Phase 1, Dose-Escalation Study to Assess the Safety and Tolerability of VM202 (Engensis) in Subjects With Critical Limb Ischemia
Phase: PHASE1
Conditions: Critical Limb Ischemia
Sponsor: Helixmith Co., Ltd.



 
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Table of Contents 
 
Page 
Table of Contents............................................................................................................. iii 
List of Tables ................................................................................................................... vii 
List of Figures................................................................................................................. viii 
List of Abbreviations and Definitions of Terms............................................................ ix 
1.0 Background Information.............................................................................................1 
1.1 
Peripheral Artery Disease ............................................................................1 
1.2 
Therapeutic Angiogenesis in Ischemic Limb Disease.................................1 
1.3 
Clinical Experience with Neo-Angiogenesis Therapeutic Products............3 
2.0 Rationale.......................................................................................................................4 
3.0 Study Objectives...........................................................................................................5 
3.1 
Primary Objective........................................................................................5 
3.2 
Secondary Objectives...................................................................................5 
4.0 Trial Design ..................................................................................................................6 
4.1 
Primary and Secondary Endpoints, Pharmacokinetics and 
Pharmacodynamics ......................................................................................6 
4.1.1 
Primary Safety Endpoints..............................................................6 
Secondary Efficacy Endpoints.....................................................................6 
Pharmacokinetic Evaluations.......................................................................6 
Pharmacodynamic Evaluations....................................................................6 
Overall Study Design...............................................................................................7 
Study Population..........................................................................................7 
Number of Study Subjects ...........................................................................7 
Schedule of Assessments.............................................................................7 
4.3 
Design of the Trial .......................................................................................9 
4.4 
Dosing Cohort Assignment..........................................................................9 
4.5 
Treatments....................................................................................................9 
4.6 
Duration .....................................................................................................10 
5.0 Selection and Withdrawal of Subjects .....................................................................11 
5.1 
Cancer Screening .......................................................................................11 
5.2 
Inclusion Criteria .......................................................................................11 
5.3 
Exclusion Criteria ......................................................................................12 
5.4 
Subject Withdrawal Criteria ......................................................................13 
6.0 Treatment of Subjects................................................................................................15 
6.1  
Treatments Administered...........................................................................15 
6.1.1 
Treatment Regimen and Follow-Up............................................15 
6.1.2 
Study Agent Handling and Accountability..................................17 
6.2 
Study Procedures and Study Procedures Chart..........................................17 
6.2.1 
Screening Visit (Day -30 to Day 1).............................................17 
6.2.2 
Day 1 ...........................................................................................19 

 
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6.2.3 
Day 8 (± 2 days) ..........................................................................20 
6.2.4 
Day 15 (± 3 days) Second Study Dose Administration...............20 
6.2.5 
Day 16 (post 2nd dosing)..............................................................21 
6.2.6 
Day 21 (+ 3 days) ........................................................................21 
6.2.7 
Day 28 ( ± 3 days) .......................................................................21 
6.2.8 
Day 59 ( ± 7 days) .......................................................................22 
6.2.9 
Day 91 (± 7 days) ........................................................................23 
6.2.10 
Day 180 (± 10 days) ....................................................................23 
6.2.11 
Day 365 (+ 10 days) ....................................................................24 
6.2.12 
Unscheduled Visits......................................................................24 
6.2.13 
Early Termination Visits .............................................................25 
6.3 
Autopsy......................................................................................................26 
6.4 
Concomitant Medications/Treatments.......................................................26 
6.4.1 
Concomitant Medications............................................................26 
6.4.2 
Replacement of Study Subjects...................................................26 
6.4.3 
Wound Care.................................................................................26 
6.4.4 
Peripheral Vascular Procedures...................................................26 
6.5 
Procedures for Monitoring Treatment Compliance...................................27 
6.6 
Study Completion and Discontinuation.....................................................27 
6.7 
Subject Classification.................................................................................27 
6.7.1 
Evaluable Subject........................................................................27 
6.7.2 
Screen failure...............................................................................27 
6.7.3 
Lost to follow-up.........................................................................28 
7.0 Assessments and Procedures.....................................................................................29 
7.1  
Safety .........................................................................................................29 
7.1.1  
Medical History...........................................................................29 
7.1.1.1  Peripheral Vascular Intervention History ....................29 
7.1.2 
Physical Examination..................................................................29 
7.1.2.1   Assessment of CLI.......................................................29 
7.1.3 
Safety Laboratory Tests...............................................................30 
7.1.4 
Retinal Fundoscopy.....................................................................30 
7.1.5 
12-Lead ECG...............................................................................31 
7.1.6 
Local Injection Site Reaction Assessment ..................................31 
7.1.7 
Incidence of Adverse Events.......................................................32 
7.1.8 
Serum Sickness............................................................................32 
7.1.9 
Dose Limiting Toxicity (DLT)....................................................32 
7.2 
Efficacy......................................................................................................33 
7.2.1 
Hemodynamic Assessments ........................................................33 
7.2.1.1 
Ankle-Brachial Index (ABI) ........................................33 
7.2.1.2 
Toe-Brachial Index (TBI) ............................................33 
7.2.1.3 
Wave Form Analysis (PVR)........................................33 
7.2.1.4 
Transcutaneous Oxygen Pressure Assessment 
(TcPO2).........................................................................33 

 
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7.2.2 
High Resolution MRA.................................................................34 
7.2.3 
Pain VAS Score...........................................................................34 
7.2.4 
Subject Analgesic Use.................................................................34 
8.0 
Adverse Events and Serious Adverse Events ....................................................35 
8.1 
Adverse Event Definition ..........................................................................35 
8.2 
Definition of an SAE .................................................................................36 
8.3 
Laboratory AEs and SAEs.........................................................................37 
8.4 
Detection of AEs and SAEs: Method, Frequency, and Time Period.........37 
8.5 
Documentation of AEs and SAEs..............................................................37 
8.6 
Follow-up of AEs and SAEs......................................................................38 
8.7 
Immediate Reporting of SAEs...................................................................39 
8.8 
Transmission of SAE Reports....................................................................40 
8.9 
Regulatory Reporting Requirements..........................................................40 
8.10 
Post-Study AEs and SAEs .........................................................................41 
8.11 
SAEs Related to Study Participation .........................................................41 
9.0  Statistics .....................................................................................................................42 
9.1 
Sample Size................................................................................................42 
9.2 
Population ..................................................................................................42 
9.3 
Statistical Analysis.....................................................................................42 
9.4 
Data Safety Monitoring Committee...........................................................43 
10.0  Quality Control and Quality Assurance ...............................................................44 
10.1 
Ethics..........................................................................................................44 
10.1.1  Responsibilities of the Investigator:...............................................44 
10.1.2 
Legal and Regulatory Considerations .........................................45 
10.1.2.1 Compliance with Law, Audit, and Debarment ............45 
10.1.2.2 Protection of Human Subjects .....................................45 
10.1.2.3 Institutional Review Board (IRB)................................46 
10.1.2.4 Institutional Biosafety Committee (IBC).....................46 
10.1.2.5 Protection of Subject Data ...........................................47 
10.2 
Study Records, Data Handling, and Record Keeping................................47 
10.2.2 
Investigator/Site Documentation.................................................47 
10.2.3 
Financial Disclosure ....................................................................48 
10.2.4 
Clinical Monitoring .....................................................................48 
10.2.5 
Recording of Data........................................................................49 
10.2.6 
Database Management and Quality Control................................49 
10.2.7 
Investigator’s Final Report..........................................................49 
10.2.8 
Record Storage and Maintenance................................................50 
10.2.9 
FDA/NIH Contact and Correspondence......................................50 
10.2.10  HIPAA .........................................................................................50 
10.2.10 Publication Policy........................................................................51 
10.3 
Handling of Investigational Drug ..............................................................51 
10.4 
Disposition of Clinical Supplies ................................................................52 
10.5 
Investigator Confidentiality .......................................................................53 

 
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Appendix A.......................................................................................................................54 
Appendix B .......................................................................................................................55 
Appendix C.......................................................................................................................57 
Appendix D.......................................................................................................................58 
Appendix E .......................................................................................................................60 
Reference ..........................................................................................................................96 
 

 
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List of Tables 
 
Page 
Table 4-1         Study Procedures Chart 
8 
Table 6-1 
Treatments 
15 
Table 7-1 
Study Specific Laboratory Procedures 
30 
Table 8-1 
SAE Reporting Requirements 
40 

 
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List of Figures 
 
Page 
Figure 4-1 
Phase I Study Design 
9 
 
 

 
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List of Abbreviations and Definitions of Terms 
 
ABBREVIATION  DEFINITION 
ABI 
ankle-brachial index 
AE 
adverse event 
ALT 
alanine transaminase (SGPT) 
AST 
aspartate transaminase (SGOT) 
AUC 
area under the plasma concentration time curve 
BUN 
blood urea nitrogen 
°C 
degrees Celsius 
CBC 
complete blood count 
cDNA 
complementary deoxyribonucleic acid 
CHF 
congestive heart failure 
CFR 
Code of Federal Regulation 
CLI 
critical limb ischemia 
Cm 
centimeter(s) 
Cmax 
maximum concentration of drug 
CRF 
case report form 
CRO 
clinical research organization 
CVD 
cardiovascular disease 
D 
day(s) 
dL 
deciliter(s) 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
ET 
endothelin 
°F 
degrees Fahrenheit 
FDA 
Food and Drug Administration 
G 
gram(s) 
GCP 
Good Clinical Practices 
HGF 
hepatocyte growth factor 
IBC  
Institutional Biosafety Committee 
ICH 
International Conference on Harmonisation 
IDUR 
investigational drug utilization record 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
IVRS 
Interactive Voice Response System 
Kg 
kilogram(s) 
LOCF 
last observation carried forward 
LV 
left ventricular 
Mg 
milligram(s) 
Min 
minute(s) 
mmHg 
millimeters mercury 

 
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ABBREVIATION  DEFINITION 
MRA 
magnetic resonance angiography 
MTD 
maximum tolerated dose 
N 
number 
Ng 
nanogram(s) 
NIH 
National Institutes of Health 
NYHA 
New York Heart Association 
O2 
oxygen 
OBA 
Office of Biotechnology Activities 
PAD 
peripheral artery disease 
pH 
hydrogen ion concentration 
PHI 
protected health information 
PPG 
photoplethysmograph 
PTA 
percutaneous transluminal angioplasty 
QD 
once daily 
® 
registered trademark 
RBC 
red blood count 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sDBP 
sitting diastolic blood pressure 
SE 
standard error 
SGPT 
serum glutamic pyruvic transaminase (same as ALT) 
SOC 
System Organ Class 
SVR 
systemic vascular resistance 
t½  
elimination half-life 
tmax 
time of occurrence for maximum (peak) drug concentration 
™ 
trademark 
TBI 
toe-brachial index 
TcPO2 
Transcutaneous Oxygen Pressure Assessment 
VAS 
visual analog scale 
VEGF 
vascular endothelial growth factor 
vs. 
versus 
WBC 
white blood count 
WHO 
World Health Organization 

 
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PROTOCOL SYNOPSIS 
Protocol Number: 
US 06-1-001 
Title: 
A Phase I, Dose-Escalation Study to Assess the Safety and 
Tolerability of VM202 in Subjects with Critical Limb Ischemia 
Study Phase: 
I 
Treatment Duration: Study drug administered on two separate occasions, Days 1 and 
15.  Each treatment is divided into 4 or 8 IM injections. 
Study Duration: 
30 months  
Individual Subject  
Enrollment: 
12 months 
 
Name of Drug: 
VM202 
Dosage: 
Cohort I-VM202  2 mg with the first half of the total dose given 
on Day 1 and the second half given on Day 15 
 
Cohort II-VM202  4 mg with the first half of the total dose given 
on Day 1 and the second half given on Day 15 
 
Cohort III-VM202  8 mg with the first half of the total dose 
given on Day 1 and the second half given on Day 15 
 
Cohort IV-VM202  16 mg with the first half of the total dose 
given on Day 1 and the second half given on Day 15 
Route of Administration: 
Intramuscular (IM) injection into the muscle closest to the 
affected area.  Volume determined by dose. 
Study Objectives: 
To evaluate VM202 administered by intramuscular injection in 
subjects with critical limb ischemia for the following: 
1. Safety 
2. Tolerability 
3. Preliminary efficacy 
Study Design: 
This is a prospective, dose-escalation study to evaluate the safety 
and tolerability of intramuscular VM202 in subjects with critical 
limb ischemia. 
The study will consist of four (4) cohorts with a total of 3 
subjects enrolled in each cohort to VM202.  For each dose 
cohort, VM202 will be administered as a local intramuscular 

 
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injection in 2 divided doses with a 2-week interval between the 
injections.  Preliminary efficacy (hemodynamic assessments), 
safety and tolerability will be evaluated at Baseline (screening) 
and at designated time points throughout the study. 
After the first subject in each cohort completes day 30 (± 2 
days), subsequent to day 15 dosing of the other 2 subjects in the 
same cohort, an interim safety evaluation will be performed with 
the submission of safety data to the Data Safety Monitoring 
Committee (DSMC).  If the DSMC recommends continuing the 
study, the next dose cohort will be treated.  This process will be 
repeated between the second and third dose cohort and between 
the third and fourth dose cohort.  All 4 dose cohorts will be 
followed for one year from the time of the first dose of study 
drug administration.  If a dose limiting toxicity is observed in 
one subject in any dose group, three additional subjects will be 
added to the dose cohort in which the toxicity was observed.  If 
no additional DLTs are observed in the 6 subjects in this dose 
level, it will be considered the Maximum Tolerated Dose 
(MTD).  If a DLT occurs in 2/6 subjects, then the preceding dose 
level will be considered the MTD. 
Structure: 
Single center 
Sample Size: 
Approximately 12-15 subjects 
Study Population: 
Subjects selected for this study will have critical limb ischemia 
that has not responded to standard therapy with symptoms 
including pain at rest, and/or ischemic ulcers. 
Study Assessments: 
The following assessments will be performed at screening and / 
or at designated time points throughout the study: 
• Informed Consent  
• Physical Exam 
• Vital Signs 
• Pregnancy Test 
• Photograph and measurement of ulcer 
• Mammogram 
• Collection of concomitant medications 
• Collection of medical history  
• Assessment of CLI 
• Collection of adverse events 
• Ankle Brachial Index (ABI) 
• Toe Brachial Index (TBI)  

 
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• Wave Form Analysis 
• Transcutaneous Oxygen Pressure Assessment (TcPO2) 
• High resolution MRA 
• Visual Analog Scale (VAS) for pain 
• Analgesic usage 
• Safety Laboratory Testing (Hematology, Chemistry, 
Urinalysis) 
• Retinal fundoscopy 
• 12-lead ECG 
• Tumor marker testing (Alpha feto-protein, CEA, PSA [males 
only], CA19-9 & CA125) 
• Infection testing (HIV, Hepatitis B, CMV, HTLV, VDRL) 
• HGF levels 
• Anti-HGF antibody levels 
• VM202 DNA levels 
• Endothelial progenitor cell assay 
• Chest X-ray or CT scan of the chest (if the subject has a 
previous history of tobacco use, a CT scan will be performed 
instead of the chest X-ray) 
 
Rationale: 
This Phase I study is designed to determine the safety and 
tolerability of intramuscular injections of VM202 using standard 
objective and subjective measurements.  Assessment of safety 
will be accomplished through monitoring vital signs, monitoring 
signs and symptoms of acute and chronic hypersensitivity 
reaction and evaluating all observed and reported adverse events, 
retinal fundoscopy, clinical laboratory results, tumor lab testing, 
infection testing and urinalysis.  There will also be a long-term 
follow-up to determine the extent of new onset of malignancy in 
treated subjects.  CA-125 will be done in females and a PSA will 
be done in males to rule out any occult malignancy prior to first 
study drug administration and throughout the study. 
While the primary objectives are safety and tolerability, 
preliminary efficacy evaluations will include evaluation of 
changes from Baseline in hemodynamics (ABI, TBI, Wave 
Form), TcPO2, VAS pain assessment, analgesic use, and MRA 
measurements. 
Procedures: 
After the study subject is identified, a written informed consent 
will be obtained and screening process will be initiated.  
Hemodynamic assessments, TcPO2, retinal fundoscopy and high 
resolution MRA will be done at Baseline.  For subjects with 

 
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ischemic ulcer, a photograph and measurement of the ulcer will 
be obtained.  Safety laboratory (hematology, chemistry, 
urinalysis), tumor marker tests, infection tests, chest X-ray or CT 
scan of the chest (if the subject has a previous history of tobacco 
use, a CT scan will be performed instead of the chest X-ray), and 
ECG will also be done at Baseline. 
Subjects will be administered two doses of study drug on Days 1 
and 15 as a local intra-muscular injection in the affected 
ischemic limb.  There will be 4 or 8 injections depending on the 
dose level administered slowly for 20~30 seconds at pre-
determined sites on only one affected leg (mainly at the calf 
muscles) without local anesthesia.  After treatment 
administration, subjects will be observed for 1 hour in a 
comfortable supine position. 
Analgesic usage and Serum HGF will be assessed on Day 8 post 
first dose treatment. 
After the second dose is administered (Day15) to the leg 
previously injected, hemodynamic assessments (ABI, TBI, Wave 
Form Analysis), TcPO2, photograph and measurement of 
ischemic ulcer, VAS for pain, and safety labs will also be 
assessed on Days 28, 59, 91, 180 and 365.  High resolution MRA 
with flow assessment will be done at Days 91 and 180. 
After the first subjects in each dose cohort have completed the 
Day-30 (± 2 days) follow-up visit and subsequent to day 15 
dosing of the other subjects in the same cohort, an interim safety 
evaluation will be performed with the submission of data to the 
DSMC.  If the DSMC recommends continuing the study, the 
next cohort will be dosed.  All subjects will be followed for up to 
1 year from the time of first dose of study drug administration. 
Pharmacokinetic assessment will be performed using VM202 
DNA levels at selected time points.  Pharmacodynamic 
assessments will be performed using anti-HGF antibodies, 
endothelial progenitor cell assay and serum HGF levels at 
selected time points.  
Safety Monitoring: 
Monitoring and collection of adverse event information (nature, 
frequency and incidence of occurrence) will be performed 
throughout the study period. 
Blood and urine samples for safety laboratory analyses will be 
performed at screening and at specified time points throughout 
the study period.  Safety laboratory analyses will be completed at 
screening and at specified time points throughout the study. 

 
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Physical examination, vital signs and retinal fundoscopy will 
also be performed as part of safety monitoring at screening and 
at specified time points throughout the study. 
Efficacy Evaluation: The study will attempt to gather preliminary efficacy information 
based on VAS score, MRA, TcPO2 and hemodynamics.   
Exploratory analyses will include pharmacokinetic and 
pharmacodynamic evaluations. Pharmacokinetic evaluations will 
be based on VM202 DNA levels post dosing.  Pharmacodynamic 
evaluation will be based on anti-HGF antibodies and serum HGF 
levels pre treatment and endothelial progenitor cell assay post 
treatment. 
Sample Size 
This is a Phase I, dose-escalation study.  The sample size is  
and Power 
based on the feasibility to assess safety.  No statistical analysis of 
efficacy is planned. 
Statistical Analysis: 
Safety and Tolerability: 
The incidence and nature of adverse events will be reported in 
tabulated format.  Adverse events will be described according to 
severity and to its relationship with the study drug.  Serious 
adverse events and adverse events leading to treatment 
discontinuation will be listed 
Descriptive statistics (N, mean, median, SD, minimum and 
maximum values, where applicable) of safety laboratory 
parameters to include tumor markers will be reported.  
Abnormalities will be summarized for low and high values.  
Frequency counts for normal/abnormal findings for retinal 
fundoscopy will be presented. 
Efficacy: 
Descriptive statistics (N, mean, median, SD, minimum and 
maximum values) of vascular assessments (ABI, TBI, Wave 
Form Analysis), TcPO2, High resolution MRA, and VAS for pain 
will be reported.  Frequency counts for analgesics use by dose 
cohort will be reported. 
Pharmacokinetics: 
Descriptive statistics (N, mean, median, SD, minimum and 
maximum values, where applicable) of VM202 DNA levels will 
be reported. 
Pharmacodynamics: 
Pharmacodynamics will assess change from Day 1 in anti-HGF 
antibodies and serum HGF levels at pre treatment and 

 
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1.0 Background Information 
1.1 
Peripheral Artery Disease 
Peripheral arterial disease (PAD) is a common disorder usually caused by atherosclerotic 
changes in the arteries supplying the lower extremities, resulting in ischemic limb 
disease.  Clinical manifestations of lower extremity PAD are related to the severity of 
muscular ischemia, which depends on the degree of arterial stenosis.  Intermittent 
claudication is a common, initial presentation.  Critical limb ischemia denotes a condition 
of severe arterial obstruction due to advanced PAD, associated with breakdown of the 
skin or pain in the lower limb at rest (Appendix A).  The natural history of critical limb 
ischemia has been well documented to have an inexorable downhill course, frequently 
leading to the amputation of the affected limb.  Two main etiologies of PAD are known 
as atherosclerotic peripheral arterial disease and thromboangiitis obliterans (Buerger's 
disease). 
Bypass surgery can be recommended for subjects with critical leg ischemia if the arterial 
circulation of the lower calf or foot includes a reconstituted artery, the outcomes of 
surgery involving small-size arteries are often unsatisfactory due to a high failure rate.  
Many subjects face amputation of their limb as the sole therapeutic option for the severe 
symptoms of critical limb ischemia, when PTA or bypass surgery fails to improve the 
symptoms.  Psychological testing of such subjects typically shows quality-of-life indices 
similar to those of subjects with terminal cancer.  It is estimated that about 150,000 
subjects per year require lower-limb amputations for ischemic diseases in the United 
States alone (corresponding statistics is not available in Korea).  Their prognosis after 
amputation is even worse.  The perioperative mortality for below-knee amputation is 5 to 
10 percent and for above-knee amputation 15 to 20%.  Moreover, full mobility is 
achieved in only 50% of below-knee and 25% of above-knee amputees.  These 
forbidding statistics result from the lack of efficacious drug therapy for PAD.  
Consequently, there is an urgent need for novel treatment strategies for subjects with 
critical limb ischemia. 
1.2 
Therapeutic Angiogenesis in Ischemic Limb Disease 
In subjects with ischemic limb disease, some angiogenesis occurs, creating collateral 
vessels that appear in relation to a gradually developing stenosis or occlusion.  These new 
collateral vessels provide tissue perfusion and relieve clinical symptoms.  The term 
"therapeutic angiogenesis" was coined to describe intervention used to stimulate or 
induce neovascularization by administering angiogenic factors, either as recombinant 
protein or by gene transfer, to the ischemic sites.  Therapeutic angiogenesis represents a 
novel strategy for the treatment of cardiac and vascular diseases.  Recently, hepatocyte 
growth factor (HGF) gene therapy for therapeutic angiogenesis was introduced by 

 
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Morishita and others as a promising new strategy for treating ischemic cardiovascular 
diseases.1  
Morishita’s group first proposed a novel hypothesis that the administration of HGF is 
effective for the treatment of PAD by augmenting collateral vessel development and 
tissue perfusion in ischemic limb muscles.2,3 They have published the results of various 
animal studies of HGF therapy.4,5,6  Morishita and others are currently conducting a phase 
III clinical trial in Japan and a phase II trial in the U.S. to investigate a plasmid vector 
containing the HGF gene for the indication of PAD.7 
A product, VMDA-3601, with the same plasmid backbone, pCK, as VM202, and 
containing the therapeutic gene expressing vascular endothelial growth factor 
(VEGF)165 protein, has been studied for the indication of PAD in a phase I clinical trial 
in Korea (Samsung Seoul Hospital) and is currently under phase II investigation.8  
Animal studies of HGF therapy indicate that HGF gene therapy can improve anatomical 
and physiological functions in animal models of ischemic cardiovascular disease.  No 
growth-promoting effects on tumors have been observed.  HGF gene therapy induces 
formation of collateral vessels, inhibition of fibrosis, and suppression of apoptosis of 
cardiac myocytes, improving physiological cardiac functions measured by increased 
blood flow, ejection fraction, intra-ventricular dimensions and anterior wall thickness of 
left ventricle.  Moreover, HGF protein used in combination with VEGF demonstrated that 
the angiogenic effect of VEGF can be enhanced by HGF.9  These results demonstrate the 
concept that HGF gene can be used for safe and effective treatment of ischemic 
cardiovascular diseases, and that HGF gene therapy might be a more effective and safer 
treatment for ischemic cardiovascular diseases, compared to gene therapies using VEGF. 
VM202 contains a novel structure of the HGF gene as a therapeutic gene, HGF-X7.  The 
key feature of HGF-X7 is that it was designed by inserting a series of intron sequences 
into certain sites of HGF cDNA so that both isoforms of HGF protein are expressed 
simultaneously and as efficiently as in the human genome.  Because there was no change 
in the coding region of the HGF gene, HGF proteins generated from VM202 are identical 
to the wild-type human HGF proteins. 

 
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1.3 
Clinical Experience with Neo-Angiogenesis Therapeutic 
Products 
The DNA vector used in VM202 has been studied for the indication of PAD in a Phase I 
clinical trial in Korea and is currently under Phase II investigation.  The Phase I study 
consisted of 3 cohorts with a total of 3 subjects enrolled in each cohort.  For each dose 
cohort, VMDA-3601 gene therapy was administered as an intramuscular injection (2, 4 or 
8 mg) in two divided doses with a 2-week interval between the injections.  An increase in 
the number of vessels and reduction in pain were observed in 7 out of 9 subjects.  The 
drug was well tolerated.  There were no serious adverse events attributed to study drug 
administration. 

 
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2.0 Rationale 
The gene product VM202 has demonstrated potential for stimulating angiogenesis in 
peripheral blood vessels in animal models.  The development of new blood vessels may 
improve ischemic limb tissues with an increase in skin temperature and a reduction in 
pain both at rest and with exercise as well as numbness in the affected area.  In addition, 
wound ulceration may be reduced or eliminated, need for amputation may decrease and 
exercise capacity may be increased.  This trial is being performed as the first step in 
evaluating safety, tolerability and preliminary efficacy of VM202.  Future trials will 
address dosing, pharmacokinetics and efficacy of VM202 in an expanded cohort of 
subjects with varying degrees of peripheral vascular disease. 

 
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3.0 Study Objectives 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of 
intramuscular VM202 as a vehicle for therapeutic angiogenesis in subjects with critical 
limb ischemia. 
3.2 
Secondary Objectives 
The secondary objectives of the study will include the following exploratory evaluations: 
• To investigate the effects of the intramuscular VM202 to improve pain at rest 
and/or to heal ischemic ulcers of the affected limb. The VAS assessment tool will 
be used for this evaluation. 
• To evaluate the anatomic and physiological extent of collateral vessel 
development in subjects with critical limb ischemia as measured by MRA. 
• To evaluate the change in serum HGF levels from Day 1 to Day 59. 
• To evaluate the change in VM202 DNA levels from Day 1 to Day 21. 
• To evaluate the immune response to HGF in subjects with CLI as measured by the 
change in anti-HGF antibodies from Day 1. 
• To evaluate the ability of VM202 to stimulate endothelial progenitor cells as 
measured by the change in endothelial cell progenitor assay levels from screening 
to Day 59. 
 
 

 
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4.0 Trial Design 
4.1 
Primary and Secondary Endpoints, Pharmacokinetics and 
Pharmacodynamics 
The primary endpoints of this study are the safety and tolerability of escalating doses of 
VM202.  Preliminary effectiveness will also be assessed. 
4.1.1 Primary Safety Endpoints 
The primary safety endpoints include the following: 
1. Incidence of adverse events through Day 365. 
2. Change from Baseline in clinical chemistry, hematology, u/a at Days 15, 28, 59, 
91, 180 and 365. 
3. Injection site reactions, as measured by assessments at Days 1, 8, 15, 21, 28, 
and 59 using National Cancer Institute’s Common Terminology for Adverse 
Events v3.0 criteria as follows:  
Grade 1=Pain, itching, erythema;  
Grade 2=Pain or swelling with inflammation or phlebitis; 
Grade 3=Ulceration or necrosis that is severe or operative intervention 
indicated. 
4. Clinically significant changes in physical examination from Baseline at Days 
15, 28, 59, 91, 180 and 365. 
 
Secondary Efficacy Endpoints 
The Secondary Efficacy endpoints include the following: 
1. Change from Baseline in hemodynamic measurements (Appendix B: ABI, TBI, 
and Wave Form Analysis) and TcPO2 at Days 15, 28, 59, 91, 180 and 365. 
2. Change from Baseline in subject-assessed pain, as measured by the VAS 
(Appendix C) at Days 15, 28, 59, 91, 180 and 365. 
3. Change from Baseline in ulcer area, in square millimeters, as assessed by digital 
photograph and measurement of the largest contiguous ulcerated area, at Days 
15, 28, 59, 91, 180 and 365. 
 
Pharmacokinetic Evaluations 
Pharmacokinetics of VM202 will be assessed using blood VM202 DNA concentration 
levels from samples obtained pre-dose at the first dose administration (Day 1).  In 
addition, levels will be measured at Days 21, and 59 (if DNA is detected at Day 21). 
 
Pharmacodynamic Evaluations 
Pharmacodynamics will be assessed as the change from Day 1 in serum HGF level at 
Days 8, 15, 21 and 59.  Potential immune response to HGF will be assessed as change 

 
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ViroMed Co., Ltd 
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from Day 1 in level of neutralizing antibodies (anti-HGF antibodies) at Days 15, 28, 59 
and 180.  The ability of HGF to stimulate cell growth will be assessed as the change from 
Baseline in level of endothelial progenitor cell assay at Days 15, 28, 59 and 180. 
 
Overall Study Design 
The overall trial design includes: 1) a multi-dose Phase I safety and tolerability 
evaluation; 2) a preliminary efficacy, pharmacokinetic and pharmacodynamic evaluation; 
and 3) a safety review between dosing cohorts in order to meet defined safety criteria.  
The study will evaluate vascular assessments as primary measures of efficacy and 
adverse event collection and laboratory parameters as the primary monitored measures of 
safety (see Table 4-1). 
 
Study Population 
Subjects selected for this study will all have critical limb ischemia defined as partial or 
complete obstruction of a major artery perfusing either the upper or lower extremity that 
results in pain either at rest or with exertion, numbness, coldness and/or skin ulceration.  
They may also be a history of prior amputation, dry gangrene or atrophy associated with 
the above symptoms.  Subjects will not be a candidate for either surgical 
revascularization or angioplasty. 
 
Number of Study Subjects 
There will 12-15 subjects selected for participation in this study with 3 subjects treated in 
each of four (4) study cohorts. There will be an additional 3 patients treated in a cohort if 
1/3 subjects experiences a DLT and if the DSMC recommends continuing the trial. 
 
Schedule of Assessments 
The schedule of assessments is listed below in Table 4-1.

 
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Table 4-1         Study Procedures Chart 
Screen / 
Baseline 
Treatment Period 
 
 
First Dose 
1st 
Follow-
Up 
Second Dose 
2nd Follow-Up5 
 
 
Day -30 to Day 
1 
Day 1  
pre-dose 
Day 1 
post-dose 
Day 8  
(+/- 2days) 
Day 15 
Pre dose 
(+/- 3 days) 
Day15 
Post-dose 
Day 16 
Day 21 
(+/- 3 days) 
Day 28 
(+/- 3 days) 
Day 59 
(+/- 7 days) 
Day 91 
(+/- 7 days) 
Day 180 
(+/- 10 days) 
Day 365  
(+/- 10 days) 
Unscheduled 
Visit 
Early 
Termination 
Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or CT scan of chest1 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Physical Exam 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (HR, BP, Respiratory) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retinal Fundoscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Pregnancy Test 
X 
 
 
 
  X 6 
 
 
 
 
 
 
 
 
 
 
Photograph and measurement of ulcer 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
Clinical Lab Tests  
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Tumor markers2  
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Infection tests3 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
Serum HGF 
 
X 
 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
anti-HGF antibodies 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
Blood VM202 DNA 
 
X 
 
 
 
 
 
X 
 
X7 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High Resolution MRA 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Hemodynamic Assessment (ABI, TBI, 
Wave Form) 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Pain VAS  
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Subject Analgesic use 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
TcPO2  
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Injection site reaction assessment 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Mammogram4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endothelial Progenitor Cell Assay 
X 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1      CT scan of the chest instead of chest X-ray will be performed if previous tobacco use          
                5      A serum test will be done at screening and a urine test on all other days  
2     Tumor markers include: AFP, CEA,CA19-9 PSA (males) & CA125 (females)   
 
                6      Complete draw if detected at Day 21 
3     Infection tests include: HIV, Hepatitis B, HCV, HTLV, CMV, VDRL5                                  
      
4     If not performed in last 12 months prior to start of study

 
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4.3 
Design of the Trial 
This Phase I multi-dose study will enroll a total of 12-15 subjects with documented 
critical limb ischemia (Appendix A).  All subjects must meet inclusion and exclusion 
criteria as listed in Section 0.  Each of 3 subjects in each of 4 cohorts will be evaluated as 
indicated following 2 IM doses of VM202 administered at 2-week intervals.  Subjects in 
each of the four cohorts will all receive the same dose (2, 4, 8 or 16 mg) of VM202. 
 
 
Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(-30) - 
(1) 
1,15 
30-37 
39 
69,84 
99-106 
108 
138, 
153 
168-175 
177 
207, 
222 
237-245 
365 
434 
503 
572 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 
I 
Screen 
Treat
ment 
Safety 
Review 
 
 
 
 
 
 
 
 
 
End of  
Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 
II 
 
 
 
Screen 
Treat
ment 
Safety 
Review 
 
 
 
 
 
 
 
End of 
Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 
III 
 
 
 
 
 
 
Screen 
Treat
ment 
Safety 
Review 
 
 
 
 
 
End of  
Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 
IV 
 
 
 
 
 
 
 
 
 
Screen 
Treat
ment 
Safety 
Review 
 
 
 
End of  
Study 
Figure 4-1 
Phase I Study Design 
 
4.4 
Dosing Cohort Assignment 
A 3-digit subject number will be sequentially assigned to each study subject beginning 
with 101 when the informed consent is signed and any screening procedures are 
performed. Separate screening numbers will not be assigned.  The subject will retain the 
original subject number assigned throughout the trial.  If the subject is withdrawn from 
the study prior to receiving the first dose of study drug, that subject will be replaced but 
the subject number will not be reused. 
 
A study pharmacist will be responsible to prepare the assigned study drug according to 
detailed instructions provided by the Sponsor or their designee. 
 
4.5   Treatments 
The test product used in this study is VM202, a plasmid DNA-based therapeutic product 
expressing HGF.  The HGF gene, HGF-X7 is a genomic-cDNA hybrid HGF construct 
(HGF-X), which expresses both isoforms of HGF with high efficiency.  VM202 has been 
developed using pCK DNA which has been safely used in previous human clinical trials 
with VEGF as the therapeutic vector.[8]  The VM202 plasmid, also identified as pCK-
HGFX7 with 7377 base pairs, is composed of a HCMV enhancer/promoter, a growth 
hormone polyadenylation terminator sequence, ColE1 originator, and the Kanamycin 
resistance gene, on a pCK backbone. 
For each of the 4 cohorts a different dose level will be administered as follows: 

 
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Cohort I- 2 mg of VM202  
Cohort II- 4 mg of VM202  
Cohort III-8 mg of VM202  
Cohort IV-16 mg of VM202  
In the event that a dose limiting toxicity (DLT) is determined after the safety review 
between Cohort I and Cohort II, between Cohort II and Cohort III or between Cohort III 
and Cohort IV, there will be 3 additional subjects treated at the same dose.  If a DLT 
occurs in 2/6 patients, then the preceding dose level will be considered the MTD.  
4.6   Duration 
Each subject will be screened up to 30 days prior to receiving the first dose of study drug.  
Following screening, subjects will receive study drug on Day 1 and Day 15 and will be 
followed up until Day 365 post first dose of study medication.  There will be safety 
evaluations that will begin 30 days after the first dose of study drug (Day 30) for all 
cohorts.  Safety evaluations to encompass 30 days post the first dose of the first subject 
and subsequent to day 15 dosing of the other subjects in the same cohort will be 
completed for each cohort and will be evaluated by the DSMC prior to dose escalation to 
the next cohort. This 30-day window will include a 2-week safety evaluation following 
each dose at Day 1 and 15.  The study will take approximately 30 months to complete.  
The individual subject enrollment will be approximately 12 months. 

 
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5.0 Selection and Withdrawal of Subjects 
Subjects must meet the following inclusion and exclusion criteria in order to be enrolled 
into the study. 
5.1   Cancer Screening 
All subjects participating in this trial must undergo routine cancer screening.  The history 
and diagnosis of potential, or apparent malignant, and non-malignant diseases and 
neoplasms will be assessed through several diagnostic tests and procedures.  Some 
diagnostic tests and procedures performed prior to study consent and documented in the 
patient’s medical history may be acceptable where noted.  Routine cancer screening 
includes the following: 
1. Current fecal occult blood test and flexible sigmoidoscopy within 5 years 
prior to treatment.  Colonoscopy within cancer screening guidelines.  Patients 
presenting with positive fecal occult will require flexible sigmoidoscopy 
during screening 
2. Chest X-ray or CT scan of the chest (if the subject has a previous history of 
tobacco use, a CT scan will be performed instead of the chest X-ray) within 3 
months prior to study entry 
3. Mammogram (females only)-within 1 year prior to study entry 
4. Papanicolaou (Pap) testing - women within 1 year prior to study entry 
5. Prostate specific antigen (PSA) – men within 3 months prior to study entry 
6. Current alpha-fetoprotein (AFP) – will be performed at screening 
7. CA-125 – will be performed at screening (females only) 
5.2       Inclusion Criteria 
To participate in this study the subject must meet all of the following criteria: 
1. Male or female, between 20 and 90 years of age 
2. Have critical limb ischemia (Rutherford Class 4 and 5) and considered not a 
candidate for bypass graft surgery or percutaneous angioplasty due to co-
morbid conditions, failure of previous surgical or interventional procedures or 
caliber of grafting arteries 
Critical limb ischemia is defined as: 
• Stable symptoms on standard therapy including anti-platelet agents, 
vascular rheologic agents, cilostazol, anticoagulant and pain medication 
for 30 days 
• Pain at rest and/or ischemic ulcers for a minimum of 4 weeks 

 
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3. Have diagnostic angiography of the affected limb in the last 12 months 
demonstrating a significant occlusion of one or more of the following arteries: 
iliac, superficial femoral, popliteal, and one or more infra-popliteal arteries 
4. Have a resting ankle systolic pressure (in either the dorsalis pedis or posterior 
tibial arteries) of ≤ 60 mmHg or a resting toe systolic pressure of ≤ 40 mmHg 
in the affected limb 
5. Be willing to maintain current drug therapy for peripheral arterial disease 
throughout the course of the study including an anti-platelet and statin (CoA 
Reductase) inhibitor treatment 
6. Be capable of understanding and complying with the protocol and signing the 
informed consent document prior to being subjected to any study related 
procedures. 
7. Women who are surgically sterile or at least 1 year postmenopausal or who 
have been practicing adequate contraception for at least 12 weeks prior to 
entering the study.  If the subject is of child-bearing potential, she must have a 
negative serum pregnancy test result prior to study enrollment and must agree 
to repeat pregnancy screening tests during the study. 
8. If the subject or the subject’s partner(s) is of child bearing potential, the 
subject and the subject’s partner(s) must agree to use a “double barrier” 
method of birth control while participating in this study. 
5.3  Exclusion Criteria 
To participate in this study a subject may not meet any of the following criteria: 
1. Subjects who have undergone a revascularization procedure or 
sympathectomy within 12 weeks prior to study entry that remains patent.  A 
failed revascularization procedure in the previous 4 weeks is acceptable.   
2. Subjects with grade 3 (hemorrhages, exudates) or grade 4 (papilledema) 
retinopathy 
3. Subjects currently receiving immunosuppressive medications, chemotherapy, 
radiation therapy 
4. Subject with aorto-iliac occlusion (greater than 75%) 
5. Subjects that will require amputation within 4 weeks of randomization 
6. Subjects with any co-morbid conditions likely to interfere with assessment of 
safety or efficacy or with an estimated life expectancy of less than 6 months 
7. Subjects with history of drug (defined as illicit drug use) or a history of 
alcohol abuse (defined as regular or daily consumption of more than 4 
alcoholic drinks per day) within the past 3 months 

 
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8. Subjects with a current history or new screening finding of malignant 
neoplasm except for basal cell carcinoma of the skin and squamous cell 
carcinoma of the skin (if excised and no evidence of recurrence) 
9. Subjects with evidence of active infection (e.g., cellulitis, osteomyelitis) or 
deep ulceration exposing bone or tendon in the extremity planned for 
treatment 
10. Subjects with a clinically significant abnormality in routine hematology, 
urinalysis, chemistry, liver function or other laboratory tests, including HIV, 
Hepatitis B (HepBSAg), Cytomegalovirus (CMV), Hepatitis C Virus (HCV), 
Venereal Disease Research Laboratory test  (VDRL), prostate-specific antigen 
(PSA) and chorio-embryonic antigen (CEA), or signs of malignant neoplasm 
by radiological imaging tests, including chest radiograph at Screening or Day 
1. 
Specific laboratory exclusion criteria include the following: 
• Hemoglobin less than 9.0 G/dl 
• WBC count less than 3,000 
• Platelet count less than 75,000 
• Fasting glucose greater than 250 mg/dl 
• AST and/or ALT greater than 3x upper limit of normal 
11. Subjects with any other condition that in the opinion of the Investigator might 
put the subject at risk or interfere with his/her participation 
12. Subjects unwilling or unable to comply with the protocol or to cooperate fully 
with the Investigator or site personnel 
13. Subjects that have received any other investigational drug within the 30 days 
prior to study drug administration or will receive such a drug during the 
timeframe of this study 
14. Subjects with uncontrolled hypertension defined as systolic blood pressure 
greater than 200 mmHg or diastolic blood pressure greater than 115 mmHg at 
Baseline evaluation 
15. Subjects with advanced liver disease including decompensated cirrhosis, 
jaundice, ascites or bleeding varices 
 
5.4  Subject Withdrawal Criteria 
Subjects will be discontinued from the study prematurely if any of the following occur: 
• The subject requests to be withdrawn from the study 
• The Principal Investigator decides that it is in the subject’s best interest 

 
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• The subject requires percutaneous or surgical intervention for treatment of acute 
limb ischemia. 
• The subject is noncompliant with the protocol 
If a subject withdraws from the study at any time, either at his request or at the Principal 
Investigator’s discretion, the reason(s) for withdrawal will be recorded by the Principal 
Investigator on the Case Report Form (CRF).  If the subject withdraws after receiving 
any study drug, the subject will be encouraged to continue to be monitored after 
withdrawal.  In this regard, they will be informed that it is in their best interest to return 
for all follow-up visits to monitor for possible delayed safety effects from the 
investigational therapy.  If possible, all final visit tasks will be completed for all subjects 
who withdraw from the study.  Subjects who withdraw prior to receiving the first dose of 
study drug will be replaced.  Subjects who have received the first dose of the study agent 
will not be replaced.  Subjects withdrawn due to AEs will be monitored until resolution 
of the AE, as described in Section 8.6. 

 
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6.0 Treatment of Subjects 
6.1  
Treatments Administered 
This study will be conducted using the dosing schedule shown in Table 6-1.  Projected 
doses are based on an 80 kg human.  The dose has been selected based upon assumptions 
that the allometric scaling of terminal t½ will apply.  
Table 6-1 Treatments 
Cohort 
Number of 
Subjects 
Total Dose 
(mg) 
Number of 
Doses 
Time of 
Dosing 
3 
2 
I 
 
 
2; each divided 
among 8 
injection sites 
Day 1, Day 15 
3 
4 
II 
 
 
2; each divided 
among 16 
injection sites 
Day 1, Day 15 
3 
8 
III 
 
 
2; each divided 
among 16 
injection sites 
Day 1, Day 15 
3 
16 
IV 
 
 
2, each divided 
among 16 
injection sites 
Day 1, Day 15 
 
6.1.1 Treatment Regimen and Follow-Up 
For each cohort, VM202 will be administered as either 8 or 16 local intramuscular 
injections to the affected limb in 2 divided doses with a 2-week interval between the 
injections.  A total of 4 or 8 different injection sites will be arbitrarily chosen dependent 
on the dose and the location of the occluded vessels.  The location of the injections sites 
will be documented on a leg diagram provided in the CRF.  Each injection will contain a 
maximum of 2 ml (regardless of weight) and will be injected at each site slowly for about 
20 to 30 seconds as described in Appendix D. 
VM202 is provided in a sterile glass vial containing lyophilized 2.0 mg of study drug.  
Before use, it will be reconstituted with 4 ml of water for injection (WFI).  Each 
reconstituted vial is only to be used for one patient.  After the vial is reconstituted the 
following dosing information is applicable: 
Cohort I has a total dose of 2.0 mg which is 1.0 mg per administration (0.25 mg per 
syringe in 0.5 ml for 4 injection sites per administration)  
 
Cohort II has a total dose of 4.0 mg which is 2.0 mg per administration (0.25 mg per 
syringe in 0.5 ml for 8 injection sites per administration)   
 
Cohort III has a total dose of 8.0 mg which is 4.0 mg per administration (0.5 mg per 
syringe in 1.0 ml for 8 injection sites per administration)  

 
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Cohort IV has a total dose of 16.0 mg which is 8.0 mg per administration (1.0 mg per 
syringe in 2.0 ml for 8 injection sites per administration)  
 
VM202 will be administered in a 1.0 ml syringe for Cohorts I, II and III and a 3.0 ml 
syringe for Cohort IV.  The volume of medication to be used for the four dose cohorts is 
as follows: 
• Cohort I-fill 4 syringes with 0.5 ml per syringe 
• Cohort II-fill 8 syringes with 0.5 ml per syringe 
• Cohort III-fill 8 syringes with 1.0 ml per syringe 
• Cohort IV-fill 8 syringes with 2.0 ml per syringe 
The same volume will be used for both the first and the second doses (series of either 4 or 
8 injections in only one affected leg) for each subject. 
Injection volume by ml  
 
 
 
 
 
Cohort Dose
Volume/ 
administration 
Volume/ 
injection site 
Injections/Administration 
I 
1mg 
2ml 
0.5ml 
4 
II 
2mg 
4ml 
0.5ml 
8 
III 
4mg 
8ml 
1ml 
8 
IV 
8mg 
16ml 
2ml 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection volume by units 
 
 
 
 
 
 
Cohort Dose
Volume/ 
administration 
Volume/ 
injection site 
Injections/Administration 
I 
1mg 
200units 
50units 
4 
II 
2mg 
400units 
50units 
8 
III 
4mg 
800units 
100units 
8 
IV 
8mg 
1600units 
200units 
8 
 
There will be a mandatory review of all safety data between the treatments of all dose 
cohorts (Cohorts I-IV).  No subject may be enrolled in subsequent cohorts until the 
DSMC has reviewed the data and provided a written notice to the sponsor that the trial 
may continue. 
In the event that a DLT is determined after the safety review in any cohort, there will be 3 
additional subjects treated at the same dose level.  If no further DLTs are observed in the 
6 subjects and the DSMC approves dose escalation, then subjects can be enrolled to the 

 
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next higher dose level.  If 2/6 subjects experience a DLT then the preceding dose level 
will be considered the MTD.  
6.1.2 Study Agent Handling and Accountability 
The vials will be labeled as required by all applicable regulations.  The vials will be 
stored at 2-8ºC.  The vials (containing lyophilized VM202) may be kept up to 6 hours at 
room temperature prior to injection.  If the vial is not used by 6 hours at room 
temperature, it must be discarded. 
The vials of VM202 reconstituted with WFI may be kept up to 6 hours at room 
temperature prior to injection.  If the vial is not used by 6 hours at room temperature, it 
must be discarded. 
The study pharmacist will maintain accurate records of receipt of all test articles, 
including dates of receipt.  In addition, accurate records will be kept regarding when and 
how much test article is administered to each individual subject in the study.  Reasons for 
deviation from the expected regimen must also be recorded.  An Investigational Drug 
Utilization Record will be provided for this purpose and will be signed by the study 
pharmacist at the conclusion of the study.  At completion of the study in order to satisfy 
regulatory requirements regarding drug accountability and destruction, the study 
pharmacist will return all used, unused, empty, and partially used vials, with dispensing 
records, to the Sponsor for final accountability, inventory, and destruction. 
6.2  Study Procedures and Study Procedures Chart 
Study procedures to be performed are described by visit in the following sections and 
summarized in Table 4-1.  Prior to performing any study-related procedures, the Principal 
Investigator (or his/her designated staff) will obtain written informed consent from the 
subject or the subject’s legally authorized representative.  After reading the informed 
consent document, the subject must give consent in writing.  The subject's consent must 
be confirmed at the time of the subject’s signature by the personally dated signature of 
the person conducting the informed consent discussions.  The Investigator will retain the 
original signed consent document.  A copy of the signed consent document will be given 
to the subject or the subject's legally authorized representative.  “Legally authorized 
representative” means an individual or judicial or other body authorized under applicable 
law to consent on behalf of a prospective subject to the subject’s participation in the 
procedure(s) involved in the clinical study.  The Investigator will not undertake any 
measures specifically required for the clinical study until valid consent has been obtained. 
6.2.1 Screening Visit (Day -30 to Day 1) 
Subjects will be assessed for all inclusion/exclusion criteria.  The screening visit may 
occur up to 30 days prior to the Day 1 visit.  Data for any screening subject, regardless of 

 
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their eventual eligibility to participate in the study, will be documented in the study case 
report forms.  The following procedures will be completed: 
• Obtain written informed consent 
• Medical history 
• Chest X-ray or CT scan of the chest (if the subject has a previous history of 
tobacco use, a CT scan will be performed instead of the chest X-ray) 
• Full physical examination including stool for occult blood 
• Photograph and measurement of ulcer 
• Vital signs 
• Retinal fundoscopy 
• Pregnancy test (female subjects only) 
• Clinical laboratory tests, including: chemistry, hematology, urinalysis  
• Tumor markers assessment 
• Infection tests 
• 12-lead electrocardiogram 
• High resolution MRA 
• Hemodynamic assessments (ABI and TBI) 
• TcPO2 
• Assessment of all concomitant medications 
• Pain VAS 
• Analgesic use  
• Mammogram/pap smear (for females) – if not performed one year prior to study 
entry 
• PSA (for males) 
• CA-125 (for females) 
• Endothelial progenitor cell assay 
The subject will be screened for cancer and retinopathy to confirm that the patient is free 
of apparent neoplasms and proliferative retinopathy using any prior documentation of 
diagnostic tests and procedures performed prior to study consent and documented in the 
patient’s medical history.   
If the screening process is delayed and the assessments have fallen outside the screening 
period windows, then they must be repeated.  If there are any questions regarding a 
subject’s eligibility, please contact the Project Manager for clarification. 

 
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6.2.2 Day 1 
Based on the subject meeting all of the screening procedures, the Investigator may 
administer the study agent to the patient following the Cohort assignment described 
above.  If a subject is unable to receive the study agent because a clinically significant 
condition has evolved which, in the Investigator’s opinion, represents a potential safety 
risk, the study drug will not be reassigned and the patient will be considered a screen 
failure.  Therefore, it is important to determine the patient’s medical status prior to the 
Day 1 visit and delay assignment until the condition resolves. 
The following evaluations will be performed prior to study drug administration: 
• Review all prior evaluations and confirm that subject meets all entry criteria 
• Vital signs 
• Digital photography and measurement of ulcer (if present) 
• Clinical laboratory tests (chemistry, hematology, and urinalysis) 
• Serum HGF 
• Anti-HGF antibody level 
• VM202 DNA level 
• Hemodynamic assessments (ABI, TBI, Wave Form) 
• TcPO2 
• Pain VAS 
• Analgesic use 
• Concomitant medications 
• Adverse Events 
If the subject meets all eligibility criteria, the following will be performed: 
• Obtain study drug from the pharmacy 
• Administer study drug in 8 separate injections as described above 
After study drug administration, the subject will remain in a comfortable, supine position 
for observation for at least 60 minutes prior to being discharged.  Any adverse reaction 
occurring during this period will be documented on the CRF. 
Following study drug administration, the following evaluations will be performed: 
• Vital signs (immediately after study drug administration and at 15, 30, and 60 
minutes post-dose) 
• Endothelial progenitor cell assay 
• Concomitant medications 
• Injection site reaction assessment 

 
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• Adverse events 
The subject is instructed to call the Study Coordinator if any of the following occur after 
discharge from the clinic:   
• Hives 
• Fever 
• Rash 
• Difficulty breathing 
• Itching 
• Worsening of a leg ulcer 
• Redness or flushing at the site of the test dose 
If any of the above occurs, the subject will be instructed to call the clinic immediately 
and seek medical attention either at the clinic or to go to the nearest Emergency Room for 
immediate treatment and evaluation.  No further study drug administration will occur 
until it is determined if this is a DLT or as directed by the treating physician. 
6.2.3 Day 8 (± 2 days) 
The following evaluations will be performed at Day 8 (± 2 days): 
• Vital signs 
• Serum HGF 
• Injection site reaction assessment 
• Analgesic use  
• Concomitant medications 
• Adverse events 
6.2.4 Day 15 (± 3 days) Second Study Dose Administration 
The second dose of study drug will be administered at Day 15 (± 3 days).  Prior to the 
administration of the study agent, the following will be performed: 
• Physical exam 
• Vital signs (immediately after study drug administration and at 15, 30, and 60 
minutes post-dose) 
• Photograph and measurement of ulcer 
• Urine Pregnancy test (females of childbearing potential) 
• Clinical laboratory tests 
• Tumor markers 
• Serum HGF level 

 
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• anti-HGF antibodies 
• TcPO2 
• Hemodynamic assessment 
• Pain VAS 
• Analgesic use 
• Concomitant medications  
• Adverse events 
The study drug will be administered in the same manner and in the same dose as 
performed on Day 1.  Following study drug administration, the following evaluations will 
be performed: 
• Vital signs 
• Injection site reaction assessment 
• Endothelial progenitor cell assay 
• Adverse events 
6.2.5 Day 16 (post 2nd dosing)  
The following procedures will be performed at the Day 16 visit: 
• Vital signs 
• Adverse events 
• Clinical laboratory tests 
• Analgesic use 
• Injection site reaction assessment 
• Concomitant medications 
6.2.6 Day 21 (+ 3 days) 
The following procedures will be performed at the Day 21 (+ 3 days) visit  
• Vital signs 
• Serum HGF 
• VM202 DNA levels 
• Injection site reaction assessment 
• Analgesic use  
• Concomitant medications 
• Adverse events 
6.2.7 Day 28 ( ± 3 days) 
The following evaluations will be performed at Day 28 (± 3 days): 

 
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• Physical exam 
• Vital signs 
• Photograph and measurement of ulcer 
• Clinical laboratory tests 
• Hemodynamic assessments (ABI, TBI, Wave Form) 
• Pain VAS 
• TcPO2 
• Endothelial progenitor cell assay 
• Analgesic use 
• Injection site reaction assessment 
• Concomitant medications 
• Adverse events 
After all subjects in Cohort I have completed the Day 28 visit, enrollment will be 
temporarily suspended until the DSMC has reviewed all of the safety data for all subjects.  
If the DSMC recommends that the trial continue, enrollment in Cohort II will commence 
and all of the procedures from Day -30 through Day 28 will be repeated for Cohort II. 
After all subjects in Cohort II have completed the Day 28 visit, enrollment will be 
temporarily suspended until the DSMC has reviewed all of the safety data for all subjects.  
If the DSMC recommends that the trial continue, enrollment in Cohort III will commence 
and all of the procedures from Day -30 through Day 28 will be repeated for Cohort III. 
After the first subjects in Cohort III have completed the Day 28 visit and subsequent to 
the dosing of the other subjects in the same cohort, enrollment will be temporarily 
suspended until the DSMC has reviewed all of the safety data for all subjects.  If the 
DSMC recommends that the trial continue, enrollment in Cohort IV will commence and 
all of the procedures from Day -30 through Day 28 will be repeated for Cohort IV. 
6.2.8 Day 59 ( ± 7 days) 
The following evaluations will be performed at Day 59 ( ± 7 days): 
• Physical exam 
• Vital signs 
• Photograph and measurement of ulcer 
• Clinical laboratory tests  
• Infection tests 
• Tumor markers 
• Serum HGF 

 
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• anti-HGF antibodies 
• VM202 DNA levels (If DNA is detected at Day 21) 
• Hemodynamic assessments (ABI, TBI, Wave Form) 
• Pain VAS 
• TcPO2 
• Endothelial progenitor cell assay 
• Analgesic Use 
• Injection site reaction assessment 
• Concomitant medications 
• Adverse events 
6.2.9 Day 91 (± 7 days) 
The following evaluations will be performed at Day 91 ( ± 7 days): 
• Physical exam 
• Vital signs 
• Photograph and measurement of ulcer 
• Clinical laboratory tests  
• Hemodynamic assessments (ABI, TBI, Wave Form) 
• TcPO2 
• Pain VAS 
• High resolution MRA of lower extremity 
• Analgesic use 
• Concomitant medications 
• Adverse events 
6.2.10 Day 180 (± 10 days) 
The following evaluations will be performed at Day 180 (± 10 days): 
• Physical exam 
• Vital signs 
• Photograph and measurement of ulcer 
• Clinical laboratory tests  
• Tumor markers 
• Anti-HGF antibodies 
• Infection tests 
• TcPO2 

 
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• Hemodynamic assessments (ABI, TBI, Wave Form) 
• Pain VAS 
• Analgesic use 
• Endothelial progenitor cell assay 
• High resolution MRA of lower extremity 
• Concomitant medications 
• Adverse events 
6.2.11 Day 365 (+ 10 days) 
The following evaluations will be performed at Day 365 (+10 days): 
 
• Chest X-ray or CT scan of the chest (if the subject has a previous history of 
tobacco use, a CT scan will be performed instead of the chest X-ray) 
• Physical exam 
• Vital signs 
• Photograph and measurement of ulcer 
• Clinical laboratory tests  
• Tumor markers 
• Retinal fundoscopy 
• Infection tests 
• TcPO2 
• Hemodynamic assessments (ABI, TBI, Wave Form) 
• Pain VAS 
• Analgesic use 
• Endothelial progenitor cell assay 
• Concomitant medications 
• Adverse events 
 
6.2.12 Unscheduled Visits 
The data collected during the entire study period are critical for the safety and efficacy 
assessments, therefore, every effort must be made to bring the subject back to the study 
site for all visits. 
If a subject notifies the site that they have experienced an SAE, or experience an event 
such as peripheral bypass surgery, peripheral angioplasty or amputation during the 
follow-up period, they will be encouraged to return to the study site for additional 
assessments.  These events will be reported immediately and the necessary 

 
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documentation will be collected.  All adverse events that a patient experiences must be 
reported.  The following procedures will be performed for all subjects who have an 
unscheduled visit: 
• Physical exam 
• Vital signs 
• Anti-HGF antibodies 
• Endothelial progenitor cell assay 
• Clinical laboratory tests 
• Hemodynamic assessments (ABI, TBI, Wave Form) 
• Pain VAS 
• TcPO2 
• Analgesic Use 
• Concomitant medications 
• Adverse events 
6.2.13 Early Termination Visits 
Subjects who have had at least one dose of test material will return to the study site for 
study specific safety and efficacy assessment visits for the total study period (through 
Day 365), unless the subject withdraws study consent and refuses to participate.  If the 
subject wishes to withdraw study consent, every effort must be made to encourage the 
subject to return to the study site for a termination visit assessment prior to withdrawing 
consent.  The following procedures will be performed at the study termination visit: 
• Chest X-ray or CT scan of the chest (if the subject has a previous history of 
tobacco use, a CT scan will be performed instead of the chest X-ray) 
• Physical exam 
• Vital signs 
• Retinal fundoscopy 
• Photograph and measurement of ulcer 
• Clinical laboratory tests  
• Infection tests 
• Anti-HGF antibodies 
• Endothelial progenitor cell assay 
• High resolution MRA 
• Hemodynamic assessments (ABI, TBI, Wave Form) 
• Pain VAS 

 
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• TcPO2 
• Concomitant medications 
• Adverse events 
If a subject refuses to communicate with the study site, all attempts to contact the subject 
will be documented.  The subject will be sent a certified letter to the subject’s last known 
address. 
6.3 Autopsy 
In the event of the death of the study subject, the investigator will be required to request 
an autopsy from the family of the deceased.  An autopsy will assist ViroMed in learning 
more about the safety and efficacy of gene transfer.  If an autopsy is performed, the final 
autopsy report will be included in the subject’s study file and a copy of the report will be 
sent to both ViroMed and the designated Clinical Research Organization (CRO).  The 
refusal of the family to permit an autopsy will be documented in the study subject’s file 
and on the CRF. 
6.4 Concomitant Medications/Treatments 
6.4.1 Concomitant Medications 
All concomitant medications will be recorded on the CRF at each study visit.  There are 
no prohibited concomitant medications except for other investigational products. 
6.4.2 Replacement of Study Subjects 
Subjects requiring percutaneous or surgical intervention for treatment of limb ischemia 
will be withdrawn from treatment.  If the subject has received at least the first dose of 
study drug, the subject will not be replaced.  If the subject has received one or both doses 
of study drug, the subject will remain in the study through the five year follow-up period. 
6.4.3 Wound Care 
Standard wound care techniques are acceptable (e.g., approved dressings, debridement).  
No un-approved pharmacological wound care therapies or experimental research 
materials may be used to treat the wounds during the study observation period.  The 
application of approved growth factors or engineered skin replacements (e.g. 
Dermagraft®) is permitted.  Patients who require hyperbaric treatment as part of their 
standard of care will be permitted to participate in the study. 
6.4.4 Peripheral Vascular Procedures 
The performance of any peripheral vascular procedures, including, but not limited to, 
peripheral bypass surgery, peripheral endarterectomy, peripheral angioplasty or 
amputation, are events that may occur during the course of the study.  The Investigator 
will document all peripheral vascular interventions performed during the study period. 

 
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If the subject reports the occurrence of any disease-related events (e.g., amputation, 
revascularization bypass, angioplasty), every effort must be made to bring the subject 
back to the study site for full documentation of the event including sufficient information 
from the subject, hospital, any treating physician for each peripheral vascular procedure.  
This information is required by the Sponsor and will be added to the SAE CRF.  
Information will include: 
• Date of intervention 
• Type of intervention (e.g., PTA, peripheral bypass, amputation) 
• Surgical location (e.g., iliac, femoro-popliteal, infra-popliteal; amputation: AKA 
BKA) 
• Surgical materials (e.g., PTFE, HUV, Dacron) 
6.5 Procedures for Monitoring Treatment Compliance 
The study pharmacist, using study drug accountability documents (IDUR), will record the 
preparation and administration of each required dose of IM study drug.  Any missed dose 
will be noted in the pharmacy source documents and on the subject’s CRF.  The 
Investigator is responsible for compliance with the protocol procedures and for 
monitoring the subject’s compliance with the visit schedule. 
6.6 Study Completion and Discontinuation 
A subject may refuse test material treatment, or study procedures at any time during the 
study.  Participation is voluntary, and refusal to participate will involve no penalty, or 
loss of benefits to which the subject is otherwise entitled.  Due to the nature of the test 
material, the subject will be encouraged to maintain contact with the Investigator and 
report any SAEs experienced for the entire study period. 
The Principal Investigator is permitted to discontinue the subject from test material 
treatment for medical reasons at any time.  However the subject will continue to return 
for protocol specific safety and efficacy assessments visits for the remainder of the total 
study period (12-month post dose visit). 
6.7 Subject Classification 
6.7.1 Evaluable Subject 
Any subject who receives at least one dose of study drug and has at least one post dose 
assessment. 
6.7.2 Screen failure 
Any subject who was consented and entered into the screening process appropriately, but 
subsequently did not meet the entry criteria in order to be treated.  Subjects who fail 

 
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screening will not be followed for safety or efficacy assessment, and no other study 
procedures will be performed. 
6.7.3 Lost to follow-up 
A subject deemed to be lost to follow-up is any subject who received treatment, but who 
does not complete scheduled study visits.  This includes those subjects who withdraw 
consent and refuse further study participation and all attempts to contact the subject are 
deemed unsuccessful. 
 

 
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7.0 Assessments and Procedures 
7.1  
Safety 
7.1.1  Medical History 
A complete medical history will be obtained at Baseline.  All positive and negative 
findings will be carefully documented on the CRF.  Any new finding discovered during 
the Baseline evaluation will be considered to be part of the medical history and will not 
be recorded as an adverse event. 
7.1.1.1  
Peripheral Vascular Intervention History 
The Investigator will perform detailed assessment of all past peripheral vascular 
interventions prior to study enrollment.  If the subject has never undergone a peripheral 
vascular intervention, then the lack of these events will be documented as well.  
Information will include: date(s) of intervention, type(s) of intervention (e.g., PTA, 
peripheral bypass, amputation), intervention site (e.g., iliac, femoro-popliteal, infra-
popliteal; and patency of most recent intervention prior to study start (including a 
description of the most recent vascular imaging if available).  Effort will be made to 
obtain sufficient information for each peripheral vascular procedure to confirm the 
subject’s PAD status at Baseline. 
7.1.2 Physical Examination 
The Investigator will perform a full physical examination at Baseline and at Days 15, 28, 
59, 91, 180 and 365.  All changes from the Baseline will be documented on the CRF 
pages at the time of the follow-up physical examination. 
7.1.2.1   Assessment of CLI 
The lower extremities will be examined specifically for clinical evidence of CLI, such as 
ischemic rest pain, ischemic ulceration, gangrenous skin changes, or residual open 
wound(s) from minor amputation. 
Subjects will be classified as having ischemic rest pain if the pain required analgesics for 
more than 2 weeks, and includes the following clinical characteristics: 
1. Persistent or recurrent pain of the distal portion of the leg (usually toes, forefoot 
or ankle), 
2. Pain begins or is increased, on elevation of the leg and improved by dependency. 
Ischemic ulceration and gangrenous skin changes are equivalent necrotizing processes for 
the purpose of this study.  In the case of residual open wound(s) from minor amputation, 
these will be considered ulceration(s) for the purposes of this assessment. 

 
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The Investigator will assess the number of individual ulcers and/or gangrenous tissue 
site(s) for location and size.  Excess necrotic tissue and eschar will be removed when 
possible before taking measurements.  Photographs of each ulceration/gangrene area will 
be taken for documentation purposes only.  Two photographs of each ulceration/gangrene 
area will be obtained at each efficacy time point regardless of whether the area still 
contains the ulcer/gangrene, and regardless of how many doses of test material the 
subject received.  During the monitoring visit, the monitor will retrieve one of the two 
photographs for each ulceration/gangrene area.  The border of all photographs will be 
labeled with the photograph date, subject’s initials, and the subject’s study number 
assignment. 
On efficacy assessment visits, the ulceration/gangrene area will be considered completely 
healed if assessed as having complete skin closure without drainage or dressing 
requirements.  An ulceration/gangrene area that heals but re-appears and is unhealed at 
the assessment will be considered not healed.  If the subject is discontinued from 
treatment, he/she will continue to be followed for ulceration/gangrene evaluations so that 
the subject’s data can be included in analyses.  If the subject is lost to follow-up without a 
proper ulceration/gangrene evaluation, the subject will be considered not to have healed. 
7.1.3 Safety Laboratory Tests 
Safety laboratory tests will include hematology, chemistry and urinalysis.  A list of the 
specific safety and other laboratory tests (tumor markers and infection tests) required is 
provided in Table 7-1. 
7.1.4 Retinal Fundoscopy 
Proliferative retinopathy is defined as the presence of new proliferating blood vessels 
(neovascularization) arising from the retina or optic disc and growing on the retinal 
surface or into the vitreous cavity screened by an acceptable method (e.g. dilated retinal 
examination and retinal photographs) at Baseline and Day 365.  An ophthalmology 
examination for proliferative retinopathy must be performed by an ophthalmologist.  
Results from such evaluations performed within 3 months of Baseline will be accepted. 
Table 7-1 Study Specific Laboratory Procedures 
Hematology 
Chemistry 
Red blood cell  (RBC) count 
BUN 
Hemoglobin 
Bicarbonate 
Hematocrit 
Albumin 
Mean corpuscular volume 
Creatinine 
Mean corpuscular hemoglobin 
Glucose 
Mean corpuscular hemoglobin concentration 
Potassium 
White blood cell count 
Sodium 
Neutrophils 
Chloride 
Lymphocytes 
Uric acid 
Monocytes 
Calcium 

 
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Table 7-1 Study Specific Laboratory Procedures 
Eosinophils 
Phosphorous 
Basophils 
Total protein 
Blood smear 
Tumor markers 
Platelet count 
Prostate specific antigen (PSA) 
Liver Function Tests 
Alpha-fetoprotein 
GGT 
Cancer antigen 19-9 (CA 19-9) 
ALT 
CA125 
AST 
Carcinoembryonic antigen (CEA) 
Alkaline phosphatase 
Infection tests 
LDH 
HIV 
Total bilirubin 
HepBSAg 
 
HCV 
Endothelial Progenitor Cell Assay (EPC) 
HTLV 
 
CMV 
 
VDRL 
 
7.1.5 12-Lead ECG 
A screening ECG will be obtained at Baseline.  All ECG recordings will be printed in 
duplicate.  The site will provide the final interpretation of the Screening ECG. 
7.1.6 Local Injection Site Reaction Assessment 
Local injection sites reactions will be assessed using the grading defined by the National 
Cancer Institute’s Common Terminology for Adverse Events v3.0.  The grading 
categories are as follows and will be recorded on the CRF: 

 
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Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Injection site 
reaction 
Pain; itching; 
erythema 
Pain or swelling, 
with 
inflammation or 
phlebitis 
Ulceration or 
necrosis that is 
severe; operative 
intervention 
indicated 
 
 
Ulceration 
 
Superficial 
ulceration <2 cm 
size; local wound 
care; medical 
intervention 
indicated 
Ulceration ≥2 cm 
size; operative 
debridement, 
primary closure 
or other invasive 
intervention 
indicated (e.g. 
hyperbaric 
oxygen) 
Life-
threatening 
consequences; 
major invasive 
intervention 
indicated (e.g., 
complete 
resection , 
tissue 
reconstruction, 
flap, or 
grafting 
Death 
Allergic reaction/ 
hypersensitivity 
Transient 
flushing or rash; 
drug fever <38ْC 
(<100.4ْF) 
Rash; flushing ; 
urticaria; 
dyspnea; drug 
fever ≥38ْC 
(≥100.4ْF 
Symptomatic 
bronchospasm, 
with or without 
urticaria; 
parenteral 
medications(s) 
indicated; 
allergy-related 
edema/ 
angioedema; 
hypotension 
Anaphylaxis 
Death 
 
7.1.7 Incidence of Adverse Events 
All adverse events and serious adverse events will be recorded on the CRF at each visit. 
7.1.8 Serum Sickness 
Serum sickness is defined as low grade fever, joint pain, lassitude and myalgias within 72 
hours of study drug administration.  The incidence of serum sickness will be documented 
on the CRF. 
7.1.9 Dose Limiting Toxicity (DLT) 
Dose limiting toxicity will be defined as the occurrence of any of the following: 
• Acute anaphylaxis including erythema, hives, wheals, wheezing, stridor or 
respiratory distress 
• Temperature >102ºF with negative blood cultures within 24 hours of study drug 
administration 
• Evidence for active tissue necrosis at the injection site within two weeks of study 
drug administration 

 
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Dose limiting toxicities will be recorded on the CRF.  In the event of a DLT at any dose, 
3 additional subjects will be added to the dose cohort in which the toxicity was observed.  
If no additional DLTs are observed in the 6 subjects in this dose level, it will be 
considered the Maximum Tolerated Dose (MTD).  If a DLT occurs in 2/6 patients, then 
the preceding dose level will be considered the MTD. 
7.2 Efficacy 
7.2.1 Hemodynamic Assessments 
7.2.1.1 Ankle-Brachial Index (ABI) 
Ankle-Brachial index will be obtained using standard, calibrated instruments as described 
in Appendix B.  The pressure in both arms with be measured, and the higher of the two 
pressures will be used.  All values will be recorded at each assessment in the Case Report 
Form. 
7.2.1.2 Toe-Brachial Index (TBI) 
Toe-Brachial index will be obtained using standard, calibrated instruments as described 
in Appendix B.  The pressure in both arms with be measured, and the higher of the two 
pressures will be used.  All values will be recorded at each assessment in the Case Report 
Form. 
7.2.1.3 Wave Form Analysis (PVR) 
A copy of the arterial flow wave form will be obtained at each assessment.  This will be 
placed in the subject’s record and sent for analysis at the end of the study. 
7.2.1.4 Transcutaneous Oxygen Pressure Assessment (TcPO2) 
During the screening period the TcPO2 will be measured at pre-defined locations on the 
anterior and posterior calf and dorsum of the foot.  The limb/chest TcPO2 index will be 
calculated by using the lesser of the lower limb measurements.  Transcutaneous oxygen 
pressure methodology is instrument dependent and therefore the investigator will follow 
the standard procedures defined by their instrument’s manufacturer and the written 
instructions provided by the Sponsor to standardize this procedure. 
At multiple time points prior to and after treatment (Days 1, 15, 28, 59, 91, 180 and 365), 
the subject will have TcPO2 measured at pre-defined locations on the anterior and 
posterior calf and dorsum of the foot.  For analysis purposed, it is important that 
placement of the sensor used for the TcPO2 measurement is always on the same 
pre-defined limb locations for screening and follow-up visits unless it is not possible (site 
amputated, areas of ulceration/gangrene).  Marking the site with indelible ink is 
recommended.  If a sensor placement site is unavailable due to amputation or areas of 
ulceration/gangrene, sensor placement site will be assigned a clinically equivalent default 

 
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TcPO2 value of zero pressure (“0 mmHg”).  Hard copy instrumentation printout will be 
included in the source documentation to support the TcPO2 data. 
7.2.2 High Resolution MRA 
Subjects will have High Resolution MRA at Baseline and at 3 months and 6 months post-
treatment.  Area of Ischemic Ulcer (Digital Photography and Ulcer Measurement) 
If one or more ischemic ulcer is present on the subject’s studied limb, a digital 
photograph will be taken of the largest contiguous area of ulceration with a target plate 
included in the image for calibration purposes.  The wound perimeter will be traced and 
the area of ulceration will be calculated in square millimeters.  If a MRA can not be done, 
a CT-Angio (CTA) can be performed on the subject.   
7.2.3 Pain VAS Score 
Pain intensity will be assessed by subjects marking a place on a 100 mm visual analog 
scale ranging from 0=no pain to 100=worst possible pain as described in Appendix C.  
The distance from 0 to the mark will be measured in millimeters (0 to 100) and recorded 
on the CRF as the VAS score. 
7.2.4 Subject Analgesic Use 
Analgesic use including generic name, dose and frequency will be collected at Baseline 
and each subsequent visit and will be recorded on the CRF.  Any change from in the dose 
level or frequency of analgesics used will be documented. 
 

 
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8.0 Adverse Events and Serious Adverse Events 
8.1 
Adverse Event Definition  
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  AEs will be graded according 
to the National Cancer Institute’s Common Terminology for Adverse Events v3.0 
criteria. 
An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or abnormal results of an investigation (e.g., laboratory 
findings, electrocardiogram). 
Therefore, an AE would include the following: 
• Any event that is new (i.e., was not seen prior to the start of the study). 
• A condition detected or diagnosed after the trial medication administration, even 
though it may have been present prior to the start of the study. 
• A pre-existing intermittent event or condition that recurs with increased intensity 
and/or frequency after the start of the study. 
• A pre- or post-treatment event that results from study participation (i.e., invasive 
procedures, modification of subject’s therapeutic regimen) 
• A change in blood pressure or heart rate that results in discontinuation of dosage 
or that exceeds protocol-specified criteria 
An AE does not include the following: 
• The disease or disorder being studied, or a sign or symptom of that disease or 
disorder, unless it is more severe than expected for the subject’s condition. 
• An overdose of the study medication if the subject is asymptomatic. 
• A medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction).  
Depending on the trial design, such a procedure may be the result of an AE or 
may result in an AE, but is not an AE itself. 
• A pre-existing condition or disease that does not worsen following study drug 
administration. 
• Hospitalization for elective surgery for a pre-existing disease or condition that did 
not worsen or for cosmetic surgery. 
In this study an AE can include an undesirable medical condition occurring at any time 
after screening procedures have been started until the final follow-up visit, even if no 
study treatment has been administered. 
When an adverse event occurs, the Investigator must: 

 
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1. assess whether or not the test article caused the AE;  
2. determine the intensity of the AE;  
3. record the action taken regarding the test article; 
4. indicate whether the AE led to discontinuation of the subject from the study; and  
5. determine if the AE is serious. 
All AEs that occur in any subject enrolled, before treatment, during treatment, or up to 
and including study Day 365 whether or not related to the study drug, must be recorded 
on the appropriate CRF form provided. 
The following are definitions of levels of severity: 
• Mild:  an awareness of symptoms but easily tolerated 
• Moderate:  symptoms interfering with daily activities 
• Severe:  incapacitating, with inability to perform normal daily activities. 
8.2  Definition of an SAE 
For each AE, you must determine if it is a serious adverse event (SAE) according to the 
following definition. 
An SAE is an AE, occurring at any dose, which fulfills one or more of the following 
criteria:  
• An event that results in death. 
• An event that is immediately life threatening.  This does not include an event that, 
had it occurred in a more serious form, might have caused death. 
• An event that results in persistent or significant disability or incapacity. 
• An event that is a congenital abnormality/birth defect  
• An event that requires in-subject hospitalization or prolongs an existing 
hospitalization.  Complications that occur during hospitalization and do not meet 
at least one of the above criteria for seriousness are AEs, not SAEs.  
Hospitalization means that the subject was formally admitted to the hospital, and 
does not include presentation at an emergency room. 
• An event that, though not included in the above list, is an important medical event 
that may jeopardize the safety of the subject or may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Medical and scientific judgment will be exercised in deciding whether a case is serious in 
those situations where important medical events may not be immediately life threatening 
or result in death, hospitalization, disability or incapacity.  These include events that may 
jeopardize the subject or may require medical or surgical intervention to prevent one or 

 
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more outcomes listed in the definition of serious.  Such events will usually be considered 
as serious.  Examples of such events are: 
• Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment 
• Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
• Intensive treatment at the study site, in an emergency room, or at home for 
allergic bronchospasm 
• Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion) or 
convulsions that do not result in hospitalization 
• Development of drug dependency or drug abuse (e.g., analgesics). 
8.3  Laboratory AEs and SAEs 
Abnormal laboratory findings (e.g., serum chemistry, hematology) or other abnormal 
assessments (e.g., ECGs, vital signs) that are judged by the Investigator to be clinically 
significant must be recorded as AEs or SAEs if they meet the definition of an AE or SAE, 
as defined in Sections 0 and 8.2, respectively.  Clinically significant abnormal laboratory 
or other assessment findings that are detected following study drug administration or that 
are present at Baseline and worsen following the start of the study constitute AEs or 
SAEs.  The Investigator will exercise clinical judgment in deciding whether an abnormal 
laboratory finding or other abnormal assessment is clinically significant. 
8.4    Detection of AEs and SAEs: Method, Frequency, and Time 
Period 
The methods of detection for AEs and SAEs include, but are not limited to, the use of 
non-leading verbal questioning of the subject (e.g., how do you feel?), clinical 
observation by the Investigator or study staff, physical examinations, monitoring of vital 
signs, or laboratory assessments. 
AEs will be recorded for each subject from the time the subject signs the informed 
consent form through the subject’s final follow-up visit.  AEs and SAEs that result from 
study participation and occur prior to the start of the study drug will be recorded. 
8.5  Documentation of AEs and SAEs 
All AEs occurring during the study must be recorded in the subject’s medical records and 
on the AE page of the CRF, even if the AE is considered by the Investigator to be 
unrelated to the use of the study drug.  SAEs that occur during the study must be 
documented in the subject’s medical record, on the AE page of the CRF, and on the SAE 
Report Form. 

 
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A separate SAE CRF will be used for all SAEs.  For SAEs which are related and within a 
specific time period, a single form can be used.  An assessment of the relationship of each 
event to the study therapy will be added for each SAE on the form.  Following initial 
reporting of the event, the Investigator will make every effort to establish a diagnosis of 
the event based on the presenting signs, symptoms, and/or other clinical information.  In 
such cases, the diagnosis will be documented as the AE and/or SAE and not the 
individual signs/symptoms. 
Death will not be reported as a serious adverse event.  Death will be reported as the 
outcome of the event.  When a subject expires, please use the cause of Death (acute MI, 
CVA, sepsis) as the SAE and the outcome as Death.  When no cause of Death is 
apparent, please use cardio-pulmonary arrest as the SAE.   
If a clinically significant, abnormal laboratory finding or other abnormal assessment 
meets the definition of an AE or SAE, then the AE page of the CRF and the SAE Report 
Form must be completed, as appropriate.  A diagnosis, if known, or clinical signs and 
symptoms if the diagnosis is unknown, rather than the clinically significant abnormal 
laboratory finding, will be recorded on the AE page of the CRF and on the SAE Report 
Form, as appropriate.  If no diagnosis is known and clinical signs and symptoms are not 
present, then the abnormal finding will be recorded.  If an isolated laboratory abnormality 
is an SAE, then the following will be performed: 1) the laboratory data will be recorded 
in the SAE Report Form with the reference range and all preceding measurement(s) 
value(s), including Baseline value(s), and 2) copies of the laboratory reports and 
reference ranges will be sent with the SAE Report Form. 
The SAE CRF used to report an SAE will be completed as thoroughly as possible and 
signed by the Investigator or designee before transmittal.  The Investigator must provide 
the relationship of the event to the study drug (assessment of causality to the trial 
medication), action taken with the study drug and outcome (if known) at the time of the 
initial report.  SAE CRFs will be sent via Datafax to:  760-268-6550. 
8.6  Follow-up of AEs and SAEs 
All AEs and SAEs must be followed until resolution, the condition stabilizes, the event is 
otherwise explained, or the subject is lost to follow-up.  The Investigator is responsible to 
ensure that follow-up includes any supplemental investigations as may be indicated to 
elucidate as completely as possible the nature and/or causality of the AE or SAE.  This 
may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.  ViroMed or their designee may 
request that the Investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations.  If a subject dies during participation in the study or 

 
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during a recognized follow-up period, a copy of any post-mortem findings will be 
provided to ViroMed or their designee. 
New or updated information will be recorded on the initial SAE Report Form.  All 
corrections to the initial report will be dated and initialed.  Each version will need to be 
sent to the designated CRO via DataFax. 
In the event that a subject is lost to follow-up prior to the Investigator’s being able to 
verify that an AE or SAE is resolved, stabilized, or otherwise explained, the site must 
document in the subject’s medical records the repeated attempts (at least 3) to contact the 
subject and/or his/her care provider to retrieve the information; documentation will 
include date and mode of communication.  In the case of “lost to follow-up.” the event is 
considered as ongoing. 
8.7  Immediate Reporting of SAEs 
ANY SERIOUS AE THAT OCCURS DURING THIS INVESTIGATION (SEE 
SECTION 8.2.), WHETHER OR NOT RELATED TO THE STUDY MEDICATION, 
MUST BE REPORTED IMMEDIATELY TO THE SPONSOR AND/OR THE 
DESIGNATED CRO. 
The reporting timeframes and the required documentation for any SAE occurring during 
the study are summarized in Table 2. 
In the event of an AE leading to hospitalization, every effort will be made by the 
investigational site to obtain a hospital discharge summary. 
In the event of a fatal AE, documentation of any available postmortem findings, 
including autopsy, will be provided to ViroMed or their designee.  In any event, the 
Investigator will provide a narrative summary of circumstances, events related to the 
death, and cause of death, if known. 

 
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Table 8-1 SAE Reporting Requirements 
 
Initial Reports 
Follow-up Reports 
 
Type of SAE 
Fatal/Life Threatening 
and all other SAEs 
Any SAE 
 
Timeframes 
24 hours  
As additional information become available. 
Documents 
 
24 hours: Completed 
initial SAE Report 
Form with minimum 
requirements (subject 
#, date of birth, event 
and start date)  
 
 
Follow-up SAE Report Form and CRF 
documentation 
Hospital discharge summary 
Any relevant diagnostic test results/reports, 
including pathology reports 
Any postmortem findings/histopathology results 
a Within 24 hours after the site learns about the event. 
  NOTE: SAE = Serious Adverse Event. 
 
8.8  Transmission of SAE Reports 
DataFax facsimile transmission of the SAE Report is the preferred method to transmit 
this information.  The facsimile information for reporting of SAEs is:   
 
DataFax number: 760-268-6550 
Additional information beyond the SAE CRF will be faxed separately to 760-268-6500. 
 
8.9  Regulatory Reporting Requirements 
The Investigator must promptly report all SAEs in accordance with the procedures 
detailed in Section 7.3.8.  ViroMed has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about the safety of a drug under 
clinical investigation (21 CFR §312.32). 
The Investigator must comply with the applicable local regulatory requirements related to 
the reporting of SAEs to regulatory authorities and the Institutional Review Board (IRB) 
or Institutional Ethical Committee (IEC). 
This protocol has been filed under an Investigational New Drug (IND) application with 
the US Food and Drug Administration (FDA).  An SAE may qualify as an IND Safety 
Report (21 CFR §312.32) if the SAE is unexpected, serious, and there is a reasonable 
possibility that it may have been caused by the investigational drug.  In this event, all 
Investigators filed to the IND (and associated INDs for the same medicinal product) will 
receive a copy of the IND Safety Report as submitted to the US FDA. 
Upon receipt from ViroMed of an initial or follow-up IND Safety Report or other safety 
information (e.g., revised IDB), the Investigator must promptly notify his or her IRB or 
IEC. 

 
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8.10 Post-Study AEs and SAEs 
Investigators are not obligated to actively seek AEs or SAEs beyond the reporting 
timeframes defined in Section 0.  However, if the Investigator learns of any AE or SAEs 
occurring after the subject’s last study visit and the event is deemed by the Investigator to 
be reasonably possibly related to the use of the study drug, he or she will promptly 
document and report the event to the safety monitor. 
8.11 SAEs Related to Study Participation 
An SAE considered related to study participation (e.g., procedures, invasive tests), even 
if it occurs during the pre- or post-treatment period will be reported promptly to the 
safety monitor in accordance with the procedures detailed above. 

 
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9.0  Statistics  
The following sections provide an overview of the planned analysis.  A statistical 
analysis plan (SAP) will be prepared separately from this protocol, which will provide 
detailed descriptions of the analysis population, statistical methods and models, and 
tested hypotheses to be analyzed.  The SAP will serve as a companion to the protocol and 
as the de facto documentation of the proposed statistical evaluation. 
9.1  Sample Size 
This is a Phase I, dose-escalation study.  The sample size is based on the feasibility to 
assess safety.  No statistical analysis of efficacy is planned. 
9.2   Population 
Statistical analysis will be based on an Intent-to-Treat design, but subjects must receive at 
least one dose of study drug and have at least one post-dose assessment. 
9.3   Statistical Analysis 
Safety and Tolerability: 
The incidence and nature of adverse events will be reported in tabulated format.  Adverse 
events will be described according to severity and to its relationship with the study drug.  
Serious adverse events and adverse events leading to treatment discontinuation will be 
listed. 
Descriptive statistics (N, mean, median, SD, minimum and maximum values, where 
applicable) of safety laboratory parameters infection tests and tumor markers will be 
reported.  Abnormalities will be summarized for low and high values. 
Retinal fundoscopy results per treatment group will be reported as change from baseline 
and subsequent evaluation at day 365. 
Efficacy: 
Descriptive statistics (N, mean, median, SD, minimum and maximum values) of vascular 
assessments (ABI, TBI, Wave Form Analysis), TcPO2, High Resolution MRA, VAS for 
pain, analgesic use, and ulcer size will be reported.  Frequency counts for analgesics use 
by dose cohort will be reported. 

 
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Pharmacokinetics: 
Descriptive statistics (N, mean, median, SD, minimum and maximum values, where 
applicable) of VM202 DNA levels will be reported. 
Pharmacodynamics: 
Descriptive statistics (N, mean, median, SD, minimum and maximum values, where 
applicable) of endothelial progenitor cell assay levels, anti-HGF antibody levels and 
serum HGF levels will be reported. 
Change in endothelial progenitor cell levels from Baseline will be described for each 
treatment dose at each selected time point. 
9.4   Data Safety Monitoring Committee 
A Data Safety Monitoring Committee will review all safety data available 30 days after 
the first subject in each cohort is dosed and subsequent to day 15 dosing of the other 2 
subjects in the same cohort.  The committee will operate via Guidance Document and 
will have pre-specified stopping rules.  The committee will review all safety data 
including severity, relationship to study drug, action taken with study drug and outcome.  
Study drug administration for the next cohort cannot begin until the committee reviews 
all of the data and reports its findings to ViroMed or their designee.  There will also be 
continuing review of safety events after the Day 59 visit for all subjects at defined 
intervals until all subjects have completed the 6 month and 12 month follow-up visit (Day 
365).  
 

 
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10.0  Quality Control and Quality Assurance 
10.1 Ethics 
10.1.1  Responsibilities of the Investigator: 
The procedures set out in this study protocol, pertaining to the conduct, evaluation and 
documentation of this study, are designed to ensure that the Sponsor and the Investigator 
abide by Good Clinical Practice (GCP) as described in 21 Code of Federal Regulations 
(CFR) Parts 50, 56 and 312 and the FDA Guidelines for the Monitoring of Clinical 
Investigations, January 1988.  Compliance with these regulations also constitutes 
compliance with the ethical principles described in the current revision of the Declaration 
of Helsinki, Tokyo 2004. 
Copies of these materials are available from ViroMed by request.  The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific and 
regulatory communities.  They are not intended to impede or restrict clinical research. 
The ethical standards defined within GCP are intended to ensure that: 
• human subjects/subjects are provided with an adequate understanding of the 
possible risks of their participation in the study, and that they have a free choice to 
participate or not; 
• the study is conducted with diligence and in conformance with the protocol in 
such a way as to insure the integrity of the findings; 
• the potential benefits of the research justify the risks. 
ViroMed is the Sponsor of the Investigational New Drug Application (IND) under which 
this study is being performed.  ViroMed is responsible for the following: 
• selecting qualified Investigators, 
• providing Investigators with the information they need to properly conduct an 
investigation, 
• ensuring proper monitoring of the investigation,  
• ensuring that the study is conducted according to the general investigational plan 
and protocols contained in the IND,  
• maintaining the IND, and 
• ensuring that FDA and all participating Investigators are properly informed of 
significant new information regarding adverse effects or risks associated with the 
drug being studied. 
As the Sponsor, ViroMed has delegated some responsibilities to the CRO. 

 
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The Investigator is responsible for ensuring that the study is conducted according to the 
signed Statement of Investigator (Form FDA-1572), the protocol, and all applicable 
regulations.  The Investigator is responsible for protecting the rights, safety and welfare 
of subjects/subjects under his/her care, and for the control of the drugs under 
investigation. 
10.1.2 Legal and Regulatory Considerations 
10.1.2.1 Compliance with Law, Audit, and Debarment 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current GCP standards and all applicable federal, state and local laws, 
rules, and regulations related to the conduct of a clinical study using recombinant DNA 
and gene transfer technology. 
The Investigator is required to make all study documentation promptly available for 
inspection, review, or audit upon request by ViroMed, its representatives, or any 
appropriate regulatory agencies. 
Individuals ineligible from conducting or working on clinical studies, including those 
ineligible as a result of debarment under the Generic Drug Enforcement Act of 1992, will 
not be allowed to conduct or work on studies sponsored by ViroMed.  The Investigator is 
required to immediately disclose to ViroMed, in writing, if any person involved in the 
conduct of the study is debarred pursuant to a hearing by U.S. FDA under this anti-fraud 
law, or if any proceeding for debarment is pending, or is (to the best of your knowledge) 
threatened. 
10.1.2.2 Protection of Human Subjects 
The Investigator will be provided with a sample Informed Consent Form (ICF) for this 
study by ViroMed.  It is requested that the study site use the sample form provided.  
However, the site may adapt the information to suit the needs of the study institution, if 
necessary.  If changes are made by the site to the ICF, the modified ICF must be 
reviewed and approved prior to submission to the IRB.  The final ICF must be approved 
by the Institutional Review Board (IRB) and accepted by ViroMed.  The Investigator 
must provide ViroMed with an unsigned copy of the final ICF following approval by the 
IRB. 
• The consent form must reflect the required elements of informed consent 
specified in 21 CFR Part 50.25. 
• The Investigator must provide all subjects/subjects with all the information 
necessary to make an informed decision about their participation in the study, 
including the nature and intended purpose of the study, possible benefits and 
possible risks. 

 
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• All information in the informed consent form will be provided in language 
understandable to the subject. 
• Before the subject/subject undergoes procedures specific to the protocol, the 
informed consent form must be signed and dated by the subject/subject (or the 
subject’s legally authorized representative). 
• If the subject/subject (or legally authorized representative) cannot read, the 
informed consent form must be signed and dated by an impartial witness. 
• The person who discussed the informed consent information with the 
subject/subject must also sign and date the form. 
• After all required signatures have been obtained, a copy of the informed consent 
form will be provided to the subject/subject, and the original must be kept on file 
at the site. 
10.1.2.3 Institutional Review Board (IRB) 
The Investigator is required to obtain initial and continuing review and approval by an 
IRB that complies with the requirements specified in 21 CFR Part 56.  The protocol (and 
any amendments to it) and the ICF must be reviewed by the IRB.  The IRB must provide 
the study site with written approval that must be forwarded to the CRO prior to study 
initiation.  In addition, the IRB must also approve all advertising used to recruit subjects 
for the study.  If the duration of the study is greater than one year, re-approval by the IRB 
must be obtained on a yearly basis (or at more frequent intervals if required by the IRB). 
The Investigator must provide progress reports to the IRB, as well as any reports of SAE 
from the study site.  The Investigator is also responsible for providing the IRB with 
reports of any IND Safety Reports from any other study site, or from any other study 
conducted with the study drug.  ViroMed will provide this IND Safety Report to the 
study site. 
10.1.2.4 Institutional Biosafety Committee (IBC) 
The site at which this trial is being conducted will ensure that an Institutional Biosafety 
Committee is in place that is composed of at least 5 appropriately-qualified members.  
The IBC will ensure that the site conforms to the requirements set forth in the Section IV-
B-2 of the NIH Guidelines for Research Involving Recombinant DNA Molecules, 
promulgated by the National Institutes of Health/Office of Biotechnology Activities 
(NIH/OBA). 
The Investigator will be responsible for petitioning the IBC and obtaining approval prior 
to enrolling any subject in the study.  The Investigator will also be required to obtain and 
follow all biohazard safety guidelines promulgated by the IBC, and to report all findings 
as required to the IBC and to NIH/OBA. 

 
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10.1.2.5 Protection of Subject Data 
The Investigator is responsible for keeping a record of all screened subjects including full 
names and last known addresses.  All subjects will be identified in the CRF by initials, 
date of birth, gender, and race.  An enrollment number will additionally identify subjects 
in the CRF. 
The Investigator will inform the subject, in writing, about the possibility of audits by 
authorized representatives of ViroMed, the CRO and/or regulatory authorities.  Such 
audits may require a review of those parts of the subject records relevant to the study.  
Confidentiality of subject data will be maintained in accordance with local laws.  The 
informed consent form must contain a statement describing the extent to which 
confidentiality of the subject will be maintained. 
10.2 Study Records, Data Handling, and Record Keeping 
10.2.2 Investigator/Site Documentation 
The Investigator must provide the CRO with the following documents prior to study 
initiation and retain a copy in the study file. 
• A current and complete curriculum vitae for the Primary Investigator and each 
Sub investigator, 
• Completed Form FDA-1572 signed and dated by the Primary Investigator,  
• Approved ViroMed protocol (and any protocol amendments) signed and dated by 
the Primary Investigator, 
• IBC membership list 
• IRB membership list or assurance number, 
• Informed Consent Form approved by the IRB and accepted by ViroMed,  
• Written IRB approval of the protocol, 
• Certifications and laboratory reference ranges for all local laboratories used for 
this study. 
In addition to the documents listed above, the study site will also retain the following 
items: 
• All original informed consent forms with required signatures 
• All IRB approvals and correspondence (i.e., informed consent [including any 
approved revisions], protocol, AE, advertisements, newsletters) 
• Copy of the Study Monitoring Log Sheet 
• Clinical and non-clinical supply shipment forms 
• Copies of all correspondence pertaining to the study (except budget issues) 
between ViroMed or the CRO and the site 

 
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• Copies of all SAE reports submitted to ViroMed or designated CRO 
• Copies of all IND Safety Reports submitted to the site by ViroMed 
• Copies of approved package labeling 
• Study personnel signature log 
The Clinical Study Agreement will be kept in a file separate from any study documents 
because this is a confidential agreement between the study site and/or the Principal 
Investigator and/or the study institution and ViroMed. 
10.2.3 Financial Disclosure 
Before the start of the study, the Investigator will disclose to the Sponsor any proprietary 
or financial interests he or she might hold in the investigational product or the Sponsor’s 
company as outlined in the financial disclosure form provided by the Sponsor (or CRO).  
This will be documented in writing at the beginning and at the end of the trial.  The 
Investigator agrees to update this information in case of significant changes during the 
study or within one year of its completion.  The Investigator also agrees that where 
required by law or regulation, the Sponsor may submit this financial information to 
domestic or foreign regulatory authorities in applications for marketing authorizations. 
10.2.4 Clinical Monitoring 
The study will be monitored in compliance with Section 9 (Commitments) of FDA Form 
1572, the relevant parts of 21 CFR, and according to the ICH GCP Guidelines (E6 
Section 5). 
A representative of the designated CRO will visit the institution prior to initiating the 
study and periodically thereafter to monitor acceptability of facilities, the agreement 
between CRF entries and original source documentation, adherence to the protocol, Good 
Clinical Practice (GCP) and to applicable FDA regulations and the maintenance of 
adequate clinical records.  This representative is a Clinical Research Associate (CRA).  
The CRA will have access to subject records, medication sheets, laboratory data and 
other source documentation. 
The frequency of monitoring visits will depend on subject enrollment.  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 CRA for the review and verification of all CRFs, drug supply and 
inventory records, and any additional records requested for review. 
All information contained in a subject’s CRF must have corresponding source 
documentation.  This source documentation includes, but is not limited to, notes taken at 
subject visits recording the date of the visit, vital signs, physical findings, adverse events, 

 
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or concomitant medications; laboratory reports; hospital records; and clinic records.  All 
electronic progress notes must be printed, signed and dated by the principal Investigator. 
The records of the study may be subject to audit by the Sponsor’s representative or by 
government regulatory authorities (e.g., U.S. Food and Drug Administration or NIH).  
The Investigator must agree to allow access to the required subject records in the event of 
such an audit. 
10.2.5 Recording of Data 
The study site will be provided with multi-part CRFs for collecting subject data.  All 
entries on these forms must be printed legibly using black ballpoint pen.  All information 
recorded on the forms must be supported by documentation in the subject’s file, with the 
exception of the subject’s responses to self-administered assessments (e.g., SF-36).  The 
site will be visited at regular intervals by a representative of the CRO called a Clinical 
Research Associate (CRA).  The CRA will verify all CRF entries against subject records.  
CRFs and all supporting information will be readily available for review during 
scheduled monitoring visits. 
The CRA is responsible for returning all completed forms to CRO.  One copy must be 
retained at the site.  CRF pages will not be mailed or faxed directly to the CRO unless the 
site has received specific permission to do so. 
10.2.6 Database Management and Quality Control 
Data items from the CRFs will be entered into a study database.  Specific details of data 
collection and management procedures for this study will be provided in the Operations 
Manual for this trial. 
Data Management staff, using error messages printed from validation programs and 
database listings, will systematically check the information entered into the database.  
The CRO will be responsible for the data management and will correct obvious errors in 
accordance with ViroMed-approved Data Management Guidelines.  Other errors or 
omissions will be entered onto Data Clarification Forms (DCF), which will be returned to 
the investigational site for resolution.  The site will retain a copy of the DCF.  Once the 
original DCF is returned to the CRO the DCF will be reviewed, appropriate action will be 
taken, and the original signed DCF will be kept with the original CRFs.  Quality control 
audits of all key safety and efficacy data in the database will be made prior to database 
lock according to CRO standard operating procedures (SOPs). 
10.2.7 Investigator’s Final Report 
A summary report must be submitted to the Institutional Review Board and ViroMed or 
their designee within eight weeks after the study’s completion or termination. 

 
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10.2.8 Record Storage and Maintenance 
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 will ensure that the following records are maintained: 
• Subject 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 and all Sub-Investigators, copy of the IRB approval of the 
Protocol and Informed Consent form), all approved versions of the protocol and 
informed consent form and copies of correspondence received from and sent to 
ViroMed.  In addition to these records required by regulations, ViroMed requests 
that the Investigator keep a copy of the Financial Agreement between ViroMed 
and the Investigator. 
• Pharmacy files containing copies of the Investigational Drug Utilization Records 
(IDUR) or an equivalent form approved by ViroMed, instructions for the use of 
the IDUR and package inserts and/or the Investigator’s Brochure. 
10.2.9 FDA/NIH Contact and Correspondence 
The Investigator will notify ViroMed or the Medical Monitor within three days following 
FDA or NIH contact with the investigative site.  The Investigator will provide ViroMed 
or their designee with copies of all correspondence with the FDA or NIH which may 
affect the review of the current study (e.g., Form 483, Inspectional Observations) or their 
qualification as an Investigator in studies conducted by ViroMed (e.g., warning letters).  
ViroMed reserves the right to be present at the site during any FDA or NIH inspection 
that involves this protocol. 
10.2.10  HIPAA  
The Health Insurance Portability and Accountability Act requires that health 
professionals with access to protected health information (PHI) maintain the confidence 
of this information.  In this case, this includes the Principal Investigator if the PI has 
billed a third party for subject services.  Pharmaceutical companies and CROs are not 
entities covered by HIPAA directly.  The Investigator is aware that review of subjects’ 
medical information by a CRO or its designees is permitted as long as the Investigator or 
physician caring for the subject gives permission to review the information and that the 

 
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information is not removed from the subject’s medical record.  The Sponsor will protect 
individual subject information to the full extent possible during this trial.  At no time will 
a subject become identified in any publication or presentation.  However, the subject may 
have to become identified in the event of an FDA audit or inspection in order to verify 
the accuracy of the data.  The subject will remain blinded to the results of this trial for the 
duration of the trial and for a continuing period of time following completion of the 
study.  Access to un-blinded subject information is at the discretion of the Sponsor and 
cannot occur prior to database lock or other specified events as determined solely in the 
discretion of the Sponsor. 
10.2.10 Publication Policy 
ViroMed has the right to publish, independently, the results of this clinical study.  
Authorship will depend on the degree of participation in protocol design, data analysis 
and manuscript preparation. 
The Investigator may not publish the results from this clinical study without the prior 
written permission of ViroMed.  Such permission will not be unreasonably withheld.  If 
ViroMed grants such permission, the Investigator must submit a copy of any manuscript 
and/or abstract to ViroMed for review and comment at least 90 days prior to its 
submission for publication.  ViroMed will provide the Investigator with comments within 
90 days. 
10.3 Handling of Investigational Drug 
In accordance with federal regulations (21 CFR 312.62), all Investigators are required to 
keep accurate records showing final disposition of all investigational drugs.  The study 
pharmacist in charge of the investigational drug may keep the records and sign an 
Investigational Drug Utilization Record (IDUR) or equivalent form.  These records must 
be available to ViroMed on request, showing accurate reconciliation of each and every 
shipment of investigational drug.  A separate IDUR (or the equivalent) must be made for 
each test material received. 
The study pharmacist will be listed on the Site Delegation Log.  The study pharmacist 
will be designated as the person responsible for the handling and dispensing of the test 
article.  The study pharmacist will sign all forms related to study drug inventory, 
dispensing, storage and return. 
Information regarding the handling of study drug will include the following: 
Unique Vial Number:  The unique vial number is indicated on the label applied to each 
container of the product. 

 
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Manufacture Date:  The date the test material was manufactured will be listed on the 
label of the product 
Date Shipment Received:  including the number of vials and lot number. 
Date Used:  Date administered or dispensed to the subject. 
Disposition of Material:  Indicate if administered, destroyed, damaged in transit and 
destroyed, or other final disposition of material. 
Unused Containers:  Indicate any unopened units returned, as well as opened and 
partially used containers. 
Date Returned:  At the termination of the study, all study drug that is not assigned to a 
subject will be returned to ViroMed or their designee.  Indicate the date when unused 
containers are returned (dd/mmm/yyyy).  Any deviations from this procedure will be 
reported to the assigned Project Manager. 
Disposition of Investigational Drug Utilization Records:  When an IDUR (or the 
approved equivalent form) is complete for any given lot, it is to be signed by the study 
pharmacist in charge of the investigational drug.  The CRA will make a photocopy of the 
original, which will be filed in the Investigator’s file. 
10.4 Disposition of Clinical Supplies 
Ultimate accountability for the receipt, dispensation and record keeping of the test 
material lies with the Investigator.  Federal regulation requires that storage of the 
substance be in a secure enclosure, access to which is limited, to prevent theft or 
diversion.  Neither the study pharmacist nor Investigator may supply the test material to 
any person outside of the protocol.  (See previous section for details of the record keeping 
for the investigational material.) 
The investigational drug provided by ViroMed for use in this study is intended for use 
only in the clinical trial outlined in this protocol and will be administered only to subjects 
appropriately enrolled in this trial.  The use of the drug for other clinical or pre-clinical 
situations is strictly prohibited.  The use of the investigational drug by the Investigator, 
sub-Investigators or any third party, outside of the provisions stated in the protocol, 
without the express written permission of ViroMed is strictly prohibited.  VM202 is an 
investigational drug for the use in Clinical Trial US 06-1-001.  The possession and use of 
VM202 must be closely controlled and monitored by the Investigator.  Upon completion 
of the study, the CRA will arrange for return of all used and unused VM202 to the 
Sponsor along with a copy of the drug supply and inventory records. 

 
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10.5 Investigator Confidentiality 
All information and data, including this protocol, and all data, clinical results and 
research conducted hereunder concerning Sponsor’s products and operations including 
Sponsor’s patent applications, formulas, manufacturing processes, basic scientific data 
and formulation information that has been supplied by Sponsor and not previously 
published are considered confidential by Sponsor and will remain the sole property of 
Sponsor.  The Investigator understands and agrees that said proprietary and/or 
confidential information disclosed to or produced by him/her is highly valuable to the 
Sponsor and will be used EXCLUSIVELY by the Investigator in accomplishing this 
study and will not be used for any other purpose without the Sponsor’s prior written 
consent. 
The Investigator agrees that he/she will not use any such proprietary and/or confidential 
information for any other purpose.  The Investigator also understands and agrees that 
such disclosure will not be deemed to grant to the Investigator a license for use of said 
proprietary and/or confidential information, except as expressly provided herein.  It is 
understood by the Investigator that the information developed in the clinical study will be 
used by Sponsor in connection with the development of VM202.  Therefore the 
information may be disclosed and used solely by Sponsor as required to such third parties 
and agencies as Sponsor, in its sole discretion, warrants.  In order to allow for the use of 
the information derived from the clinical studies, it is understood that there is an 
obligation to provide to the Sponsor complete test results and all data developed in this 
study.  The Investigator agrees to promptly answer all inquiries from the Sponsor’s 
representative (CRO) regarding completion, legibility or accuracy of trial data on the 
CRFs. 
 

 
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Appendix A 
Clinical categories of chronic limb ischemia* 
 
Grade 
Category 
Clinical description 
Objective criteria 
0 
0 
Asymptomatic – no 
hemodynamically 
significant occlusive 
disease 
 
Normal treadmill or reactive 
hyperemia test 
 
1 
Mild claudication 
Completes treadmill exercise 1; after 
exercise >50 mm Hg but at least 20 
mm Hg lower than resting value 
 
I 
2 
Moderate claudication 
 
Between categories 1 and 3 
II 
3 
Severe claudication 
Cannot complete standard treadmill 
exercise1 and AP after exercise <50 
mm Hg 
II2 
4 
Ischemic rest pain 
Resting AP <40 mm Hg, flat or 
barely pulsatile ankle or metatarsal 
PVR; TP <30 mm Hg 
 
III2 
5 
Minor tissue loss – non 
healing ulcer, focal 
gangrene with diffuse 
pedal ischemia 
 
Resting AP <60 mm Hg, ankle or 
metatarsal PVR flat or barely 
pulsatile; TP <40 mm Hg 
 
 
6 
Major tissue loss – 
extending above TM 
level, functional foot 
no longer salvageable 
 
Same as category 5 
AP, Ankle pressure; PVR, pulse volume recording; TP, toe pressure; TM, 
transmetatarsal. 
Reference: Journal of Vascular Surgery. 1997;26(3). 
 
 
 
                                          
1 Five minutes at 2 mph on a 12% incline. 
 
2 Grades II and III, categories 4, 5, and 6, are embraced by the term chronic critical ischemia. 

 
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Appendix B 
Hemodynamic Procedures 
ABI and TBI Assessment 
Explain the procedure and reassure the subject and ensure that he/she is lying flat and is 
comfortable, relaxed and rested with no pressure on the proximal vessels.  Laying the 
subject supine reduces hydrostatic pressure inaccuracies.  Reliability and ability to 
reproduce results both over time and between observers was tested and the index was 
found to vary by 0.06, considered acceptable.  Measuring the pressure in both arms and 
using the higher of the two pressures increases the non- invasive accuracy of 
measurement of central systolic pressure but will not eliminate this potential limitation to 
the method. 
Measure the brachial systolic blood pressure:  
1. Place an appropriately sized cuff around the upper arm  
2. Locate the brachial pulse and apply ultrasound contact gel 
3. Angle the Doppler probe at 45 degrees and move the probe to obtain the best 
signal 
4. Inflate the cuff until the signal is abolished then deflate the cuff slowly and record 
the pressure at which the signal returns being careful not to move the probe from 
the line of the artery 
5. Repeat the procedure for the other arm  
6. Use the higher of the two values to calculate the ABPI. 
Measure the ankle systolic pressure:  
1. Place an appropriately sized cuff around the ankle immediately above the malleoli 
having first protected any ulcer that may be present 
2. Examine the foot, locating the dorsalis pedis or anterior tibial pulse and apply 
contact 
3. Continue as for the brachial pressure, recording this pressure in the same way 
4. Repeat this for the posterior tibial arteries 
5. Use the highest reading obtained to calculate the ABPI for that leg 
6. Repeat for the other leg (At the screening visit only.   The index leg will be used 
for future measurements). 

 
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Measure the toe systolic pressure: 
1. Place an appropriately sized cuff around the hallux (1" toe) having first protected 
any ulcer that may be present.  If the 1st toe is unavailable you may use other toes 
if appropriate 
2. Examine the toe with the Doppler or photoplethysmograph (PPG), locating the 
pulse and apply contact 
Note: The same method (Doppler or PPG) must be used on the patient for all 
assessments through study completion. 
3. Continue as for the ankle pressure, recording this pressure in the same way 
4. Repeat this for the other toe artery  
5. Use the highest reading obtained to calculate the TBI for that leg  
6. Repeat ABI and TBI for the other leg 
Calculate the ABI and TBI for each leg using the formula below:  
ABI = Highest Ankle systolic pressure/ Highest Brachial systolic  
TBI = Highest Toe systolic pressure/ Highest Brachial systolic 
Problems and errors may arise if: 
1. The cuff is repeatedly inflated or inflated for long periods.  This can cause the 
ankle pressure to fall 
2. The cuff is not placed at the ankle 
3. Ankle systolic pressure is not measured, pressure recorded is usually higher than 
ankle pressure 
4. The pulse is irregular or the cuff is deflated too rapidly 
5. The true systolic pressure may be missed and inappropriately high reading will be 
obtained, if the vessels are calcified (associated with diabetes), the legs are large, 
fatty or edematous, the cuff size is too small, or the legs are dependent, 
6. Central systolic pressure may influence the 'normal' range for the ABPI 
 

 
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Appendix C 
The Visual Analog Scale (VAS) Procedures 
Pain Intensity Rating using a Visual Analog Scale (VAS) 
The visual analog scale (VAS) is a 10-cm line, oriented horizontally, with one end 
indicating “no pain” and the other end representing “pain as bad as it can be”. 
1. The subject is asked to mark a place on the line corresponding to the current pain 
intensity. 
2. The distance along the scale is then converted into a numeric reading by measuring 
the distance of the subjects mark in centimeters from the beginning of the scale (the 0 
mark). 
3.  The CRF will be faxed into DataFax and the measurement will be electronically 
recorded in the database  
 

 
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Appendix D 
VM202 Test Material Preparation and Administration 
1. Selection of injection sites  
Identify occluded sites using contrast magnetic resonance (MRA) or computerized 
tomography (CTA) angiography. Select injection sites with the objective of inducing the 
formation of bridging collaterals from areas with normal blood flow and improving run-
in.  Therefore, areas adjacent to the occluded sites and areas where blood flow through 
good collateral blood vessels decreases are desirable as injection sites. Documentation of 
injections sites will be indicated by placing an X on the diagram provided in the CRF and 
shown below. 
 
2. Test material administration  
On Day 1 and Day 15 the subject will receive test material. The study treatment will be 
administered as up to 8 injections. A fine needle (e.g. 27 gauge, 1”) suitable for IM 
injections will be used; 2.0 ml will be administered per injection site (total volume of 8 or 
16 ml per administration, determined by cohort assignment). Inject the entire amount of 
the drug in about 20-30 seconds.  Immediately after completion of injection, lightly press 
the injection site with the finger head in order to prevent reflux.  Do not massage the 
injection site. 
 
3. Second test material administration 
Each administration will be given at least 2 cm from the previous injection site. It is 
recommended that an indelible marker be used to mark the location of previous injections 
to ensure that repeat injections are not delivered to exact same location with the 
subsequent administration. 
 

 
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Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected 
Pages 
Reason(s) for the 
Modification(s) 
Section 6.2.1 Screening Day (D) 
Section 6.2.5 Day 15 (D) 
Section 6.2.8 Day 28 (D) 
Section 6.2.9 Day 59 (D) 
Section 6.2.11 Day 180 (D) 
Section 6.2.12 Day 365 (D)  
Section 6.2.15 Early Termination Visits (D) 
Formerly: 
Quality of Life (QOL) 
Section 7.2.6 Quality of Life Score (D) 
Formerly: 
Quality of Life (QOL) will be measured using the 
Medical Outcomes Study short form (SF-36).10  The 
survey should be self-administered by the subject or 
administered by the Investigator or designee.  The 
survey should be administered the same way each time 
it is completed.  Responses will be documented on the 
CRF.  If SF-36 testing falls on a study drug 
administration day, the questionnaire will be taken 
before study drug administration so that study related 
discomforts do not influence the subject’s health 
perception. 
Section 9.3 Statistical Analysis (C) 
Formerly: 
Descriptive statistics (N, mean, median, SD, minimum 
and maximum values) of vascular assessments (ABI, 
TBI, Wave Form Analysis), TcPO2, High Resolution 
MRA, VAS for pain, analgesic use, ulcer size and 
QOL response will be reported.  
Modified to: 
Descriptive statistics (N, mean, median, SD, minimum 
and maximum values) of vascular assessments (ABI, 
TBI, Wave Form Analysis), TcPO2, High Resolution 
MRA, VAS for pain, analgesic use, and ulcer size will 
be reported. 
Protocol Synopsis (C) 
Formerly: 
All subjects will be followed for two years from the 
time of the first dose of study drug administration. 
Modified to: 
All 4 dose cohorts will be followed for up to five years 
xii, xiv, 8, 
25, 28 
Extend long-term 
follow-up from 2 
to 5 years from the 
time of the first 
dose of study drug 
administration 

 
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Pages 
Reason(s) for the 
Modification(s) 
from the time of the first dose of study drug 
administration. 
Formerly: 
All subjects will be followed for two years from the 
time of first dose administrations.  
Modified to: 
All subjects will be followed for two years from the 
time of first dose administrations and will be in long 
term follow-up for a total of 5 years. 
Section 4.2.3 Schedule of Assessments Table 4-1 (C) 
Modified to include: 
6Annual telephone follow-up contacts will continue for 
4 years after day 365 
Delete: 
Annual telephone follow-up at day 365 
Section 6.2.13 Long-term Follow-Up (C) 
Formerly: 
In keeping with current recommendations by FDA to 
maintain a long-term follow-up on subjects who receive 
gene transfer therapy, safety data will be collected for 
one (1) additional year following the subject’s 
completion of study-related procedures.   
Modified to: 
In keeping with current recommendations by FDA to 
maintain a long-term follow-up on subjects who receive 
gene transfer therapy, safety data will be collected for 
up to 5 years (i.e., 4 additional years following the 
subject’s completion of study-related procedures).   
Section 6.4.2 Replacement of Study Subjects (C) 
Formerly: 
If the subject has received one or both doses of study 
drug, the subject will remain in the study through the 
two year follow-up period. 
Modified to: 
If the subject has received one or both doses of study 
drug, the subject will remain in the study through the 
five year follow-up period. 
(requested by the 
FDA at the Oct. 
31, 06 meeting). 
Protocol Synopsis (C) 
xii, 7, 10, Clarification of the 

 
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Reason(s) for the 
Modification(s) 
Formerly: 
If a dose limiting toxicity is observed at any dose 
group, three additional subjects will be added to the 
dose cohort in whom the toxicity was observed and to 
all lower dose cohorts and all evaluations will be 
repeated for these additional subjects. 
Modified to: 
If a dose limiting toxicity is observed in one subject in 
any dose group, three additional subjects will be added 
to the dose cohort in which the toxicity was observed. 
If no additional DLTs are observed in the 6 
subjects in this dose level, it will be considered the 
Maximum Tolerated Dose (MTD). If a DLT occurs 
in 2/6 subjects, then 3 additional subjects will be 
enrolled at the previous dose level. If no DLTs 
occur at this level it will be considered the MTD. 
 
Section 4.2.2 Number of Subjects (C) 
Formerly: 
There will 12 subjects selected at one site for 
participation in this study with 3 subjects treated in 
each of four (4) study cohorts. 
Modified to: 
There will 12-15 subjects selected at one site for 
participation in this study with 3 subjects treated in 
each of four (4) study cohorts. There will be an 
additional 3 patients treated in a cohort if 1/3 
subjects experiences a DLT and if the DSMC 
recommends continuing the trial. 
 
Section 4.5 Treatments (A) 
Addition: 
If a DLT occurs in 2/6 subjects then 3 additional 
subjects will be treated at the previous dose level 
and if no DLT occurs in that cohort, it will be 
considered the MTD. 
 
Section 6.1.1 Treatment Regimen and Follow-Up (C) 
Formerly: 
In the event that a dose limiting toxicity (DLT) is 
determined after the safety review between Cohort I 
and Cohort II, between Cohort II and Cohort III or 
between Cohort III and Cohort IV, there will be 3 
additional subjects treated at the same dose and at all 
17, 35 
standard 3+3 Phase 
1 trial design 
(requested by the 
FDA at the Jan. 06 
Pre-IND meeting). 

 
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Modification(s) 
lower doses (either 2 mg only, 2 mg and 4 mg or 2 
mg, 4 mg and 8 mg) 
Modified to: 
In the event that a DLT is determined after the safety 
review in any cohort, there will be 3 additional 
subjects treated at the same dose level.  If no further 
DLTs are observed in the 6 subjects and the DSMC 
approves dose escalation, then subjects can be 
enrolled to the next higher dose level.  If 2/6 
subjects experience a DLT then the preceding dose 
level treatment group will be considered the MTD.  
 
Section 7.1.9 Dose Limiting Toxicity (DLT) (C) 
Formerly: 
In the event of a DLT at any dose, 3 additional 
subjects will be treated at that dose and at all lower 
doses. 
Modified to: 
In the event of a DLT at any dose, 3 additional 
subjects will be added to the dose cohort in which 
the toxicity was observed.  If no additional DLTs are 
observed in the 6 subjects in this dose level, it will be 
considered the Maximum Tolerated Dose (MTD).  If 
a DLT occurs in 2/6 patients, then 3 additional 
subjects will be enrolled at the previous dose level.  
If no DLTs occur at this level it will be considered 
the MTD. 
Protocol Synopsis (C) 
Formerly: 
Chest X-ray  
Modified to: 
Chest X-ray or CT scan of the chest (if the subject 
has a previous history of tobacco use, a CT scan 
will be performed instead of the chest X-ray) 
 
Formerly: 
For subjects with ischemic ulcer, a photograph of the 
ulcer will be obtained.  Safety laboratory (hematology, 
chemistry, urinalysis), tumor marker tests, infection 
tests, chest X-ray, and ECG will also be done at 
Baseline. 
xiii, 8, 11, 
18, 25, 27 
Add CT scan of 
the chest to the 
List of 
Assessments as CT 
scan will be 
performed instead 
of the chest X-ray 
if the subject has a 
previous history of 
tobacco use 
(requested by the 
Institutional 
Biosafety 
Committee (Oct. 

 
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Reason(s) for the 
Modification(s) 
Modified to: 
For subjects with ischemic ulcer, a photograph of the 
ulcer will be obtained.  Safety laboratory (hematology, 
chemistry, urinalysis), tumor marker tests, infection 
tests, chest X-ray or CT scan of the chest (if the 
subject has a previous history of tobacco use, a CT 
scan will be performed instead of the chest X-ray), 
and ECG will also be done at Baseline. 
Section 4.2.3 Schedule of Assessments Table 4-1 (C) 
Formerly: 
Chest X-ray  
Modified to: 
Chest X-ray or CT scan of chest1 
1CT scan of the chest instead of chest X-ray will be 
performed if previous tobacco use. 
Section 5.1 Cancer Screening (D) 
Formerly: 
Chest X-ray or CT scan of the chest within 3 months 
prior to study entry 
Modified to: 
Chest X-ray or CT scan of the chest (if the subject 
has a previous history of tobacco use, a CT scan 
will be performed instead of the chest X-ray) within 
3 months prior to study entry 
 
Section 6.2.1 Screening Day (C) 
Formerly: 
Chest X-ray (AP only) 
Modified to: 
Chest X-ray or CT scan of the chest (if the subject 
has a previous history of tobacco use, a CT scan 
will be performed instead of the chest X-ray) 
 
Section 6.2.12 Day 365 (A) 
Added: 
Chest X-ray or CT scan of the chest (if the subject 
has a previous history of tobacco use, a CT scan 
will be performed instead of the chest X-ray) 
  
Section 6.2.15 Early Termination Visits (A) 
Added: 
Chest X-ray or CT scan of the chest (if the subject 
06). 

 
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has a previous history of tobacco use, a CT scan 
will be performed instead of the chest X-ray) 
 
Protocol Synopsis (C) 
Formerly: 
There will be 8 injections administered slowly for 
20~40 seconds at pre-determined sites (mainly at the 
calf muscles) without local anesthesia  
Modified to: 
There will be 4 or 8 injections depending on the on 
the dose level administered slowly administered 
slowly for 20~40 seconds at pre-determined sites on 
only one affected leg (mainly at the calf muscles) 
without local anesthesia. 
 
Formerly: 
After the 2nd half of the total dose is administered 
(Day15), hemodynamic assessments (ABI, TBI, Wave 
Form Analysis), TcPO2, photograph and measurement 
of ischemic ulcer, VAS for pain, and safety labs will 
also be assessed on Days 28, 59, 91, 180 and 365. 
Modified to: 
After the second dose is administered (Day15) to the 
leg previously injected, hemodynamic assessments 
(ABI, TBI, Wave Form Analysis), TcPO2, photograph 
and measurement of ischemic ulcer, VAS for pain, 
and safety labs will also be assessed on Days 28, 59, 
91, 180 and 365. 
 
Section 6.1.1 Treatment Regimen and Follow-Up (C)  
Formerly: 
The same volume should be used for both the first and 
the second doses (series of either 4 or 8 injections) for 
each subject. 
Modified to: 
The same volume will be used for both the first and 
the second doses (series of either 4 or 8 injections in 
only one affected leg) for each subject. 
 
xiii, xiv, 
16 
Clarify that the 
doses are 
administered to 
only one leg 
(requested by the 
FDA at the Oct 31, 
06 meeting). 
Section 4.1.3 Pharmacokinetic Evaluations (D) 
Formerly: 
Pharmacokinetics of VM202 will be assessed using 
blood VM202 DNA concentration levels from 
samples obtained pre-dose and 60 minutes and 24 
6, 8, 21 
Deleted the time 
point of 24 hour 
post-drug 
administration for 
VM202 DNA 

 
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Modification(s) 
hours post-dose at the first and second dose 
administration (Day 1 and Day 15). 
Modified to: 
Pharmacokinetics of VM202 will be assessed using 
blood VM202 DNA concentration levels from 
samples obtained pre-dose and 60 minutes post-dose 
at the first and second dose administration (Day 1 and 
Day 15). 
 
Section 4.1.3 Pharmacokinetic Evaluations (D) 
Formerly: 
Pharmacokinetics of VM202 will be assessed using 
blood VM202 DNA concentration levels from 
samples obtained pre-dose and 60 minutes and 24 
hours post-dose at the first and second dose 
administration (Day 1 and Day 15). 
Modified to: 
Pharmacokinetics of VM202 will be assessed using 
blood VM202 DNA concentration levels from 
samples obtained pre-dose and 60 minutes post-dose 
at the first and second dose administration (Day 1 and 
Day 15). 
Section 4.2.3 Schedule of Assessments Table 4-1 (C) 
Formerly: 
3Blood VM202 DNA level at 1 and 24 hours post 
study agent administration 
Modified to: 
4Blood VM202 DNA level at 1 hour post study agent 
administration  
Section 6.2.3 Day 2 (D) 
Formerly: 
6.2.3 Day 2 
The following evaluations will be performed at the 
Day 2 visit: 
· VM202 DNA level at 24-hours post dose 
· Adverse events 
 
concentration level 
because 1 hour 
post-drug 
administration and 
day 8 time points 
are sufficient data 
points for this 
assessment. 
Section 4.6 Duration (C) 
Formerly: 
There will be a 7-day safety evaluation that will begin 
30 days after the first dose of study drug (Day 30) for 
cohort I.  The safety evaluation (adverse events) must 
10, 16 
Clarification of the 
timing of the 
safety evaluation 
by the DSMC. 

 
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be completed prior to the beginning of the next study 
drug administration for the following study cohort (II, 
III and IV). 
Modified to: 
There will be safety evaluations that will begin 30 
days after the first dose of study drug (Day 30) for all 
cohorts.  Safety evaluations to encompass 30 days 
post the first dose will be completed for each cohort 
and will be evaluated by the DSMC prior to dose 
escalation to the next cohort.  This 30-day window 
will include a 2-week safety evaluation following 
each dose at Day 1 and 15. 
 
Section 6.1.1 Treatment Regimen and Follow-Up (C) 
Formerly: 
There will be a mandatory review of all safety data 
between the treatments of Cohort I and Cohort II, 
between Cohort III and Cohort IV.  No subject may be 
enrolled in Cohort II, Cohort III or Cohort IV until the 
SRC has reviewed the data and provided a written 
notice to continue the trial to the Sponsor. 
Modified to: 
There will be a mandatory review of all safety data 
between the treatments of all dose cohorts (Cohort I-
IV).  No subject may be enrolled in subsequent 
cohorts until the DSMC has reviewed the data and 
provided a written notice to continue the trial to the 
Sponsor. 
 
Section 5.3 Exclusion Criteria (C) 
Formerly: 
Subjects with a current history of malignant neoplasm 
except for basal cell carcinoma of the skin and 
squamous cell carcinoma of the skin (if excised and no 
evidence of recurrence 
Modified to: 
Subjects with a current history or new screening 
finding of malignant neoplasm except for basal cell 
carcinoma of the skin and squamous cell carcinoma of 
the skin (if excised and no evidence of recurrence 
12 
Clarify that 
subjects will be 
excluded if a new 
screening finding 
of malignancy is 
observed 
(requested by the 
FDA at the Oct. 
31, 06 meeting). 
Section 6.2.2 Day 1 (C) 
Formerly: 
If any of the above occurs, the subject should be 
20, 34 
Clarify that 
subjects will 
contact the site if 

 
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instructed to immediately return to the clinic or to go 
to the nearest Emergency Room for immediate 
treatment and evaluation.  No further study drug 
administration should occur in such cases. 
Modified to: 
If any of the above occurs, the subject will be 
instructed to call the clinic immediately and seek 
medical attention either at the clinic or to go to the 
nearest Emergency Room for immediate treatment and 
evaluation.  No further study drug administration will 
occur until it is determined if this is a DLT or as 
directed by the treating physician. 
 
Section 7.1.9 Dose Limiting Toxicity (DLT) (C) 
Formerly: 
Evidence for active tissue necrosis at the injection site 
within 72 hours of study drug administration  
Modified to: 
Evidence for active tissue necrosis at the injection site 
within two weeks of study drug administration  
 
pain, redness or 
discomfort occurs 
between day 1 and 
one week 
(requested by the 
FDA at the Oct. 
31, 06 meeting). 
Section 6.1.1 Treatment Regimen and Follow-Up (C) 
Formerly: 
The location of the injections sites will be documented 
photographically and on a leg diagram.  Each 
injection will contain a maximum of 2 ml (regardless 
of weight) and will be injected at each site slowly for 
about 20 to 40 seconds. 
Modified to: 
The location of the injections sites will be documented 
on a leg diagram provided in the CRF.  Each 
injection will contain a maximum of 2 ml (regardless 
of weight) and will be injected at each site slowly for 
about 20 to 40 seconds as described in Appendix D. 
 
Appendix D (C) 
Formerly: 
Precautions in administration 
 
Inject the entire amount of the drug in about 20-30 
seconds.  Immediately after completion of injection, 
lightly press the injection site with the finger head in 
order to prevent reflux.  Do not massage the injection 
site. 
15, 62 
Specify general 
rules and 
descriptive 
schematic diagram 
in the protocol 
(Appendix D) and 
the CRF to serve 
as guidance for 
choosing injection 
sites on the leg 
(requested by the 
FDA at the Oct. 
31, 06 meeting). 

 
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Modification(s) 
Modified to: 
Documentation of injections sites will be indicated 
by placing an X on the diagram provided in the 
CRF and shown below. 
 
Test material administration 
On Day 1 and Day 15 the subject will receive test 
material. The study treatment will be administered 
as up to 8 injections. A fine needle (e.g. 27 gauge, 
1”) suitable for IM injections will be used; 2.0 ml 
will be administered per injection site (total volume 
of 8 or 16 ml per administration, determined by 
cohort assignment). Inject the entire amount of the 
drug in about 20-30 seconds.  Immediately after 
completion of injection, lightly press the injection site 
with the finger head in order to prevent reflux.  Do not 
massage the injection site. 
 
Second test material administration 
 
Each administration will be given at least 2 cm 
from the previous injection site. It is recommended 
that an indelible marker be used to mark the 
location of previous injections to ensure that repeat 
injections are not delivered to exact same location 
with the subsequent administration. 
 
[Substituted figure with Injection Documentation 
Diagram] 
 
Section 6.7.3 Lost to follow-up (C) 
Formerly: 
Any subject who is treated, but who does not complete 
all study visits through Day 365.  This includes those 
subjects who withdraw consent and all attempts to 
contact the subject are unsuccessful. 
Modified to: 
A subject deemed to be lost to follow-up is any 
subject who received treatment, but who does not 
complete scheduled study visits.  This includes those 
subjects who withdraw consent and refuse further 
study participation and all attempts to contact the 
subject are deemed unsuccessful. 
 
30 
Clarify definition 
of subjects who are 
lost to follow-up. 

 
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Modification(s) 
Section 7.3 Pharmacodynamics (D) 
Formerly: 
7.3 Pharmacodynamics 
Pharmacodynamics will be evaluated based on HGF 
antibodies, endothelial progenitor cell assay and serum 
HGF levels present prior to and following injections.  
Endothelial progenitor cell levels will be evaluated for 
all subjects enrolled.  Levels will be obtained at 
Baseline and at specific time points in the study as 
outlined in the schedule of assessments.  Serum level 
of anti-HGF antibodies will be evaluated for all 
subjects enrolled.  If anti-HGF antibodies are detected, 
cell-based assays will be performed to assess 
neutralization activity of the antibodies. Serum HGF 
levels will be evaluated at the intervals described in 
the section on study drug administration. 
7.4 Pharmacokinetics 
Pharmacokinetics will be evaluated based VM202 
DNA levels obtained at Baseline, 60 minutes and 24-
hours after the first series of injections, 60 minutes 
and 24-hours after the second series of injections and 
at the intervals described in the section on study drug 
administration.  While this is not a true 
pharmacokinetic evaluation, it will aid in determining 
if there is a correlation between VM202 DNA levels 
and other safety and efficacy evaluations. 
 
37 
Deleted Section 
7.3 
Pharmacodynami
cs and Section 7.4 
Pharmacokinetics 
because both 
sections repeat the 
same information 
that appears in 
previous sections, 
specifically, 
Section 4.1.3 
Pharmacokinetic 
Evaluations and 
Section 4.1.4 
Pharmacodynami
c Evaluations. 
Section 9.3 
Statistical 
Analysis provides 
specifics on these 
evaluations. 
Section 8.1 Adverse Event Definition (A) 
Added: 
AEs will be graded according to the National Cancer 
Institute’s Common Terminology for Adverse Events 
v3.0 criteria. 
38 
Clarify that AEs 
will be graded 
according to the 
National Cancer 
Institute’s 
Common 
Terminology for 
Adverse Events 
v3.0 criteria and 
will be provided 
for the purpose of 
DSMC review of 
all safety data 
(including AEs) 
to determine if 
dose escalation 
should occur 

 
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Type of Modification to Protocol 
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Affected 
Pages 
Reason(s) for the 
Modification(s) 
(requested by the 
FDA at the Oct. 
31, 06 meeting). 
 
Section 8.1.5 Documentation of AEs and SAEs (C) 
Formerly: 
A ViroMed SAE Report Form should be used for each 
SAE.  If at the time of initial reporting, multiple SAEs 
are present whether or not they are temporally and/or 
clinically related, they must be reported on separate 
ViroMed SAE report forms. 
Following initial reporting of the event, the 
Investigator should make every effort to establish a 
diagnosis of the event based on the presenting signs, 
symptoms, and/or other clinical information.  In such 
cases, the diagnosis should be documented as the AE 
and/or SAE and not the individual signs/symptoms. 
Modified to: 
A separate SAE CRF will be used for all SAE’s.  
For SAEs which are related and within a specific 
time period, a single form can be used.  An 
assessment of the relationship of each event to the 
study therapy will be added for each SAE on the 
form. 
Following initial reporting of the event, the 
Investigator will make every effort to establish a 
diagnosis of the event based on the presenting signs, 
symptoms, and/or other clinical information.  In such 
cases, the diagnosis will be documented as the AE 
and/or SAE and not the individual signs/symptoms. 
 
41 
Clarify that an 
assessment of the 
relationship of 
each AE to the 
study therapy will 
be recorded and 
provided for the 
purpose of DSMC 
review of all 
safety data 
(including AEs) 
to determine if 
dose escalation 
should occur 
(requested by the 
FDA at the Oct. 
31, 06 meeting). 
Section 8.1.7 Immediate Reporting of SAEs (C) 
Formerly: 
Type of SAE - Fatal/Life Threatening 
Timeframe - 24 hours and 48 hours 
Documents - 24 hours: Telephone notification 
48 hours: Fully completed initial ViroMed SAE 
Report Form and CRF Documentation  
Any available diagnostic test results 
Modified to:  
Type of SAE - Fatal/Life Threatening and all other 
SAEs 
Timeframe - 24 hour 
Documents - 24 hours: Completed initial SAE 
43 
Correct Table 8-1. 

 
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Pages 
Reason(s) for the 
Modification(s) 
Report Form with minimum requirements (subject 
#, date of birth, event and start date) 
 
Section 9.0 Statistics (D) 
Deleted: 
The SAP will be completed and finalized prior to 
breaking the blind. 
 
45 
Delete reference 
to a blinded study.
Section 9.2 Population (C) 
Formerly: 
This study will have only an Intent-to-Treat 
population for the purposes of all statistical analyses.  
This population will include all subjects that signed 
the Informed Consent and received the test dose of 
study medication. 
Modified to: 
Statistical analysis will be based on an Intent-to-
Treat design, but subjects must receive at least one 
dose of study drug and have at least one post-dose 
assessment. 
45 
Clarify definition 
of Intent-to-Treat 
in regard to 
statistical 
analysis. 
Section 9.3 Statistical Analysis (C) 
Formerly: 
Retinal fundoscopy changes will be listed by 
frequency and treatment group only.  
Modified to: 
Retinal fundoscopy results per treatment group will 
be reported as change from baseline and 
subsequent evaluation at day 365. 
 
 
45 
Clarify statistical 
analysis of retinal 
fundoscopy. 
Version 3.0 Modifications 
 
Protocol Synopsis (C) 
Formerly: 
If a DLT occurs in 2/6 subjects, then 3 additional 
subjects will be enrolled at the previous dose level. If 
no DLTs occur at this level it will be considered the 
MTD. 
Modified to: 
If a DLT occurs in 2/6 subjects, then the preceding 
dose level will be considered the MTD. 
 
Section 4.5 Treatments (C) 
Formerly: 
xii, 11, 18, 
35 
Corrections 
overlooked in 
version 2 
amendment of the 
protocol for the 
clarification of the 
standard 3+3 Phase 
1 trial design 
(requested by the 
FDA at the Jan. 06 
Pre-IND meeting). 

 
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Affected 
Pages 
Reason(s) for the 
Modification(s) 
If a DLT occurs in 2/6 subjects then 3 additional 
subjects will be treated at the previous dose level 
and if no DLT occurs in that cohort, it will be 
considered the MTD. 
Modified to: 
If a DLT occurs in 2/6 subjects, then the preceding 
dose level will be considered the MTD. 
 
Section 6.1.1 Treatment Regimen and Follow-Up (D) 
Formerly: 
If 2/6 subjects experience a DLT then the preceding 
dose level treatment group will be considered the 
MTD. 
Modified to: 
If 2/6 subjects experience a DLT then the preceding 
dose level will be considered the MTD.  
 
Section 7.1.9 Dose Limiting Toxicity (DLT) (C) 
Formerly: 
If a DLT occurs in 2/6 patients, then 3 additional 
subjects will be enrolled at the previous dose level.  If 
no DLTs occur at this level it will be considered the 
MTD. 
Modified to: 
If a DLT occurs in 2/6 patients, then the preceding 
dose level will be considered the MTD. 
Version 4.0 Modifications 
 
Signature Page (C) 
 Formerly: Version Number: 3.0 
 
Modified to: Amended Version Number: 4.0 
ii 
Changed 
amended version 
number 
Protocol Synopsis (Study Design) (C) 
Formerly: Preliminary efficacy (hemodynamic 
assessments), safety and tolerability will be evaluated 
at Baseline (screening) and at designated time points 
after administration of VM202. 
 
Modified to: Preliminary efficacy (hemodynamic 
assessments), safety and tolerability will be evaluated 
at Baseline (screening) and at designated time points 
xii,  
Clarify time 
points of 
assessment. 

 
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Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected 
Pages 
Reason(s) for the 
Modification(s) 
throughout the study. 
 
Protocol Synopsis (Study Assessments) (A and C) 
Formerly: The following assessments will be 
performed at   screening and at subsequent follow-up 
visits for one year. 
 
Modified to: The following assessments will be 
performed at screening and / or at designated time 
points throughout the study: 
• Informed Consent  
• Physical Exam 
• Vital Signs 
• Pregnancy Test 
• Photograph and measurement of ulcer 
• Mammogram 
• Collection of concomitant medications 
• Collection of medical history  
• Assessment of CLI 
• Collection of adverse events 
xii 
Clarify time 
points of 
assessments and 
add all study 
assessments in 
trial. 
Protocol Synopsis (Rationale) (A) 
Formerly: CA-125 will be done in females and a PSA 
will be done in males to rule out any occult 
malignancy prior to first study drug administration. 
 
Modified to: CA-125 will be done in females and a 
PSA will be done in males to rule out any occult 
malignancy prior to first study drug administration 
and throughout the study. 
xiii 
Add to clarify 
time points of 
assessment. 
Protocol Synopsis (Protocol Synopsis and Section 4.6 
Duration) (A)  
Formerly: 19 months 
 
Modified to: 19 months (Not to include the 4 year 
follow-up) 
 
xi, 11 
Add to clarify 
duration. 
Protocol Synopsis (Protocol Synopsis) (A)  
Formerly: Approximately 12 subjects 
 
Modified to: Approximately 12-15 subjects 
 
xii 
Modify language 
to provided 
consistency. 

 
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Pages 
Reason(s) for the 
Modification(s) 
Protocol Synopsis (Procedures) (C) 
Formerly:  There will be 4 or 8 injections depending 
on the dose level administered slowly for 20~40 
seconds at pre-determined sites on only one affected 
leg (mainly at the calf muscles) without local 
anesthesia.   
 
Modified to:  There will be 4 or 8 injections depending 
on the dose level administered slowly for 20~30 
seconds at pre-determined sites on only one affected 
leg (mainly at the calf muscles) without local 
anesthesia.   
xiv 
Modify language 
per investigators 
brochure. 
Protocol Synopsis (Procedures) (C) 
Formerly:  Analgesic usage and safety labs will be 
assessed on Day 8 post first dose treatment. 
 
Modified to:  Analgesic usage and Serum HGF will 
be assessed on Day 8 post first dose treatment. 
xiv 
Modify 
assessments to 
match study 
procedures chart. 
Protocol Synopsis (Safety Monitoring) (C) 
Formerly:  Safety laboratory analyses will be 
completed at screening and at Day 28, 59, 91, 180 and 
365.  A follow-up phone calls will be made at Day 
365 in all subjects. An additional follow-up phone 
call will be made annually for up to five years after the 
first dose administration. 
 
Modified to:  Safety laboratory analyses will be 
completed at screening and at specified time points 
throughout the study.    Follow-up phone calls will 
be made semi-annually for up to 5 years after the first 
dose administration. 
xiv-xv 
Clarify time 
points of 
assessment. 
Protocol Synopsis (Safety Monitoring) (C) 
Formerly:  Physical examination, vital signs and 
retinal fundoscopy will also be performed as part of 
safety monitoring at screening and at Day 91, 180 and 
365 (retinal exam at screening and Day 365). 
 
Modified to:  Physical examination, vital signs and 
retinal fundoscopy will also be performed as part of 
safety monitoring at screening and at specified time 
points throughout the study. 
xv 
Clarify time 
points of 
assessment. 

 
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Type of Modification to Protocol 
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Affected 
Pages 
Reason(s) for the 
Modification(s) 
Protocol Synopsis (Efficacy Evaluation) (C) 
Formerly:   Pharmacodynamic evaluation will be 
based on anti-HGF antibodies, endothelial 
progenitor cell assay and serum HGF levels post 
treatment. 
 
Modified to: Pharmacodynamic evaluation will be 
based on anti-HGF antibodies and serum HGF levels 
pre treatment and endothelial progenitor cell assay 
levels post treatment. 
xv 
Clarify language 
to match study 
procedures chart. 
Protocol Synopsis (Statistical Analysis) (C) 
Formerly:   Pharmacodynamics will assess change 
from Baseline in anti-HGF antibodies, endothelial 
progenitor cell assay and serum HGF levels post 
treatment between all 4 doses. 
 
Modified to: Pharmacodynamics will assess change 
from Day 1 in anti-HGF antibodies and serum HGF 
levels at pre treatment and endothelial progenitor 
cell assay post treatment between all 4 dose levels. 
xvi 
Modify 
assessment time 
point to match 
study procedures 
chart and clarify 
language.  
Study Objectives (Secondary Objectives) (C) 
Formerly:  To evaluate the immune response to HGF 
in subjects with CLI as measured by the change in 
anti-HGF antibodies from Baseline. 
 
Modified to:  To evaluate the immune response to 
HGF in subjects with CLI as measured by the change 
in anti-HGF antibodies from Day 1. 
5 
Modify 
assessment time 
point to match 
study procedures 
chart. 
 Study Objectives (Secondary Objectives) (C) 
Formerly:  To evaluate the ability of VM202 to 
stimulate endothelial progenitor cells as measured by 
the change in endothelial cell progenitor assay levels 
from Day 1 to Day 59.    
 
Modified to: To evaluate the ability of VM202 to 
stimulate endothelial progenitor cells as measured by 
the change in endothelial cell progenitor assay levels 
from screening to Day 59.   
5 
Modify 
assessment time 
point to match 
study procedures 
chart. 
Section 4.1.2 Secondary Efficacy Endpoints (A) 
6 
Add assessment 

 
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Pages 
Reason(s) for the 
Modification(s) 
Formerly:  Change from Baseline in hemodynamic 
measurements (Appendix B: ABI, TBI, and Wave 
Form Analysis) and TcPO2 at Days 15, 28, 59, 91, 
and 180.   
 
Modified to:  Change from Baseline in hemodynamic 
measurements (Appendix B: ABI, TBI, and Wave 
Form Analysis) and TcPO2 at Days 15, 28, 59, 91, 180 
and 365. 
time point to 
match study 
procedures chart. 
Section 4.1.4 Pharmacodynamic Evaluations (C) 
Formerly:  Pharmacodynamics will be assessed as the 
change from Baseline in serum HGF level at Days 8, 
15, 21, 28 and 59.  Potential immune response to HGF 
will be assessed as change from Baseline in level of 
neutralizing antibodies (anti-HGF antibodies) at Days 
15, 28, 59 and 180.   
 
Modified to:  Pharmacodynamics will be assessed as 
the change from Day 1 in serum HGF level at Days 8, 
15, 21, 28 and 59.  Potential immune response to HGF 
will be assessed as change from Day 1 in level of 
neutralizing antibodies (anti-HGF antibodies) at Days 
15, 28, 59 and 180.   
7 
Modify 
assessment time 
point to match 
study procedures 
chart. 
Section 4.4 Dosing Cohort Assignment (C) 
Formerly: A sequential 3-digit subject number will be 
assigned to each study subject (beginning with 101 for 
Cohort I, 201 for Cohort II, 301 for Cohort III and 
401 for Cohort IV) when the informed consent is 
signed and eligibility is confirmed. All patients will 
be assigned to each cohort sequentially beginning 
with Cohort I until the cohort group is enrolled.  
Cohorts II, III and IV will follow in the same 
manner.  If the subject is withdrawn from the 
study prior to receiving the first dose of study 
drug, that subject will be replaced.   
 
Modified to: A 3-digit subject number will be 
sequentially assigned to each study subject beginning 
with 101 when the informed consent is signed and any 
screening procedures are performed.   Separate 
screening numbers will not be assigned.  The 
subject will retain the original subject number 
9  
Clarify to match 
database 
assignment. 

 
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Pages 
Reason(s) for the 
Modification(s) 
assigned throughout the trial.  If the subject is 
withdrawn from the study prior to receiving the 
first dose of study drug, that subject will be 
replaced but the subject number will not be reused.  
Section 4.5 Treatments (C) 
Formerly:  There will be four doses administered as 
follows: 
 
Modified to:  For each of the 4 cohorts a different 
dose level will be administered as follows: 
9 
Clarify language. 
Section 5.1 Cancer Screening (A) 
Added:  7. CA-125 –will be performed at screening 
(females only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 
Add to match 
study procedures 
chart. 

 
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80 
 
Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected Pages 
 
Reason(s) for the Modification(s) 
Section 4.1 Study Procedures Chart (C) 
Formerly: 
8 
Inconsistencies within the protocol. 
 
Screen / 
Baseline 
Treatment Period 
 
First Dose 
1st 
Follow-Up 
Second Dose 
2nd Follow-Up 
 
Day -30 
to Day 1 
Day 1  
pre-dose 
Day 1 
post-dose 
Day 8 
Day 15 
Pre dose 
Day15 
Post-dose 
Day 21 
Day 28 
Day 59 
Day 91 
Day 180 
Day 365 
Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or CT scan of chest1 
X 
 
 
 
 
 
 
 
 
 
 
X 
Physical Exam 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Vital Signs (HR, BP, Respiratory) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retinal Fundoscopy 
X 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
Photograph and measurement of 
ulcer 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Clinical Lab Tests  
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
Tumor markers2  
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
Infection tests3 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
Serum HGF 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
anti-HGF antibodies 
X 
X 
 
 
X 
 
 
X 
X 
 
X 
 
Blood VM202 DNA 
X 
X 
X4 
X 
X 
X4 
X 
X 
X 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
X 
High Resolution MRA 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Hemodynamic Assessment (ABI, 
TBI, Wave Form) 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Pain VAS  
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Subject Analgesic use 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TcPO2  
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Injection site reaction assessment 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
X 
Mammogram5 
X 
 
 
 
 
 
 
 
 
 
 
X 
Endothelial Progenitor Cell Assay 
X 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone Follow-up6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Affected Pages 
 
Reason(s) for the Modification(s) 
 
 
1 
CT scan of the chest instead of chest X-ray will be performed if previous tobacco use 
2 
Tumor markers include: AFP, CEA, PSA, CA19-9 & CA125 
3 
Infection tests include: HIV, Hepatitis B, HCV, HTLV, CMV, VDRL 
4 
Blood VM202 DNA level at 1 hour post study agent administration 
5 
If not performed in last 12 months prior to start of study 
6 
Annual telephone follow-up contacts will continue for 4 years after day 365 
 
Modified to: 
 
Screen / 
Baseline 
Treatment Period 
 
 
First Dose 
1st 
Follow-
Up 
Second Dose 
2nd Follow-Up6 
 
 
Day -30 to Day 
1 
Day 1  
pre-dose 
Day 1 
post-dose 
Day 8  
(+/- 2days) 
Day 15 
Pre dose 
(+/- 3 days) 
Day15 
Post-dose 
Day 16 
Day 21 
(+/- 3 days) 
Day 28 
(+/- 3 days) 
Day 59 
(+/- 7 days) 
Day 91 
(+/- 7 days) 
Day 180 
(+/- 10 days) 
Day 365 
(+/- 10 days) 
Unscheduled 
Visit 
Early 
Termination 
Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or CT scan of chest1 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Physical Exam 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (HR, BP, Respiratory) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retinal Fundoscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Pregnancy Test 
X 
 
 
 
  X 7 
 
 
 
 
 
 
 
 
 
 
Photograph and measurement of ulcer 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
Clinical Lab Tests  
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Tumor markers2  
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Infection tests3 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
Serum HGF 
 
X 
 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
X 
anti-HGF antibodies 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
Blood VM202 DNA 
 
X 
X4 
X 
X 
X4 
X 
X 
X 
X 
 
 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High Resolution MRA 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 

 
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Affected Pages 
 
Reason(s) for the Modification(s) 
Hemodynamic Assessment (ABI, TBI, 
Wave Form) 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Pain VAS  
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Subject Analgesic use 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
TcPO2  
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Injection site reaction assessment 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Mammogram5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endothelial Progenitor Cell Assay 
X 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1      CT scan of the chest instead of chest X-ray will be performed if previous tobacco use          
                5      If not  performed in last 12 months prior to start  of  study 
2     Tumor markers include: AFP, CEA,CA19-9 PSA (males) & CA125 (females)   
 
                6      Telephone follow-up contacts will continue for 4 years after day 365  
3     Infection tests include: HIV, Hepatitis B, HCV, HTLV, CMV, VDRL5                                  
                7      A serum test will be done at screening and a urine test on all other days  
4     Blood VM202 DNA level at 1 hour post study agent administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Type of Modification to Protocol 
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Affected 
Pages 
Reason(s) for the 
Modification(s) 
Section 6.1.1 Treatment Regimen and Follow-Up (C) 
Formerly:  Each injection will contain a maximum of 
2 ml (regardless of weight) and will be injected at each 
site slowly for about 20 to 40 seconds as described in 
Appendix D. 
 
Modified to:  Each injection will contain a maximum of 
2 ml (regardless of weight) and will be injected at each 
site slowly for about 20 to 30 seconds as described in 
Appendix D. 
15 
Modify language 
per investigators 
brochure. 
Section 6.1.2 Study Agent Handling and 
Accountability (C) 
Formerly: The vials will be labeled as required by all 
applicable regulations.  The vials will be stored at 4ºC.   
 
Modified to:  The vials will be labeled as required by 
all applicable regulations.  The vials will be stored at 2-
8ºC.   
17 
Modify language 
per investigators 
brochure. 
Section 6.2.1 Screening Visit (Day -30 to Day 1) (C) 
Formerly:  Viral Tests 
 
Modified to: Infection tests 
18, 23, 
24, 26 
Clarify term 
throughout 
protocol language 
to match study 
procedures chart. 
 Section 6.2.1 Screening Visit (Day -30 to Day 1) (A) 
Added:   
CA-125 (for females) 
Endothelial progenitor cell assay 
18 
Add to match 
study procedures 
chart. 
Section 6.2.2 Day 1 (C and D) 
Formerly:  The following evaluations will be 
performed prior to study drug administration: 
Viral Tests 
Endothelial progenitor cell assay 
 
Modified to: Following study drug administration, the 
following evaluations will be performed:  
Endothelial progenitor cell assay 
19  
Clarify sentence 
and delete to 
match study 
procedures chart. 
Section 6.2.4 Day 15 (± 3 days) Second Study Dose 
Administration (A and D) 
Formerly:  Prior to the administration of the study 
agent, the following will be performed: 
20 
Delete to match 
study procedures 
chart and add 
pregnancy test per 

 
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Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected 
Pages 
Reason(s) for the 
Modification(s) 
Endothelial progenitor cell assay 
Modified to: Prior to the administration of the study 
agent, the following will be performed: 
Urine Pregnancy test (females of childbearing 
potential) 
inclusion criteria. 
Section 6.2.4 Day 15 (± 3 days) Second Study Dose 
Administration (A) 
Added:  Following study drug administration, the 
following evaluation will be performed: 
VM202 DNA level 
Endothelial progenitor cell assay  
21 
Add to match 
study procedures 
chart. 
Section 6.2.1.2 Long-term Follow-Up (C) 
Formerly: If living-hospitalizations in the last six 
months 
 
Modified to: If living-hospitalizations since the 
previous contact 
25 
Modify language 
to capture all data.
Section 6.2.1.2 Long-term Follow-Up (A) 
Formerly: Any subject who received VM202 will be 
asked to provide contact information and will be 
contacted annually by mail or telephone by ViroMed.  
Subjects will be informed of this follow-up 
requirement of the study during the informed consent 
process.  Written instructions will be provided to each 
subject at the final visit that describe how to contact 
ViroMed if they experience and adverse event that 
could be related to participation in the study.  Subjects 
will be asked to notify ViroMed should their contact 
information change.  
 
Modified to: Any subject who received VM202 will be 
asked to provide contact information and will be 
contacted annually by mail or telephone by ViroMed 
or a ViroMed representative.  Subjects will be 
informed of this follow-up requirement of the study 
during the informed consent process.  Written 
instructions will be provided to each subject at the final 
visit that describe how to contact ViroMed or a 
ViroMed representative if they experience and 
adverse event that could be related to participation in 
the study.  Subjects will be asked to notify ViroMed or 
25 
Add to allow 
representative to 
conduct follow-up 
contact. 

 
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Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected 
Pages 
Reason(s) for the 
Modification(s) 
a ViroMed representative should their contact 
information change.  
Section 6.2.1.2 Long-term Follow-Up (A) 
Formerly: Questionnaires will be developed for the 
annual contacts for two years after Day 365 and 
annual contacts that will elicit updates on any cancer, 
neurological, autoimmune, or hematological disorder 
that has appeared or changed since the last contact.   
 
Modified to: Questionnaires will be developed for the 
semi-annual contacts for four years after Day 365 that 
will elicit updates on any cancer, neurological, 
autoimmune, or hematological disorder that has 
appeared or changed since the last contact.  
Information will also be collected on any unexpected 
health problems including hospitalizations or new 
medications. 
 Section 6.2.1.4 Early Termination Visits (A) 
Formerly: Subjects who have had at least one dose of 
test material    will return to the study site for specific 
safety and efficacy  assessment visits for the total study 
period, unless the subject withdraws study consent and 
refuses to participate.  
 
Modified to: Subjects who have had at least one dose 
of test material will return to the study site for specific 
safety and efficacy assessment visits for the total study 
period (through Day 365), unless the subject 
withdraws study consent and refuses to participate. 
25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
26 
Add to clarify 
assessment time 
points per 
Sponsor request. 
 
 
 
 
 
 
 
 
 
   
 
 
Add to clarify 
time point 
Section 6.2.1.4 Early Termination Visits (D) 
Deleted:  
12 Lead ECG 
27 
Delete to match 
study procedures 
chart 
Section 6.4.4 Peripheral Vascular Procedures (C) 
Formerly: This information is required by the Sponsor.  
 
Modified to: This information is required by the 
Sponsor and will be added to the SAE CRF.   
 
Deleted: 
• Diagnostic findings (e.g., angiographic, 
28 
Modify to clarify 
how Peripheral 
Vascular 
Procedures will 
be captured as an 
SAE. 

 
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Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected 
Pages 
Reason(s) for the 
Modification(s) 
segmental BP tests). 
• Physical findings at time of procedure 
 Infection (e.g., cellulitis, sepsis, 
osteomyelitis) that was refractory to 
antibiotics and/or had not responded to 
more conservative treatments (e.g., 
drainage, debridement) 
 tissue loss due to necrosis 
 uncontrollable rest pain that did not 
respond to more conservative standards 
of treatment (e.g., opiate analgesics). 
 
Section 7.2.2 High Resolution MRA (D) 
Formerly: At each assessment, quantitative measures 
of blood flow in the target occluded artery(s) will be 
determined.  In addition, volumetric analysis of newly 
developed vessels will also be described.   
 
Deleted: At each assessment, quantitative measures 
of blood flow in the target occluded artery(s) will be 
determined.  In addition, volumetric analysis of 
newly developed vessels will also be described.   
 
35 
Deleted to match 
CRF. 
Section 8.5 Documentation of AEs and SAEs (C) 
Formerly: 760-268-6532 
 
Modified to: 760-268-6550 
39 
Modify to correct 
telephone 
number. 
Appendix B (A) 
Formerly: Repeat for the other leg. 
 
Modify to: Repeat for the other leg (At the screening 
visit only.   The index leg will be used for future 
measurements). 
 
56 
Add to clarify 
procedure. 
Appendix C (C) 
Formerly: The measurement is recorded from 00.0 to 
10.0 onto the CRF. 
 
Modified to: The CRF will be faxed into DataFax 
and the measurement will be electronically recorded 
in the database. 
58 
Modify to match 
the CRF. 

 
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Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected 
Pages 
Reason(s) for the 
Modification(s) 
Version 5.0 Modifications  
 Protocol Title (C) 
 Formerly: A Phase I, Dose-Escalation, Single Center     
Study to Assess the Safety and Tolerability of VM202 
in Subjects with Critical Limb Ischemia 
Modified to: A Phase I, Dose-Escalation Study to 
Assess the Safety and Tolerability of VM202 in 
Subjects with Critical Limb Ischemia 
 
i, ii  
Changed to allow 
the option to use 
multi -centers to 
increase patient 
enrollment. 
 
 
 
Signature Page (C) 
 Formerly: Version Number: 4.0 
Date: September 13, 2007 
 
Modified to: Amended Version Number: 5.0 
Date: November 29, 2007 
ii 
Changed 
amended version 
number and date. 
Protocol Synopsis: Study Design (C) 
Formerly: After all subjects in the first dose cohort 
have completed the 30-day (± 2 days) follow-up visit 
following the 1st dose of study drug, an interim safety 
evaluation will be performed with the submission of 
safety data to the Data Safety Monitoring Committee 
(DSMC). If the DSMC recommends continuing the 
study, the second dose cohort will be treated. 
 
Modified to: After the first subject in each cohort 
completes day 30 (± 2 days), subsequent to day 15 
dosing of the other 2 subjects in the same cohort, an 
interim safety evaluation will be performed with the 
submission of safety data to the Data Safety 
Monitoring Committee (DSMC).  If the DSMC 
recommends continuing the study, the next dose cohort 
will be treated. 
 
xii 
The cumulative 
safety of VM202 
demonstrated in 
the first 2 cohorts 
allows 
advancement to 
future cohorts in a 
prudent and 
expeditious 
timeframe. 

 
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Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected 
Pages 
Reason(s) for the 
Modification(s) 
Protocol Synopsis: Procedures (C) 
Formerly:  After all subject in each dose cohort have 
completed the Day -30 (+ 2 days) follow-up visit, an 
interim safety evaluation will be performed with the 
submission of data to the DSMC.  
 
Modified to: After the first subject in each dose cohort 
have completed the Day -30 (+ 2 day) follow-up visit 
and subsequent to day 15 dosing of the other 
subjects in the same cohort an interim safety 
evaluation will be performed with the submission of 
data to the DSMC. 
 
xiv 
The cumulative 
safety of VM202 
demonstrated in 
the first 2 cohorts 
allows 
advancement to 
future cohorts in a 
prudent and 
expeditious 
timeframe. 
 Sample Size and Power (C) 
 Formerly: This is a Phase I, Dose-Escalation, Single     
Center Study.   
Modified to: This is a Phase I, Dose-Escalation Study. 
 
xv 
Changed to allow 
the option to use 
multi -centers to 
increase patient 
enrollment. 
 
Protocol Synopsis: Pharmacokinetics (C) 
Formerly: Pharmacokinetic evaluation will 
determine AUC0-8, Cmax, Tmax, T1/2 for all 4-dose 
levels of VM202 DNA  
 
Modified to: Descriptive statistics (N, mean, median, 
SD, minimum and maxium values, where 
applicable) of VM202 DNA levels will be reported. 
 
xv 
VM202 
disappears from 
the body 4 hours 
after injection. 
Analysis can not 
be done. 
Section 3.2 Secondary Objectives (C) 
Formerly: To evaluate the change in VM202 DNA 
levels from Day 1 to Day 59. 
 
Modify to: To evaluate the change in VM202 DNA 
levels from Day 1 to Day 21. 
5  
Changed to 
account for 
eliminated 
laboratory test 
 
 
 
 Section 4.1.3 Pharmacokinetic Evaluations (D) 
Formerly: Pharmacokinetics of VM202 will be 
assessed using blood VM202 DNA concentration levels 
from samples obtained pre-dose and 60 minutes post-
dose at the first and second dose administration (Day 1 
and Day 15).  In addition, levels will be measured at 
Days 8, 21, 28 and 59. 
6  
Deleted 
laboratory test 
 
 
 
 
 
 

 
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Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected 
Pages 
Reason(s) for the 
Modification(s) 
 
Modify to: Pharmacokinetics of VM202 will be 
assessed using blood VM202 DNA concentration 
levels from samples obtained pre-dose at the first dose 
administration (Day 1).  In addition, levels will be 
measured at Days 21 and 59 (if DNA is detected at 
day 21). 
 
 
 
 
 
 
 
 
Section 4.1.4 Pharmacodynamic Evaluations (D) 
Formerly: Pharmacodynamics will be assessed as the 
change from Day 1 in serum HGF level at Days 8, 15, 
21, 28 and 59.   
 
Modify to: Pharmacodynamics will be assessed as the 
change from Day 1 in serum HGF level at Days 8, 15, 
21 and 59. 
   
 
6  
Deleted 
laboratory test 
 
 
 
 
 
4.2.3 Number of Study Subjects (C) 
Formerly: There will 12-15 subjects selected at one 
site for participation in this study with 3 subjects 
treated in each of four (4) study cohorts. 
 
Modify to: There will 12-15 subjects selected for 
participation in this study with 3 subjects treated in 
each of four (4) study cohorts. 
7  
Changed to allow 
the option to use 
multi -centers to 
increase patient 
enrollment. 
 
 
 
 

 
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90 
Type of Modification to Protocol 
(A: Added, C: Changed, D: Deleted) 
Affected 
Pages 
 
Reason(s) for the 
Modification(s) 
Section 4.1 Study Procedures Chart (C) 
Formerly: 
 
 
8 
Deleted laboratory 
tests 
 
Screen / 
Baseline 
Treatment Period 
 
 
First Dose 
1st 
Follow-
Up 
Second Dose 
2nd Follow-Up6 
 
 
Day -30 to Day 
1 
Day 1  
pre-dose 
Day 1 
post-dose 
Day 8  
(+/- 2days) 
Day 15 
Pre dose 
(+/- 3 days) 
Day15 
Post-dose 
Day 16 
Day 21 
(+/- 3 days) 
Day 28 
(+/- 3 days) 
Day 59 
(+/- 7 days) 
Day 91 
(+/- 7 days) 
Day 180 
(+/- 10 days) 
Day 365 
(+/- 10 days) 
Unscheduled 
Visit 
Early 
Termination 
Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or CT scan of chest1 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Physical Exam 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (HR, BP, Respiratory) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retinal Fundoscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Pregnancy Test 
X 
 
 
 
  X 7 
 
 
 
 
 
 
 
 
 
 
Photograph and measurement of ulcer 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
Clinical Lab Tests  
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Tumor markers2  
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Infection tests3 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
Serum HGF 
 
X 
 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
X 
anti-HGF antibodies 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
Blood VM202 DNA 
 
X 
X4 
X 
X 
X4 
X 
X 
X 
X 
 
 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High Resolution MRA 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Hemodynamic Assessment (ABI, TBI, 
Wave Form) 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 

 
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91 
Pain VAS  
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Subject Analgesic use 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
TcPO2  
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Injection site reaction assessment 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Mammogram5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endothelial Progenitor Cell Assay 
X 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1      CT scan of the chest instead of chest X-ray will be performed if previous tobacco use          
                5      If not  performed in last 12 months prior to start  of  study 
2     Tumor markers include: AFP, CEA,CA19-9 PSA (males) & CA125 (females)   
 
                6      Telephone follow-up contacts will continue for 4 years after day 365  
3     Infection tests include: HIV, Hepatitis B, HCV, HTLV, CMV, VDRL5                                  
                7      A serum test will be done at screening and a urine test on all other days  
4     Blood VM202 DNA level at 1 hour post study agent administration 
 
 
Modified to: 
Table 4-1         Study Procedures Chart 
Screen / 
Baseline 
Treatment Period 
 
 
First Dose 
1st 
Follow-
Up 
Second Dose 
2nd Follow-Up6 
 
 
Day -30 to Day 
1 
Day 1  
pre-dose 
Day 1 
post-dose 
Day 8  
(+/- 2days) 
Day 15 
Pre dose 
(+/- 3 days) 
Day15 
Post-dose 
Day 16 
Day 21 
(+/- 3 days) 
Day 28 
(+/- 3 days) 
Day 59 
(+/- 7 days) 
Day 91 
(+/- 7 days) 
Day 180 
(+/- 10 days) 
Day 365 5 
(+/- 10 days) 
Unscheduled 
Visit 
Early 
Termination 
Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or CT scan of chest1 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Physical Exam 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (HR, BP, Respiratory) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retinal Fundoscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Pregnancy Test 
X 
 
 
 
  X 6 
 
 
 
 
 
 
 
 
 
 
Photograph and measurement of ulcer 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
Clinical Lab Tests  
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Tumor markers2  
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Infection tests3 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
Serum HGF 
 
X 
 
X 
X 
 
 
X 
 
X 
 
 
 
 
 

 
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ViroMed Co., Ltd                                                                                                02 September  2009   v:6 
 
 
 
 
 
92 
anti-HGF antibodies 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
Blood VM202 DNA 
 
X 
 
 
 
 
 
X 
 
X7 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High Resolution MRA 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Hemodynamic Assessment (ABI, TBI, 
Wave Form) 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Pain VAS  
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Subject Analgesic use 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
TcPO2  
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Injection site reaction assessment 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Mammogram4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endothelial Progenitor Cell Assay 
X 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1      CT scan of the chest instead of chest X-ray will be performed if previous tobacco use          
                5      Telephone follow-up contacts will continue for 4 years after day 365 
2     Tumor markers include: AFP, CEA,CA19-9 PSA (males) & CA125 (females)   
 
                6      A serum test will be done at screening and a urine test on all other days 
3     Infection tests include: HIV, Hepatitis B, HCV, HTLV, CMV, VDRL5                                  
                7      Complete draw if detected at Day 21 
                4     If not performed in last 12 months prior to start of study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4.6  Duration (C) 
Formerly: Safety evaluations to encompass 30 days 
post the first dose will be completed for each cohort 
and will be evaluated by the DSMC prior to dose 
escalation to the next cohort. 
 
Modify to: Safety evaluations to encompass 30 days 
post the first dose of the first subject and subsequent 
to day 15 dosing of the other subjects in the same 
cohort will be completed for each cohort and will be 
evaluated by the DSMC prior to dose escalation to the 
next cohort. 
   
10  
The cumulative 
safety of VM202 
demonstrated in 
the first 2 cohorts 
allows 
advancement to 
future cohorts in a 
prudent and 
expeditious 
timeframe. 
 
 
 
5.4 Inclusion Criteria (C) 
Formerly: Male or female, between 20 and 85 years of 
age 
Modified to: Male or female, between 20 and 90 years 
of age 
11 
Changed based on 
safety data from 
the first two 
cohorts. There are 
no safety 
concerns with 
raising the age 
limit to 90 years 
of age.  
6.2.2 Day 1 (D) 
Delete: VM202 DNA levels at 60 minutes post dose 
 
19  
Deleted 
laboratory test 
 
6.2.3 Day 8 (± 2 days) (D) 
Delete: VM202 DNA levels 
 
20 
Deleted 
laboratory test 
 
6.2.4 Day 15 (± 3 days) Second Study Dose 
Administration (D) 
Delete: VM202 DNA levels 
 
20 
Deleted 
laboratory test 
 
6.2.4 Day 15 (± 3 days) Second Study Dose 
Administration (D) 
Delete: VM202 DNA levels at 60 minutes post dose  
Delete: VM202 DNA levels 
 
20 
Deleted 
laboratory test 
 
6.2.5  Day 16 (post 2nd dosing) Administration (D) 
Delete: VM202 DNA levels at 24 hours post dose  
 
21 
Deleted 
laboratory test 
 
6.2.7 Day 28 ( ± 3 days) (D) 
Delete:   Serum HGF   
Delete: VM202 DNA levels   
Delete: Anti-HGF Antibodies 
 
22 
Deleted 
laboratory test 
 
6.2.8  Day 59 ( ± 7 days) (C) 
22 
Change due to 

 
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ViroMed Co., Ltd                                                  02 September  2009   v:6 
94 
Formerly: VM202 DNA levels  
Modified to: VM202 DNA levels (If DNA is detected 
at Day 21) 
  
deleted laboratory 
tests on Day 21 
6.2.13  Unscheduled Visits (D) 
Delete:  Serum HGF levels 
Delete: VM202 levels (if visit is before Day 59) 
 
25 
Deleted 
laboratory test 
 
6.2.14  Early Termination Visits (D)  
Delete:  Serum HGF levels 
Delete: VM202 levels  
 
26 
Deleted 
laboratory test 
 
9.4 Data Safety Monitoring Committee (C) 
Formerly:  A Data Safety Monitoring Committee will 
review all safety data after each cohort of 3 subjects 
has completed the 30-day follow-up period after the 
first dose of study drug has been administered.   
 
Modified to: A Data Safety Monitoring Committee will 
review all safety data available 30 days after the first 
subject in each cohort is dosed and subsequent to 
day 15 dosing of the other 2 subjects in the same 
cohort. 
 
43 
The cumulative 
safety of VM202 
demonstrated in 
the first 2 cohorts 
allows 
advancement to 
future cohorts in a 
prudent and 
expeditious 
timeframe. 
Version 6.0 Modifications 
 
 
Signature Page (C) 
 Formerly: Version Number: 5.0 
Date: November 29, 2007 
 
Modified to: Amended Version Number: 6.0 
Date: August 31, 2009 
 
ii 
Changed 
amended version 
number and date. 
Global Protocol Change - Study Duration 
Formerly: 19 month plus 4 year follow-up after Day 
365  
 
 
 
 
 
 
 
 
 
 
Modified to: 30 months 
xi, 
xii,xiv,8,
12, 26 
 
 
 
 
 
 
 
 
 
 
xi 
Changed due to 
no indication of 
long term 
persistence of 
plasmid in non-
target tissues and 
no evidence of 
off-target 
angiogenesis in 
any of our 
preclinical and 
clinical studies of 
VM202 to date.  
This is the actual 

 
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95 
 
study duration 
6.2.12 Long Term Follow-Up 
Add:  Reason for hospitalizations, if applicable 
 
27 
 
Added to clarify 
hospitalization 
question on CRF. 

 
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Reference 
                                          
1 Morishita R, Sakaki M, Yamamoto K, et al. Impairment of collateral formation in 
lipoprotein (a) transgenic mice: therapeutic angiogenesis induced by human hepatocyte 
growth factor gene. Circulation 2002;105(12): 1491-6. 
2 Taniyama Y, Tachibana K, Hiraoka K, et al. Development of safe and efficient novel 
nonviral gene transfer using ultrasound: enhancement of transfection efficiency of 
naked plasmid DNA in skeletal muscle. Gene Therapy 2002;9(6):372-80.  
3 Taniyama Y, Morishita R, Hiraoka K, et al. Therapeutic angiogenesis induced by 
human hepatocyte growth factor gene in rat diabetic hind limb ischemia model: 
molecular mechanisms of delayed angiogenesis in diabetes. Circulation 
2001;104(19):2344-50. 
4 Aoki M, Morishita R, Taniyama Y, et al. Angiogenesis induced by hepatocyte growth 
factor in non-infarcted myocardium and infarcted myocardium: up-regulation of 
essential transcription factor of angiogenesis. Gene Therapy 2000;7(5):417-427. 
5 Matsuki A, Yamamoto S, Nakagami H, et al. No influence of tumor growth by 
intramuscular injection of hepatocyte growth factor plasmid DNA: safety evaluation of 
therapeutic angiogenesis gene therapy in mice. Biochemical and Biophysical Research 
Communications 2004;315(1):59-65. 
6 Taniyama Y, Morishita R, Aoki M, et al. Angiogenesis and anti-fibrotic action by 
hepatocyte growth factor in cardiomyopathy. Hypertension 2002;40(1):47-53. 
7 Morishita R, Aoki M, Hashiya N, et al. Safety evaluation of clinical gene therapy using 
hepatocyte growth factor to treat peripheral arterial disease. Hypertension 
2004;44(2):203-9. 
8 Kim HJ, Jang SY, Park JI,et al. Vascular endothelial growth factor-induced angiogenic 
gene therapy in patients with peripheral artery disease. Experimental and Molecular 
Medicine 2004;36(4):366-44. 
9 Xin X, Yang S, Ingle G, et al. Hepatocyte growth factor enhances vascular endothelial 
growth factor-induced angiogenesis in vitro and in vivo. American Journal of 
Pathology 2001;158(3):1111-20. 
10 Ware JE, Sherbourne CD: The MOS 36-item short-form health survey (SF-36): 1. 
conceptual framework and item selection. Med Care 1992;30(6):473-483. 
11. Morishita R. Recent progress in gene therapy for cardiovascular disease. Circulation J 
2002;66(12):1077-86.