and blood specimens will be obtained at Visit 2 (pre-dosing and 2-hour post dosing) and 
Visits 3-8 for analysis of hSlo cDNA with PCR. If DSMB states specimens are still positive after 
6 months, then the participant will be required to return monthly until 2 consecutive specimens 
are negative and this may unblind this  participant. 
Instructions for collection of urine and 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) 
Urine 
• Collect urine sample in sterile container, label and freeze immediately at -20 (or 
colder) 
 
6.9 
Laboratory Evaluations 
 
A local safety laboratory (for example Quest) will perform analysis of all blood and urine 
specimens. The blood samples for the safety laboratories evaluations should be taken when the 
participant is fasting if possible. In addition, the participant should be asked to not perform any 
strenuous exercise or activities prior to blood  sampling. 
 
The urine analysis done immediately prior to cystometry and drug administration will be 
performed by the PI with a Dipstick™ to see if the Dipstick™ is positive for leucocytes   and 

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nitrites which may be a sign of infection. A spun microscopic evaluation may be required for 
further evaluation, 
Urine and blood specimens that are collected from the participants will have real time PCR  
testing done for detection of hSlo cDNA in the Urology laboratory at the Albert Einstein College 
of Medicine. It is anticipated that the following amounts of blood will be collected for the 
following procedures over the 6 month study  participation: 
 
 
 
Table 8.  Blood collection (minimum amount of blood that should be   taken) 
Procedure 
Visit number 
Blood volume 
drawn (mL) 
Total blood volume 
drawn (mL) 
Chemistry 
1, 3, 4, 5, 7 and 8 
15 
90 
Hematology 
1, 2, 3, 4, 5, 7 and 8 
3.0 
21 
Blood for analysis of hSlo cDNA) 
2 (pre- and 2 hr 
post-dosing), 3, 4, 
5, 6, 7 and 8 
0.5 
4 
Minimum volume of blood drawn for study over 6  months: 
115 ml 

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Table 9.  Summary of Laboratory Tests By  Visit 
Chemistry 
Fasting 
Hematology βHCG HA1c 
FSH Urine Cultures hSlo 
Blood/ 
urine 
Urinalysis 
Visit 1 
♦ 
♦ 
♦ 
♦ 
♦ 
1 (one from 
catheter 
drainage) – after 
bladder scan 
♦ 
Visit 1A 
Cystometry 
2 (one from 
catheter 
drainage pre- 
cystoscopy and 
1 from first 
clean void post- 
cystoscopy) 
via dipstick 
Visit 2 
(Treatment 
by 
Cystoscopy) 
♦ 
No PT/PTT 
2 (one from 
catheter 
drainage pre- 
treatment and 1 
from first void 
post-treatment) 
♦ 
(blood and 
urine: pre- 
dosing and 
2 hours 
post- 
dosing) 
via dipstick 
(prior to 
treatment) 
Visit 3 
♦ 
♦ 
1 (clean void) 
♦ 
♦ 
Visit 4 
♦ 
♦ 
No PT/PTT 
♦ 
♦ 
Visit 5 
Cystometry 
♦ 
♦ 
2 (one from 
catheter 
drainage pre 
and 1 from first 
clean void post) 
♦ 
♦ 
Visit 6 
♦ 
Visit 7 
♦ 
♦ 
♦ 
♦ 
Visit 8 
Cystometry 
♦ 
♦ 
2 (one from 
catheter 
drainage pre 
and 1 from first 
clean void post- 
treatment); 
Bladder scan 
prior to 
catheterization 
♦ 
♦ 

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7.1 
Schedule of Evaluations 
 
The schedule of evaluations is summarized in Table 1 and described in detail   below. 
 
7.2 
Visit 1 (Study Week - 2: Screening) 
 
The following evaluations and tests will be  performed: 
• Preliminary Screening: 
• Obtain written informed consent process for study participant; 
• A sequential participant enrollment Screening number will be assigned to each patient 
who signs an informed consent; 
• Review inclusion/exclusion criteria, medical history including history of OAB/DO and 
prior/concomitant medications to assess eligibility for study treatment; 
• Determine proof of surgical sterilization or menopause; 
• Physical examination including urogenital examination and vital signs (with height and 
weight); 
• Complete screening if entry criteria are met on preliminary screening: 
• Bladder scan for residual volume and bladder capacity (prior to catheterization for urine 
culture); 
• Obtain urine for routine urine analysis: microscopic RBC and WBC, protein, glucose, 
nitrites, pH, and specific gravity; 
• Obtain a catheterized urine specimen for culture (after bladder scan); 
• Electrocardiogram; 
• Blood specimens for the following laboratory determinations: 
o Hematology: Complete Blood Count (CBC) with differential, platelet count, 
sedimentation rate (sed rate), PTT and PT. 
o Fasting chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, 
K+, Ca++, Mg++, CO2, Cl), albumin, alkaline phosphatase, ALT, AST, GGT, 
LDH, CPK, total bilirubin, total protein, C-reactive protein (CRP), antinuclear 
antibody (ANA), and glucose 
o Serum pregnancy test; FSH > 40 IU/L if last menstrual cycle not > 12 months 
prior to study enrollment and no hysterectomy or bilateral tubal ligation 
documented. 
o Blood hemoglobin A1c 
• Provide patient with diary materials; 
• Instruct the participant to complete daily voiding diaries for 7 days prior to next visit (if 
Visit 1A is scheduled within less than 1 week, then these diaries can still be used to 
review compliance, answer any questions participants have about diary completion, and 

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review inclusion criteria such as incontinence) and return with results at next visit 
including pads used for 72 hours prior to that visit (and clean pad to be used as   baseline); 
• Inform the participants that they should not take any antiplatelet drugs including over the 
counter NSAIDS and/or anticoagulant drugs, for at least 10 consecutive days prior to  
Visit 2. 
• Schedule next study visit for Screening cystometry when Screening laboratory results are 
available (within at least 1 week). 
• Depending on the screening results some participants may be allowed to rescreen, if they 
are unable to be dosed in a timely fashion due to some unforeseen factors (e.g., 
hospitalization for fracture,  etc.). 
In this circumstance the same participant will be 
assigned a different screening number. 
• If a participant meets all inclusion/exclusion criteria, but has a positive urine culture at 
screening, then all screening evaluations performed at V1 (and V1A) may be accepted 
after the participant is treated with appropriate antibiotics and the urine cultures come 
back negative. The maximum time frame would be approximately up to 4 weeks after 
screening V1A for acceptance of these screening evaluations after discussion with the 
sponsor or designee. 
• If necessary due to scheduling issues, Visit 1A (i.e., screening cystoscopy) can overlap 
with Visit 1. In this case Visit 1A procedures not already performed at Visit 1 will be 
completed at Visit 1 (pads and diaries will not be available in this case). If V1A coincides 
with V1, then pad collection and diaries will not be completed prior to V1A and these 
must be checked for compliance at V2. 
 
7.3 
Visit 1A (Study Day - 14 to -8): Screening Cystometry 
 
• Review medical history and results of ECG and lab tests for eligibility and for any events 
which occurred after informed consent was signed at the screening visit. These events 
should be recorded on Medical History page; 
• Review concomitant meds since last visit; 
• Review voiding diaries and check compliance with completion (do not enroll 
participant who is not compliant) and for inclusion criteria such as incontinence; 
• Collect and weigh pads used for 72 hours (check for participant compliance); 
• Collect urine for urine culture prior to (using urodynamic catheter) and post cystometry 
(clean void). Also prior to cystometry, test sample of this urine by Dipstick™ in office to 
ensure there is no increase in leucocytes and nitrites; 
• Have participant empty bladder and then perform baseline cystometry using preferably 7 
or 8 French catheter (detrusor overactivity with ≥1 uncontrolled contraction(s) of the 
detrusor of at least 5 cm/ H20 pressure must be documented during this Screening 
urodynamic testing) (see Appendix D); 
• If participant is eligible, schedule Visit 2 at least 8 days (+2 days) after Visit 1A (they 
must complete 7 consecutive days of diaries prior to V2). 

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• Remind the participants that they should not take any antiplatelet/anticoagulant drugs 
including over the counter NSAIDS prior to the next visit. 
 
7.4 
Visit 2 (Study Week 0: Baseline - Administration of study drug) 
 
Based on the participant fulfilling all eligibility criteria following the screening procedures (Visit 
1 and Visit 1A) 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 participant will be considered a 
screen failure. 
 
The following tests and evaluations will be performed on eligible   participants: 
 
• Review medical history, results of ECG, cystometry and lab tests for eligibility and for 
any events which occurred after informed consent was signed at the screening visits until 
prior to dosing at this visit. These events should be recorded on Medical History page. 
New events or changes reported after dosing must be recorded on the Adverse Event log; 
• Review concomitant meds since last visit; 
• Review voiding diaries and check compliance with completion (do not enroll 
participant who is not compliant) and inclusion criteria; 
• Participants complete KHQ, SF-12 (QoL questionnaires) and global assessment of 
disease state prior to cystoscopy and study drug administration (Baseline 
questionnaires); 
• Participants complete the ICIQ-SF (Baseline) prior to cystoscopy and study drug 
administration; 
• Physical examination including urogenital exam and vital signs for changes since the 
screening visit prior to cystoscopy and study drug administration; 
• ECG prior to cystoscopy and study drug administration (and 2 hours post administration 
of study drug). If abnormalities or clinically significant changes are noted from V1 
screening ECG, then the investigator in conversation the Sponsor or designee will 
determine the participant’s eligibility to proceed with dosing. 
• Blood specimens for the following laboratory determinations prior to cystoscopy and 
study drug administration: 
o Hematology: Complete Blood Count (CBC) with differential, platelet count, 
sedimentation rate (sed rate). No chemistry testing required this visit. 
• Obtain freshly voided urine specimen for culture prior to study drug administration using 
urodynamic catheter. Also test sample of this urine by Dipstick™ in office to ensure there 
is no increase in leucocytes and nitrites; 
• Obtain urine and blood specimen for analysis of hSlo cDNA with PCR prior to 
cystoscopy and study drug administration (pre-dosing baseline) and 2 hour post-dosing; 
• Collect and weigh pads used for 72 hours; 

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• Request (kit should be at the site at least 24 hours prior to drug administration) and 
Assign participant kit number; 
• Drain the participant’s bladder through the transurethral catheter. Administer local 
anesthesia through the 7 or 8 French catheter using an instillation of 40 ml of 2% 
lidocaine and 2 % xylocaine gel in the urethra before insertion of the cystoscope. Once 
the catheter is removed administer the assigned randomized dose of study drug by sterile 
aseptic technique as follows. Approximately 10- 20 minutes after the local anesthetic has 
been administered the cystoscopic device can be inserted. Inject intravesically into the 
detrusor muscle, under cystoscopic control, 4 ml (for 16000 µg group) or 6 ml (for 24000 
µg group) of randomized selected drug.  The randomized drug is injected into   the 
detrusor muscle via a rigid cystoscope (preferably 18 to 21 French), avoiding the trigone 
(see Figure 6 below). The bladder should be instilled with enough saline to achieve 
adequate visualization for the injections, but over-distension should be avoided. The 
injection needle should be filled (primed) with approximately 1 mL of study drug prior to 
the start of injections (depending on the needle length) to remove any air. The needle 
should be inserted approximately 2 mm into the detrusor, and 20 injections of either 0.2 
ml (for 16000 ug dose) or 30 injections of 0.2 mL (for the 24000 µg dose) each (total 
volume of 4 or 6 mL, respectively) should be spaced approximately 1 cm apart (see 
Figure 6, below). For the final 5 injections of each dose, PBS 20% sucrose should be 
used in the injection syringe so that the product in the needle is delivered. After the 
injections are given, the bladder should be  drained. 
Figure 6.  Bladder Injection  Sites 
 
 
• The time of voiding following drug administration will be recorded. The participant will 
be observed in the clinic for two hours after the bladder injections are completed. During 
that time blood pressure and pulse will be measured and recorded by the nurse every 15 
minutes. The participant will be asked if there is any persistent pain/irritation in the 
bladder/urethra and will be treated symptomatically, if needed. The participant will be 
asked if they have experienced any new symptoms or problems they want to report to the 
investigator or study personnel. Emergency equipment for resuscitation will be 
immediately available in the event of an unexpected serious reaction to the study drug; 
• Participants are required to stay at the study site for at least 2 to 3 hours after dosing. 
They may be asked stay longer if the investigator believes it is necessary. 

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• Collect first voided urine (clean void) after drug administration for culture prior to 
discharge; 
• Provide participant with diary materials; 
• Provide participant with prophylactic antibiotics prior to discharge (to take immediately 
and for the 2 days following Visit 2) 
• Instruct the participant to complete daily voiding diaries for 7 days prior to next visit and 
return with results at next visit, including pads used for 72 hours prior to that visit (and 
clean pad to be used as baseline). 
 
7.5 
1-Day and 3-Day Post Visit 2 Telephone Contact 
 
One day and three days (3 days ± 1 day) following Visit 2 (when the participant received the 
bladder injections) she should be contacted to assess for any problems she may be experiencing. 
The patient must be asked in a general fashion if she has had any complaints since her last visit. 
All adverse events should be documented on the adverse event E-CRF. The patient may be 
brought back to the clinic sooner than Visit 3 if  required. 
 
7.6 
Visit 3 (Study Week 1 +2 days) 
 
The following tests and evaluations will be  performed: 
 
• Review medical history for events since last visit; 
• Review concomitant meds since last visit; 
• Review voiding diaries; 
• Participants complete global assessment of disease state and response to treatment; 
• Physical examination including urogenital examination and vital signs 
• Electrocardiogram; 
• Obtain blood for the following laboratory determinations: 
o Hematology: Complete Blood Count (CBC) with differential, platelet count, 
sedimentation rate (sed rate), PT and PTT. 
 
o Fasting chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, 
K+, Ca++, Mg++, CO2, Cl), albumin, alkaline phosphatase, ALT, AST, GGT, 
LDH, CPK, total bilirubin, total protein, C-reactive protein (CRP), antinuclear 
antibody (ANA), and glucose; 
• Obtain urine for routine urine analysis: microscopic RBC and WBC, protein, glucose, 
nitrites, and specific gravity, pH; 
• Collect and weigh pads used for 72 hours; 
• Obtain urine and blood specimen for analysis of hSlo cDNA with PCR; 
• Obtain urine culture by clean void; 

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• Provide patient with diary materials; 
• Instruct the participant to complete daily voiding diaries for 7 days prior to next visit and 
return with results at next visit including pads used for 72 hours prior to that visit (and 
clean pad to be used as a baseline). The site must call participants at least 7-8 days prior 
to next scheduled visit to remind patient to complete the diaries for 7 days prior to next 
visit; 
 
7.7 
Visit 4 (Study Week 2 +2 days) 
 
Two weeks after administration of study drug the participant will return to the clinic. The 
following tests and evaluations will be performed on the   participants: 
 
• Review medical history for events since last visit; 
• Review concomitant meds since last visit; 
• Review voiding diaries 
• Collect and weigh pads used for 72 hours 
• Participants complete global assessment of disease state and response to treatment; 
• Physical examination including urogenital examination and vital signs 
• Bladder scan for residual volume and bladder capacity (prior to catheterization); 
• Blood specimens for the following laboratory determinations: 
o Hematology: Complete Blood Count (CBC) with differential, platelet count, 
sedimentation rate (sed rate). 
 
o Fasting chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, 
K+), C-reactive protein (CRP), glucose, and ANA. 
• Obtain urine for routine urine analysis: microscopic RBC and WBC, protein, glucose, 
nitrites, pH, and specific gravity; 
• Obtain urine and blood specimen for analysis of hSlo cDNA with PCR; 
• Provide patient with diary materials; 
• Instruct the participant to complete daily voiding diaries and return with results at next 
visit including pads used for 72 hours prior to that visit (and clean pad to be used as a 
baseline) The site must call participants at least 7-8 days prior to next scheduled visit to 
remind patient to complete the diaries for 7 days prior to next visit; 
 
7.8 
Visit 5 (Study Week 4) 
 
The following tests and evaluations will be  performed: 
 
• Review medical history for events since last visit; 
• Review concomitant meds since last visit; 

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• Review voiding diaries; 
• Collect and weigh pads used for 72 hours 
• Participants complete KHQ and SF-12 (QoL), global assessment of disease state, and 
response to treatment prior to cystometry; 
• Participants complete ICIQ-SF prior to cystometry; 
• Physical examination including urogenital examination and vital signs prior to 
cystometry 
• Blood specimens for the following laboratory determinations prior to cystometry: 
o Hematology: Complete Blood Count (CBC) with differential, platelet count, 
sedimentation rate (sed rate), PT and PTT. 
o Fasting chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, 
K+, Ca++, Mg++, CO2, Cl), albumin, alkaline phosphatase, ALT, AST, GGT, 
LDH, total bilirubin, total protein, C-reactive protein (CRP), CPK, antinuclear 
antibody (ANA), and glucose. 
o Urine analysis: microscopic RBC and WBC, protein, glucose, nitrites, pH, and 
specific gravity; 
• Electrocardiogram prior to cystometry; 
• Collect urine for culture prior to cystometry using urodynamic catheter 
• Obtain urine and blood specimen for analysis of hSlo cDNA with PCR prior to 
cystometry; 
• Perform cystometry; 
• Collect first voided urine (clean void) for culture prior to discharge; 
• Provide patient with diary materials; 
• Instruct the participant to complete daily voiding diaries and return with results at next 
visit including pads used for 72 hours prior to that visit (and clean pad to be used as a 
baseline). The site must call participants at least 7-8 days prior to next scheduled visit to 
remind patient to complete the diaries for 7 days prior to next visit; 
 
7.9 
Visit 6 (Study Week 8) 
 
The following tests and evaluations will be  performed: 
 
• Review medical history for events since last visit; 
• Review concomitant meds since last visit; 
• Review voiding diaries; 
• Collect and weigh pads used for 72 hours 
• Participants complete KHQ and SF-12 (QoL), global assessment of disease state and 
response to treatment; 

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• Participants complete ICIQ-SF; 
• Physical examination including urogenital examination and vital signs; 
• Obtain urine and blood specimen for analysis of hSlo cDNA with PCR; 
• Bladder scan for residual volume and bladder capacity; 
• Provide patient with diary materials; 
• Instruct the participant to complete daily voiding diaries and return with results at next 
visit including pads used for 72 hours prior to that visit (and clean pad to be used as a 
baseline). The site must call participants at least 7-8 days prior to next scheduled visit to 
remind patient to complete the diaries for 7 days prior to next visit; 
 
7.10 Visit 7 (Study Week 12) 
 
The following tests and evaluations will be  performed: 
 
• Review medical history for events since last visit; 
• Review concomitant meds since last visit; 
• Review voiding diaries; 
• Participants complete KHQ and SF-12 (QoL), global assessment of disease state and 
response to treatment; 
• Participants complete ICIQ-SF; 
• Physical examination including urogenital examination and vital signs; 
• Obtain urine and blood specimens for analysis of hSlo cDNA with PCR; 
• Obtain blood for the following laboratory determinations: 
o Hematology: Complete Blood Count (CBC) with differential, platelet count, 
sedimentation rate (sed rate), PTT and PT. 
 
o Fasting chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, 
K+, Ca++, Mg++, CO2, Cl), albumin, alkaline phosphatase, ALT, AST, GGT, 
LDH, total bilirubin, total protein, C-reactive protein (CRP), CPK, antinuclear 
antibody (ANA), and glucose. 
• Obtain urine for routine urine analysis: microscopic RBC and WBC, protein, glucose, 
nitrites, pH, and specific gravity; 
• Collect and weigh pads used for 72 hours; 
• Provide patient with diary materials; 
• Instruct the participant to complete daily voiding diaries and return with results at next 
visit including pads used for 72 hours prior to that visit (and clean pad to be used as a 
baseline). The site must call participants at least 7-8 days prior to next scheduled visit to 
remind patient to complete the diaries for 7 days prior to next visit. 

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7.11 Visit 8 (Study Week 24) or Exit Visit: 
 
The following tests and evaluations will be  performed: 
 
• Review medical history for events since last visit; 
• Review concomitant meds since last visit; 
• Review voiding diaries; 
• Participants complete KHQ and SF-12 (QoL), global assessment of disease state and 
response to treatment; 
• Participants complete ICIQ-SF; 
• Physical examination including urogenital examination and vital signs (and weight); 
• Electrocardiogram; 
• Bladder scan for residual volume and bladder capacity (prior to catheterization); 
• Perform cystometry; 
• Obtain blood for the following laboratory determinations: 
o Hematology: Complete Blood Count (CBC) with differential, platelet count, 
sedimentation rate (sed rate), PTT and PT. 
 
o Fasting chemistry: Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, 
K+, Ca++, Mg++, CO2, Cl), albumin, alkaline phosphatase, ALT, AST, GGT, 
LDH, CPK, total bilirubin, total protein, C-reactive protein (CRP), antinuclear 
antibody (ANA), and glucose. 
• Urine analysis: microscopic RBC and WBC, protein, glucose, nitrites, pH, and specific 
gravity (prior to ultrasound and cystometry); 
• Collect and weigh pads used for 72 hours 
• Collect urine for culture prior to cystometry procedures using urodynamic catheter; 
• Collect first clean voided urine for culture prior to discharge after cystometry; 
• Obtain urine and blood specimens for analysis of hSlo cDNA. If DSMB informs the site 
that hSlo was detectible in either of two preceding specimens, participants will be 
required to return monthly to the clinic post study until there are two negative specimens. 
 
7.12 Visit schedule and Visit Windows 
 
In this outpatient study, every attempt must be made to adhere to the structured visit schedule. 
The Screening period (Visit 1 and 1A) should not exceed 14 days (±2 days) unless approved by 
Sponsor or designee (e.g., UTI found during Screening).  All other visits should occur with 
respect to previous visit: V2, at least 8 days after V1A + 2 days; V3 +2 days; V4 +2 days; V5 ±2 
days; V6± 3 days; V7± 5 days; V8± 5 days. In addition, a 1-day and 3-day (±1 day) post Visit 2 
telephone contact is required to evaluate the subject for any complaints after receiving the   study 

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drug injections. If it is necessary to bring the participant into the clinic for evaluation earlier than 
required, this may be considered an unscheduled visit, unless the participant has completed the 
necessary diary pages and the Sponsor or its designee agrees to the window   deviation. 
 
7.13 Definition of source data 
 
Source data is defined as all information in original records of clinical findings, observations, or 
other activities of the clinical trial necessary for the reconstruction and evaluation of the   trial. 
Source data are contained in source documents. Source documents are the original documents, 
data, and records. Source documents include, but are not limited to hospital records, clinical and 
office charts, laboratory notes and reports, radiological films and reports, memoranda,  
participant’s quality of life assessments, participants voiding diaries and pharmacy dispensing 
records. 
Study data that should be included in the source  documents: 
• Participant’s identity 
• History of the disease 
• Medical history, associated diseases (dates of onset) 
• History of surgical sterilization, if applicable 
• Date and time of administration of the study drug 
• Previous and concomitant treatments 
• Dates of participation in the study 
• A statement on the participant’s chart that the informed consent form was signed by 
the participant 
• Dates of study visits / telephone contacts 
• Examinations or assessments carried out during the study: 
• Laboratory results including cultures 
• Vital signs: blood pressure, heart rate, biological exams 
• ECGs 
• Cystometry readings 
• Adverse events (+ follow-up) 
• Date of drop-out and reason 
 
Study data that will be considered as raw  data: 
• Efficacy data entered by diary 
• Laboratory test results 
• Electronic cystometry results 
• ECG tracings 
• QoL data 
 
 
7.14 Access to the randomization code during the study 
 
In case of a Serious Adverse Event, the code must be broken only in exceptional circumstances 
when  knowledge  of  the  study  medication is essential for treating the participant.   If possible,  a 

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contact should be initiated with the Monitoring Team before breaking the code. The data will be 
reviewed by the DSMB. 
 
For each participant there is a supplied tear off label which should be kept in the participant’s 
source records, affixed to a study treatment label page. This removable panel contains a scratch 
off laminate which would serve to unblind the treatment if   necessary. 
 
7.15 Long-term follow-up 
 
If urine and/or blood samples are still positive for hSlo DNA assay at week 24 the participant 
will be asked to return to the site to give additional urine and/or blood specimens until 2 
consecutive specimens are  negative. 
 
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 
bladder injections of hMaxi-K will continue to be followed after the completion of all study 
related procedures (Visit 8 or last study visit) for an additional 18 months. These participants 
will be contacted at 6 month intervals to evaluate for any safety   concerns. 
 
 
8.1 Participant Withdrawal 
 
While participants are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason. 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 7.13. 
 
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. 
Up to a maximum of 3 participants per dose group may be replaced if participants drop out prior 
to completion of week 4 post study  drug. 
 
8.2 
List of withdrawal criteria 
 
WITHDRAWAL OF A PARTICIPANT DUE TO ANY SERIOUS ADVERSE EVENT 
REQUIRES THAT THE SPONSOR BE INFORMED WITHIN ONE WORKING DAY 
AFTER THE INVESTIGATOR IS MADE AWARE OF THE EVENT. PLEASE REFER 
TO SECTION 9, ADVERSE EVENT  REPORTING. 

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Those participants who do not complete the study for any reason will be considered a premature 
termination. The procedures for the Visit 8 should be completed when a participant discontinues 
the study. 
• 
Adverse Events: 
Participants 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  from  the  study  for non-
medical reasons that the investigator/patient deemed sufficient to warrant premature 
termination. 
• 
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 patient 
who fails to return to the clinic for a scheduled visit in order to complete assessments and 
retrieve any outstanding data. All such efforts should be documented in the source notes. 
• 
Sponsor/Investigator Decision: A participant may be withdrawn at any time at the 
discretion of the investigator. 
 
If a participant discontinues from the  study, she  should  always be contacted in order to give 
the investigator information about the reason(s) for discontinuation and any adverse events. 
Whenever possible, the patient should return for a clinic visit at the time of or soon after 
discontinuation. Any outstanding data or study medication should be collected. Adverse events 
should be followed up. 
 
8.3 
Reasons for withdrawal 
 
The participants may withdraw from the study if they decide to do so, at  any  time  and 
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. 
 
8.4 
Replacement of participants 
 
Up to 3 replacements per dose will be allowed for participants who received study drug and 
discontinue without follow-up data of at least one-month post study drug   administration. 
 
8.5 
Withdrawal follow-up procedure 
 
For participants considered lost to follow-up, the E-CRF must be filled in up to the last   visit. 

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9.1 
Adverse Events Definitions and Monitoring 
 
9.2 
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. 
 
9.3 
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, including emergency room care, 
• Causes persistent or significant disability/incapacity, 
• 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. 
 
 
9.4 
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 participant’s medical condition, other 
therapies, or accident. 

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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 
participant’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 participant’s medical condition or other therapies 
cannot explain the event. 
Definitely 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. 
 
9.5 
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 
living; required bed rest and/or resulted in loss of work or cancellation of social 
activities. Medical intervention required. Hospitalization possible. 
 
• Grade 4: Medical intervention is required to prevent permanent impairment or death; OR 
Permanently Disabling: bed-ridden or disabling, significant medical intervention/therapy 
required, hospitalization or hospice care possible. 
 
9.6 
Monitoring of Adverse Events 
 
The investigator will monitor participants for the occurrence of adverse events during the course 
of the study and record all observed adverse events in the electronic case report   form. 
All Adverse Events regardless of seriousness or relationship to study drug, including those 
occurring during the Screening period (where applicable), are to be recorded on the 
corresponding page(s) in the E-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. 

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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 or following the investigators awareness of the event to the Sponsor’s 
designee: 
Dr Sharon Jacobs 
212-308-0948 
Cell: 646-361-6161 
skrashes@aol.com 
Or 
Dr Arnold Melman 
Cell: 347-782-1734 
arnold.melman@gmail.com 
 
 
 
The Sponsor or designee will report all serious adverse events to the IRB, FDA, OBA, and NIH 
according to regulatory requirements. Any adverse event that is not resolved by the end of study 
(or early termination) visit and considered to be potentially related to study drug, or was   the 
cause for participant withdrawal will be followed as clinically indicated until its resolution, or if 
non-resolving, until considered  stable. 
In the case of a Serious Adverse Event the Investigator must   immediately: 
• SEND (within 1 working day if possible) the signed and dated corresponding page(s) in 
the SAE Report Form to the Sponsor (as above) or designee. The date of receipt of this 
form by the Sponsor will be the date used as “Day 1” for expedited reporting to the 
regulatory agencies as is required. 
 
• ATTACH the photocopy of all examinations carried out and the dates on which these 
examinations were performed. For laboratory results, include  the  laboratory  normal 
ranges. 
 
• All additional data or corrections are to be reported on a follow-up SAE form. 
 
• A blinded code must be broken only in exceptional circumstances when knowledge of the 
study medication is essential for treating the participant. 
 
Follow-up Procedures 

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• The Investigator should take all appropriate measures to ensure the safety of the 
participants, notably he/she should follow-up the outcome of any Adverse Events (clinical 
signs, laboratory values or other, etc.) until the return to normal or until stabilization of the 
participant condition. 
• In the case of any Serious Adverse Event, the participant must  be  followed  up  until 
clinical recovery is complete and laboratory results have returned to normal, or until 
progression has been stabilized. 
• In case of any Serious Adverse Event brought to attention of the Sponsor. 
 
ECG Monitoring 
In case of prolongation of QTcF ≥ 500 ms, or an increase in QTcF ≥ 60 ms from baseline, a 
blood sample should be drawn for potassium, calcium, magnesium and a plasma assay for hSlo 
cDNA with PCR. The hSlo analysis will be done by the under the direction of Kelvin Davies, 
PhD. of the Department of Urology Research Laboratory, Albert Einstein College of   Medicine. 
A cardiologist should be consulted, and the participant should continue to have his or her ECG 
monitored until the ECG abnormality resolves or becomes stable and part of the patient’s new 
medical history. 
 
 
10.1 Assessment of Endpoints 
 
10.2 Safety 
Safety and tolerability of the study drug will be evaluated by analysis of adverse experiences, 
clinical laboratory tests, electrocardiogram, and physical   examinations. 
 
10.3 Efficacy 
 
The sample size has been estimated assuming a standard deviation of 2.5 and a two sample t-test 
to have 80% power. 
The protocol is designed to observe a 30% reduction in the number of voids compared to placebo 
following gene transfer using the following calculations with NCSS/PASS program (NCSS, 
Kaysville,  Utah, 84037-3233). 
 
Table 10;. Powering 
Power, 
N1 
N2 
Ratio 
Alph Beta 
Mean Mean2 S1 
S2 
0.80251 
9 
10 
1.111 
0.050 0.19749 10.0 
6.6 
2.5 2.5 
 
The mean number of micturitions per 24 hours will be evaluated at all visits and changes 
compared to baseline and  placebo. 
The other secondary outcome measures will be the change in the mean number of urge 
incontinence episodes per 24 hours; urgency episodes per 24 hours; mean volume voided per 
micturition, diminished urgency perception; change in weight of 72 hour pad test; and change   in 

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detrusor overactivity (DO) including peak amplitude, volume at which DO appears and presence 
or absence of DO. The participants' perception of their bladder condition and response to  
treatment will be assessed at baseline (Week 0) and after 1, 2, 4, 8, 12, and 24   weeks. 
Improvement will be defined as a decrease of 1 point or more from baseline. Quality of Life 
(QoL) will be evaluated using the Kings Health Questionnaire (see Appendix B for algorithm). 
Change in maximum bladder capacity (difference of pre-treatment to post-treatment volume) as 
determined by cystometry of hMaxi-K versus pool of placebo participants from each treatment 
level. 
Participants will be assessed for changes from baseline in urinary symptoms following 
administration of hMaxi-K using the questions of the ICIQ-SF form and the urgency rating   scale. 
Participants will also be pooled across treatment groups (all active vs. all   placebo). 
 
10.4 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 1 study is designed to evaluate the safety of a single bladder injections 
of 2 different doses of hMaxi-K 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. 
 
11.1 Monitoring of Participant Safety 
 
11.2 Informed Consent 
 
The investigator will be responsible for obtaining from every participant prior to the participant’s 
participation 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 Consent 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 the participant. 
The original signed and dated copy of the Informed Consent must be maintained in the  
institution’s records. The names of the participants enrolled during this study will be considered 
confidential. 
 
11.3 Data Safety Monitoring Board (DSMB) 
 
In order to monitor the safety of participants participating in this study, the sponsor will establish 
an independent Data Safety Monitoring Board (DSMB). The members will have training in 
medicine and/or gene therapy.  All members will be independent of the study   conduct. 
The DSMB will review eligibility and all available safety data after the 5th participant has been 
administered study drug in the first dosing cohort. This first review will occur as soon as possible 
after the 5th  participant’s 3-Day Post-visit 2 telephone contact.  Following their review of   the 

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safety data, the DSMB will recommend whether enrollment into the first dosing cohort may 
proceed. 
The DSMB will review participant’s eligibility data and all safety data at 4 weeks following 
administration of study drug for the last participant enrolled into each dose cohort, in order to 
assess the need for modifications in safety monitoring and/or dosing. Following their review of 
the safety data for the last participant in the cohort at the 4th week post-dosing, the DSMB will 
recommend whether or not enrollment into the next dosing cohort may proceed (Section   5.2). 
The DSMB will also review the clinical safety data from the participants in all the dosing cohorts 
at the six month timepoint following the final  dose. 
 
12.1 Regulatory Standards 
 
12.2 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. For the long 
term follow-up period paper CRFs will be  used. 
 
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. 
 
12.3 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. 
 
12.3.1 
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 (CE3 Inc.) will 
visit the institution prior to initiating the study and periodically thereafter to monitor  
acceptability of facilities, the agreement between E-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 
participant records, medication sheets, laboratory data, and other source   documentation. 

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In addition to the initiation visit, the clinical sites 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 E-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 E-CRF 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 E-CRF will be first reviewed with the investigator prior to correction. The reason 
for any correction to the E-CRF will be noted along with the date and electronic signature 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 (e.g. U.S. Food and Drug 
Administration).  The Investigator agrees to allow access to the required participant records in the 
event of such an audit. 
 
12.3.2 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, FDA, and OBA2  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, and submitted to  FDA. 
 
12.4 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. 
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 
 
 
2 OBA is the Office of Biotechnical Activities of the National Institutes of Health (NIH) which includes NIH 
Genetic Modification Clinical Research Information System (GeMCRIS); OHSR is the Office of Human 
Subject Research, NIH. 

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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. 
 
12.5 Records 
 
The Food and Drug Administration requires that an investigator retain records for a period   of 
two (2) years following the date a New Drug Application or Product License Application is 
approved for the drug for the indication for which it is being investigated; or, if no application or 
license is to be filed or, if the application or license is not approved for such indication, until   two 
(2) years after the investigation is discontinued (21 CFR  312.62). 
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. 

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13.0 References 
(bolded references are included in Section 10 of the IND; others available upon request) 
 
 
1 
Flisser, A. J. and Blaivas, J. G. Role of cystometry in evaluating patients with overactive 
bladder. Urology.;60 (5 Suppl 1):33-42; discussion 42, Nov 2002 
 
2 
Andersson KE. The overactive bladder: pharmacologic basis of drug treatment. Urology 
50: 74–84, 1997. 
 
3 
Andersson KE. Advances in the pharmacological control of the bladder. Exp Biol 84: 195– 
213, 1999. 
 
4 
Abrams, P. et.al. Overactive bladder significantly affects quality  of  life.  Am J Managed 
Care 6(11):S580-S590, 2000. 
 
5 
Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL, 
Wein AJ. Prevalence and burden of overactive bladder in the United States. World J Urol. 
May, 20(6):327-36, 2003. Epub Nov 15. 2002 
 
6 
Ouslander, J. Management of overactive bladder. NEJM 350(8), 167-178, 2004 
 
7 
Milson I. How widespread are the symptoms of an overactive bladder and how are they 
manages? A population based prevalence study. BJU International, 87:760-766, 2001 
 
8 
Abrams P., Cardozo L., Fall M., et. al. for the Standardization Subcommittee of the 
International Continence Society. The standardization of  terminology  for  lower  urinary 
tract function: report from the Standardization Subcommittee of  the  International 
Continence Society. Neurourology & Urodynamics, 21(2): 167-178 2002 
 
9 
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, Van Kerrebroeck P,  
Victor A, Wein A; Standardisation Sub-Committee of the International Continence Society. 
The standardisation of terminology in lower urinary tract function: report from the 
standardisation sub-committee of the International Continence Society. 
Urology.  2003 Jan;61(1):37-49. 
10 
Tonini, M.; Messori, E.; Franceschetti, G. P.; Rizzi, C. A.; Castoldi, A. F.; Coccini, T., and 
Candura, S. M. Characterization of the 5-HT receptor  potentiating  neuromuscular 
cholinergic transmission in strips of human isolated detrusor muscle. Br J Pharmacol. Sep, 
113, 1994. 
 
11 
Sacco E and Bientinesi R. Ther Adv Urol. 2012 December; 4(6): 315–324. 
 
12 
Brading AF and Inoue R. Ion channels and excitatory transmission in the smooth muscle 
of the urinary bladder. Z Kardiol. 80, Suppl 7: 47–53, 1991. 
 
13 
Fry CH, Montegomery BSI, and Gallegos CRR. The electrophysiology of human detrusor 
smooth muscle. Scan J Urol Nephrol 29, Suppl 175: 67–73, 1995. 

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14 
Fry CH, Wu C, and Sui GP. Electrophysiological properties of the bladder. Int  Urogynecol 
J 9: 291–298, 1998. 
 
15 
G. J. Christ, N. S. Day, M. Day, C. Santizo, W. Zhao, T. Sclafani, J. Zinman, 
K. Hsieh, K. Venkateswarlu, M. Valcic, And A. Melman Bladder injection of “naked” 
hSlo/pcDNA3 ameliorates detrusor hyperactivity in obstructed rats in vivo. Am J Physiol 
Regualtory Integrqtive Comp Physiol. 281:R1699-R1709,  2001 
 
16 
Thorneloe KS, Meredith AL, Knorn AM, Aldrich RW, Nelson MT. Urodynamic properties 
and neurotransmitter dependence of urinary bladder contractility in the BK   channel 
deletion model of overactive bladder. Am J Physiol Renal Physiol. Apr 12, 2005. 
 
17 
Malmgren A, Sjogren C, Uvelius B, Mattiasson A, AnderssonKE, and Andersson PO. 
Cystometrical evaluation of bladder instability in rats with intravesical outflow obstruction. 
J Urol 137: 1291–1294, 1987. 
 
18 
Pandita RK and Andersson KE. Effects of intravesical administration of the K1 channel 
opener, ZD6169, in conscious rats with and without bladder outflow obstruction. J Urol 
162: 943–948, 1999. 
 
19 
Persson K, Pandita RK, Spitsbergen JM, Steers WD, Tuttle JB, and Andersson KE. Spinal 
and peripheral mechanisms contributing to hyperactive voiding in spontaneously 
hypertensive rats. Am J Physiol Regulatory Integrative Comp Physiol 275: R1366–R1373, 
1998. 
 
20 
Buttyan R, Chen MW, and Levin RM. Animal models of bladder outlet obstruction and 
molecular insights into the basis for the development of bladder dysfunction. Eur Urol 32, 
Suppl 1: 32–39, 1997. 
 
21 
Elliott RA, Norman RI, Parker SG, Whitaker RP, and Castleden CM. Effect of treatment 
with calcium antagonists in vitro and in vivo on the contractile response of isolated rat and 
human detrusor muscle. Clin Sci (Colch) 91: 467–474, 1996. 
 
22 
Brading AF. A myogenic basis for the overactive bladder. Urology 50, Suppl 6A: 57–67, 
1997. 
 
23 
Chai TC, Gemalmaz H, Andersson KE, Tuttle JB, and Steers WD. Persistently increased 
voiding frequency despite relief of bladder outlet obstruction. J Urol 161: 1689–1693, 
1999. 
 
24 
Lluel P, Duquenne C, and Martin D. Experimental bladder instability following bladder 
outlet obstruction in the female rat. J Urol 160: 2253–2257, 1998. 

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25 
Melman A, Tar M, Boczko J, Christ J, Leung AC, Zhao W, Russell G. The Evaluation of 
Two Techniques of Partial Urethral Obstruction in the Male Rat Model of the Bladder 
Outlet Obstruction. Urology; In Press 2005 
 
26 Draft Guidance for Industry: Considerations for Plasmid DNA Vaccines for Infectious 
Disease Indications; FDA, Feb. 2005 
 
27 
Melman A, Bar-Chama N, McCullough A, Davies K, Christ G. The first human trial for 
gene transfer therapy for the treatment of erectile dysfunction: preliminary results. Eur 
Urol. 48:314-8, 2005. 
 
28 Data on File 
 
29 
Machin, D., Campbell, M., Fayers, P., and Pinol, A. Sample Size Tables for  Clinical 
Studies, 2nd Edition. Blackwell Science. Malden, MA. 1997 
 
30 Zar, J.H. Biostatistical Analysis (Second Edition). Prentice-Hall. Englewood Cliffs, New 
Jersey 1984. 
 
 
31 Patterson, S., Jones, B. Bioequivalence and Statistics in Clinical Pharmacology. Chapman 
and Hall/CRC. Boca Raton, FL 2006, page 194. 

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APPENDIX A  Grading of Adverse 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 03 –OAB 
Amendment 5: October 1, 2015 
72 
 
 
 
 
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 0.45 – 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 

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Protocol ION 03 --OAB 
Amendment 5: Oetobcr I , 2015 
 
 
 
 
 
APPENDIX B. King's Health Questionnaire 
 
Site No. 
Subject No. 
Subject Initials 
Date   
 
I - How would you describe your health al present? 
D   Very good (I) 
D   Good (2) 
D    Fair (3) 
D   Poor (4) 
D    Very poor (5) 
2- How much do you think your bladder problem affects your life? 
D   Not at all ( J ) 
D   A lillle (2) 
D    Moderately (3) 
D   A lol (4) 
3a- To what extent does your bladder problem affect your household tasks (e.g. cleaning, 
shopping, etc.)? 
D   Not at all ( J ) 
D   A lillle (2) 
D    Moderately (3) 
D   A lol (4) 
3b- Does your bladder problem affect yourjob, or your normal daily activities out side the 
home? 
D   Not at all ( J ) 
D   A lillle (2) 
D    Moderately (3) 
D   A lol (4) 
4a- Does your bladder problem affect your physical activities (e.g. going for a walk, run, sport, 
gym, etc.)? 
D   Not at all ( J ) 
D   A lillle (2) 
D    Moderately (3) 
D   A lol (4) 
4b- Does  your bladder problem affect  your ability lo travel? 
D   Not at all ( J ) 
D   A lillle (2) 
D    Moderately (3) 
D   A lol (4) 

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Amendment 5: Oetobcr I , 2015 
 
 
 
4c- Does your bladder problem limit  your social  life? 
D   Not  at all ( I) 
D   A liHle (2) 
D    Moderately (3) 
D    A lot (4) 
4d - Does your bladder problem limit your ability to see/visit fiiends? 
D   Not  at all ( I) 
D   A liHle (2) 
D    Moderately (3) 
D    A lot (4) 
Sa- Does your bladder problem affect your relationship with your partner? 
D   Not applicable (0) 
D Not at all ( I) 
D   Slighlly (2) 
D    Moderately (3) 
D    A lot (4) 
Sb- Does your bladder problem affect your sex life? 
D   Not applicable (0) 
D Not at all ( I) 
D   Slighlly (2) 
D    Moderately (3) 
D    A lot (4) 
Sc- Does your bladder problem affect your family  life? 
D   Not applicable (0) 
D Not at all ( I) 
D   Slighlly (2) 
D    Moderately (3) 
D    A lot (4) 
6a- Does your bladder problem make you feel depressed? 
D   Not  at all ( I) 
D 
Slighlly (2) 
D   Moderately (3) 
D    Very much (4) 
6b- Does your bladder problem make you feel anxious or nervous? 
D   Not  at all ( I) 
D 
Slighlly (2) 
D   Moderately (3) 
D    Very much (4) 

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Amendment 5: Oetobcr I , 2015 
 
 
 
6c- Does your bladder problem make you feel bad about  yourself? 
D   Not  at all ( I) 
D 
Slighlly (2) 
D    Moderately (3) 
D    Very much (4) 
7a- Does your bladder problem affect your sleep? 
D   Never ( I ) 
D    Sometimes (2) 
D   Often (3) 
D  All the lime (4) 
7b- Do you  feel worn oul/tired? 
D   Never ( I ) 
D    Sometimes (2) 
D   Often (3) 
D  All the lime (4) 
8a - Wear pads lo keep dry? 
D   Never ( I ) 
D    Sometimes (2) 
D   Often (3) 
D  All the lime (4) 
8b- Be careful how much fluid you drink? 
D   Never ( I ) 
D    Sometimes (2) 
D   Often (3) 
D  All the lime (4) 
8c- Change your underclothes when  they gel wet? 
D   Never ( I ) 
D    Sometimes (2) 
D   Often (3) 
D  All the lime (4) 
8d- Worry  in case you smell? 
D   Never ( I ) 
D    Sometimes (2) 
D   Often (3) 
D  All the lime (4) 
8e- Gel embarrassed because of your bladder problem? 
D   Never ( I ) 
D    Sometimes (2) 
D   Often (3) 
D  All the lime (4) 
Sign with Participant Initials 
Date Fonn Completed : 

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Amendment 5: October 1, 2015 
 
 
 
 
Calculation of KHQ–QoL domain scores 
KHQ–QoL domain scores were calculated using the following  formulae. 
1. General health perceptions: 
Score= ((score to Q1 - 1)/4) x  100 
2. Impact on life: 
Score = ((score to Q2 - 1)/3) x  100 
3. Role limitations: 
Score= (((score to Q3a + Q3b) - 2)/6) x 100 
4. Physical limitations: 
Score = (((score to Q4a + Q4b) - 2 /6) x  100 
5. Social limitations: 
if score Q5c > 1, 
Score = (((score to Q4c + Q4d + Q5c) - 3)/9) x 100 
if score Q5c = 0, 
Score= (((score to Q4c + Q4d) - 2)/6) x 100 
6. Personal Realtionships: 
if score Q5a + Q5b > 2, 
Score = (((score to Q5a + Q5b) - 2)/6) x 100 
if score Q5a +Q5b = 1, 
Score = (((score to Q5a + Q5b) - 1)/3) x  100 
if score Q5a + Q5b = 0, treat as missing value (not  applicable), 
7. Emotions: 
Score = (((score to Q6a + Q6b + Q6c) - 3)/9) x  100 
8. Sleep/energy: 
Score = (((score to Q7a + Q7b) - 2)/6) x  100 
9. Incontinence severity measure: 
Score = (((score to Q8a + Q8b + Q8c + Q8d +Q8e) - 5)/15) x   100 

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Protocol I0N 03 –OAB 
Amendment 5: October 1, 2015 
 
 
 
 
APPENDIX C. Participant Assessment of Disease and Response to 
Treatment 
 
 
Site No.    
 
 
Subject No.   
 
 
Subject Initials   
 
 
Date   
 
 
1. Participant Assessment of Disease 
Participants will rate their perceived bladder condition severity as follows: 
Using validated 6-point rating scale participants will be asked the   following. 
 
“How bothersome do you consider your bladder problems? “ 
1- No problems 
2 - Very minor problems 
3 - Minor problems 
4 - Moderate problems 
5 - Severe problems 
6 - Many severe problems 
Improvement will be defined as a decrease of 1 point or more from   baseline. 
 
 
2. Participant Assessment of Response to Treatment 
Participants' assessment of their response to treatment will be measured by asking: 
"Has the treatment been of benefit to  you?" 
1. No benefit 
2. Yes, a little benefit 
3. Yes, very much benefit 
Improvement will be defined as a decrease of 1 point or more from   baseline. 
 
 
 
 
Sign with Participant Initials:   
 
 
Date Form Completed:   
 

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Ion Channel Innovations 
Protocol I0N 03 –OAB 
Amendment 5: October 1, 2015 
 
 
 
APPENDIX D. Cystometry Procedure Guidance 
The importance of performing well-controlled cystometries cannot be over-emphasized. The 
methodology advocated by the International Continence Society in Neurourology and 
Urodynamics 21:261-274, 2002 should be  followed. 
Minimally, patients should be positioned in the sitting position.  Using sterile aseptic techniques, 
a 7 or 8 Fr double-lumen transurethral catheter will be inserted into the urethra and a 9 Fr balloon 
catheter will be placed in the rectum to measure abdominal pressure. Room-temperature saline 
will be used at a filling rate of 50 ml/min. Either fluid filled catheters connected to pressure 
transducers or solid-state catheters should be used to help minimize artifact. The same system 
must be used for pre and post transfer studies on each patient. Participants should be instructed 
to neither void nor to try to inhibit micturition, but to simply report their sensations to the 
examiner. Participants should be instructed to indicate first desire to void, strong urge to void, 
and/or when they can longer tolerate infusion (i.e. no longer delay micturition). Bladder filling 
should be discontinued as soon as the participant experiences a strong desire to void, 
uncomfortable fullness or pain. 
Digitized recordings should be captured and stored for each participant. Waveforms from filling 
cystometries and pressure flow studies should be interpreted by a trained professional for each 
parameter noted in the following Table A. A cystometry overreader as well as the investigator 
will be required to interpret the results. The central overreader’s interpretation will take priority. 
Printed waveforms should be kept with the patient’s source records, with items such as artifacts 
and peak pressure measurements clearly identified. Digitized pressure recordings will be 
analyzed for the following  parameters: 

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Protocol I0N 03 –OAB 
Amendment 5: October 1, 2015 
 
 
 
 
 
 
 
 
 
 
 
Table A: Cystometry Parameters and  Definitions 
Parameter 
Description 
Definition 
DO; Yes/No 
Detrusor overactivity ≥ 5 cm H2 O 
Any involuntary contraction that has a pressure 
>/= 5 cm H2 O (INCLUSION CRITERIA) 
VFirst des 
(mL) 
Volume at first desire to void 
The volume attained during filling cystometry that 
would lead the patient to pass urine at the next 
convenient moment but voiding can be delayed if 
necessary (ICS definition). 
Pdet. open (cm 
H2 O) 
Detrusor pressure at beginning of 
voiding (prior to onset of first 
contraction (either volitional or 
involuntary) 
Detrusor pressure at onset of the first detrusor 
contraction (either volitional or involuntary). 
V1st (mL) 
Volume at first involuntary contraction; 
if detrusor overactivity (DO) present. 
Not applicable if no DO present. 
Volume infused at the point of maximum detrusor 
pressure during the 1st contraction. 1 
Detfrq 
Total number of detrusor contractions 
during procedure (voluntary AND 
involuntary) 
Total number of detrusor contractions including 
voluntary AND involuntary 
Leak 
(Yes/no) 
Was there a leak with overactivity 
Involuntary detrusor contractions resulting in leak 
(NOT counting voluntary voids). 
DO Leak freq 
Number of involuntary detrusor 
contractions resulting in leak (if DO 
present) 
Number of involuntary detrusor contractions 
resulting in leak (if DO present).1 
Vleak  (mL) 
If yes, Volume of each leak 
Volume of each leak for each episode of leak2 
Vleak cum 
(mL) 
If yes, cumulative volume of ALL 
leaks during procedure 
Cumulative volume of leaks (calculated by 
computer from individual volumes) 2 
DO No Leak freq 
Number of involuntary detrusor 
contractions NOT resulting in leak. 
Total number of involuntary detrusor contractions 
that do not have an associated leak. 1 
Pdet  Max 
(cm H2 O) 
Maximum detrusor pressure at 
involuntary contraction 
Maximum amplitude of detrusor contraction 
during an involuntary contraction (if present) 3 
Pdet 1st 
(cm H2 O) 
Maximum detrusor pressure at FIRST 
contraction 
Max detrusor pressure at FIRST contraction 
(voluntary or involuntary). 1 
PDet Any 
(cm H2 O) 
Maximum detrusor pressure at ANY 
contraction 
MAXIMUM detrusor pressure attained during the 
entire study (voluntary or involuntary). 4 
Cys Cap 
(mL) 
Cystometric Capacity: Volume at 
strong urge to void 
The volume at which the patient feels that he/she 
can no longer delay micturition (has a strong 
desire to void). (ICS definition) 
Qmax 
(mL / sec) 
Peak flow rate during voiding (for both 
leaks and voluntary voids) 
The Maximum rate of flow during any void (for 
both involuntary and voluntary voids) 
V voided (mL) 
Total voided volume (leaks and 
voluntary) 
Total volume voided for leak and volitional voids 
during the procedure 
PVR (mL) 
Post Void Residual Volume (PVR) 
(from  catheterization) 
Volume left in bladder after voiding at the 
conclusion of the study. This is measured by 
urodynamic catheterization. 
(Vtotal bladder) 
(mL) 
Total Bladder Volume 
(Total voided 
volume +catheterized PVR) 
Post void residual volume + total voided volume 
(will be calculated) 

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Amendment 5: October 1, 2015 
 
 
 
DO dur 
(seconds) 
Duration of detrusor overactivity 
Duration of MAXIMUM detrusor activity. 2 
PDet,  Q Max 
(cm H2 O) 
Detrusor pressure at maximum flow 
during an involuntary contraction 
Maximum detrusor pressure during terminal void 
(voluntary or involuntary). 2 
Vbladder  DO 
(mL) 
Bladder volume at each involuntary 
detrusor contraction 
Infused bladder volume at the peak pressure of 
each involuntary contraction minus the amount 
leaked at each point for each involuntary 
contraction; Total will be calculated by the 
computer. 2 
Pabd (cm 
H2 O) 
Maximum abdominal pressure during 
any contraction 
MAXIMUM abdominal pressure during ANY 
contraction. This will assess the abdominal 
straining component to voiding. 2 
5. This is done by overreader, but not the sites 
6. Done by site only 
7. Detrusor pressure at first involuntary contraction is called “Detrusor Pressure” for sites on eCRF. 
8. Maximum detrusor pressure at ANY contraction is called “Maximum Detrusor Pressure” for sites 
on eCRF. 

Ion O,anncl  Innovatio 
Protocol ION 03 --OAB 
Amendment 5: Oetobcr I , 2015 
80 
 
 
·
 
APPENDIX E. International Consultation on Incontinence 
Questionnaire: Short Form1 • 
 
Site No. 
Su bject No. 
Subj ect Initials---- Date 
How often do you leak urine? 
Never 
0 
About  once a week or less ofien 
I 
Two to three limes a week 
2 
About once a day 
3 
Several times a day 
4 
All oflhe lime 
5 
 
We would like to know how much urine you think leaks. How much urine do you usually 
leak (whether you wear protection or not)? 
None 
0 
A small amount 
2 
A moderate amount 
4 
A large amount 
6 
 
Overall how much does leaking u rine interfere with your everyday life? 
Please circle a number between O (not at all) and 10 (a great deal). 
 
0 
1 
Not all 
2 
3 
4 
5 
6 
7 
8 
9 
10 
A great deal 
 
When does urine leak? (Please check all that apply) 
 
Never - urine does not leak 
D 
Leaks before you can get to the toilet 
D 
Leaks when you cough or sneeze 
D 
Leaks when you are asleep 
D 
Leaks when you are physically active/exercising 
D 
Leaks when you have finished urinating and are dressed D 
Leaks for no obvious reason 
D 
Leaks all the time 
D 
Sign with Participant In itials: 
_ 
Date Form Completed: 
_ 
 
 
3_Hajebrahimi  S, Corcos J, Lemieux  MC.International  consultation on incontinence questionnaire short form: 
comparison of physician versus patient completion and immediate and delayed self-administration.Urology. 
2004 Jun;63(6):I 076-8. 
 
• Avery  K, Donovan   J,  Alrams  P. Validation   of  a  new  questionnaire   for  incontinence: the  International 
Consultation on InC(HJtincncc Questionnaire (ICIQ).abstract n• 86 of the International  Continence Society 31st 
annual mcctin Seoul, Korea.Neurourol Urodynamics 200 I;20:510- 1. 
------ 

Ion Channel Innovations 
Protocol I0N 03 –OAB 
Amendment 5: October 1, 2015 
81 
 
 
 
APPENDIX F. Participant Daily Diary 
 
Please complete the information below every day for the 7 days prior to your next scheduled 
visit. 
DAILY DIARY 
Site # 
Subject # 
Subject initials 
 
Start Date: 
/ 
/ 
to End Date: 
/ 
/  
 
 
# 
Time of 
Urination 
(circle AM or PM) 
Urgency 
(Scale 
0-3) * 
Was this 
an 
accident? 
Y/N 
Volume 
(mL)** 
# 
Time of 
Urination 
(circle AM or PM) 
Urgency 
(Scale 
0-3) * 
Was this 
an 
accident? 
Y/N 
Volume 
(mL)** 
1 
: 
AM 
PM 
11 
: 
AM 
PM 
2 
: 
AM 
PM 
12 
: 
AM 
PM 
3 
: 
AM 
PM 
13 
: 
AM 
PM 
4 
: 
AM 
PM 
14 
: 
AM 
PM 
5 
: 
AM 
PM 
15 
: 
AM 
PM 
6 
: 
AM 
PM 
16 
: 
AM 
PM 
7 
: 
AM 
PM 
17 
: 
AM 
PM 
8 
: 
AM 
PM 
18 
: 
AM 
PM 
9 
: 
AM 
PM 
19 
: 
AM 
PM 
10 
: 
AM 
PM 
20 
: 
AM 
PM 
**Urgency Scale 
0=None: No Urgency 
1=Mild: Awareness of urgency or need to go to the bathroom but easily tolerated 
2= Moderate: Enough urgency discomfort that it interferes with usual activities and tasks 
3=Severe: Extreme urgency and discomfort that stops all activities and tasks 
 
** Urinate into supplied cylinder and measure the volume 
 
Number of pads used on this day: 
(Daily pad count includes all pads newly applied during a calendar 
day- dates as above). Be sure to seal used pads for 3 days prior to next visit in the provided zip lock bag to bring 
to clinic at next visit.).  Also bring one new clean pad for comparison. 
 
 
Sign with Participant Initials:   
 
Date Form Completed:   
 
To be completed at Study Center 
Total number of urinations on this day   
  
Mean volume per urination on this day  
  

Ion Channel Innovations 
Protocol I0N 03 –OAB 
Amendment 5: October 1, 2015 
82 
 
 
 
APPENDIX G. Components and Guidelines for Health Status 
Questionnaire (SF-12) 
 
 
 
 
Site No. 
Subject No.   
 
 
Subject Initials   
 
 
Date   
 
INSTRUCTIONS: This questionnaire asks for your views about your health. This information will help 
keep track of how you feel and how well you are able to do your usual   activities. 
 
Please answer every question by marking one box. If you are unsure about how to answer, please give 
the best answer you can. 
 
In general, would you say your health  is: 
 
□ 
□ 
□ 
□ 
□ 
Excellent 
Very good 
Good 
Fair 
Poor 
 
The following items are about activities you might do during a typical day. Does your health now limit 
you in these activities?  If so, how  much? 
 
 
Yes, 
Yes, 
No, Not 
Limited 
Limited 
Limited 
A Lot 
A Little 
At All 
 
2. Moderate activities, such as  moving 
□ 
□ 
□ 
a table, pushing a vacuum cleaner, 
bowling or playing golf 
 
3. Climbing several flights of  stairs 
□ 
□ 
□ 
During the past 4 weeks, have you had any of the following problems with your work or other regular 
daily activities as a result of your physical  health? 
 
 
4. 
Accomplished less than you would  like 
Yes 
□ 
No 
□ 
5. 
Were limited in the kind of work or other  activities 
□ 
□ 
5 Ware JE, Kosinski M, Keller, SD. SF-12: How to score the SF-12 Physical and Mental Health Summary Scales. 
Lincoln, RI: Quality Metric Incorporated, third Edition, 1998 
SF-12 HEALTH SURVEY (STANDARD)5 

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Amendment 5: October 1, 2015 
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During the past 4 weeks, have you had any of the following problems with your work or other regular 
daily activities as a result of any emotional problems (such as feeling depressed or anxious)? 
 
Yes 
No 
 
6. Accomplished less than you would  like 
□ 
□ 
 
7. Didn’t do work or other activities as carefully as  usual 
□ 
□ 
8. During the past 4 weeks, how much did pain interfere with your normal work (including both work 
outside the home and housework)? 
 
□ 
□ 
□ 
□ 
□ 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
These questions are about how you feel and how things have been with you during the past 4 weeks. For 
each question, please give the one answer that comes closest to the way you have been feeling.  How 
much of the time during the past 4  weeks 
 
All 
Most 
A Good 
Some 
A Little 
None 
of the 
of the 
Bit of 
of the 
of the 
of the 
Time 
Time 
the Time 
Time 
Time 
Time 
 
9. Have you felt 
□ 
□ 
□ 
□ 
□ 
□ 
calm and peaceful? 
 
10. Did you have a 
lot of energy? 
□ 
□ 
□ 
□ 
□ 
□ 
 
11. Have you felt 
down-hearted and 
blue? 
□ 
□ 
□ 
□ 
□ 
□ 
 
12. During the past 4 weeks, how much of the time has your physical health or emotional problems 
interfered with your social activities (like visiting with friends, relatives, etc.)? 
 
□ 
□ 
\\\   □ 
□ 
□ 
All of 
Most of 
Some of 
A little of 
None of 
the time 
the time 
of the time 
the time 
the time 
 
 
 
Sign with Participant Initials:   
 
 
Date Form Completed: