A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of VM202 (Engensis) in Subject With Critical Limb Ischemia
Phase: PHASE2
Conditions: Critical Limb Ischemia
Sponsor: Helixmith Co., Ltd.



 
 
 
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INVESTIGATOR’S AGREEMENT 
 
 
I, the undersigned, am responsible for the conduct of the study at the site below and agree to the 
following:   
 
• I understand that this protocol is a confidential document.  I agree that the information within 
it will not be disclosed to anyone without prior written authority from the sponsor, ViroMed, 
Inc. except to the extent necessary to conduct this study and obtain approval from an ethical 
review committee or other approving body.   
• I understand and will conduct the study according to the protocol, any approved protocol 
amendments, ICH GCP and all applicable regulatory authority requirements and national 
laws.   
• I will not deviate from the protocol without prior written permission from the sponsor and 
prior review and written approval from the Institutional Review Board or Independent Ethics 
Committee, except where necessary to prevent any immediate danger to the patient.   
• I have read and understand fully the Investigator Brochure.   
• I have sufficient time to properly conduct and complete the study within the agreed study 
period, and I have available an adequate number of qualified staff and adequate facilities for 
the foreseen duration of the study to conduct the study properly and safely.   
• I will ensure that any staff at my site(s) who are involved in the study conduct are adequately 
trained regarding this trial’s operations, the protocol and their responsibilities. In the case of 
delegating any of my study responsibilities I will provide the sponsor with a delegation of 
investigators responsibilities log.   
• I understand that the study may be terminated or enrollment may be suspended at any time by 
ViroMed, Co., Ltd. with or without cause, or by me or my institution if it becomes necessary 
to protect the best interest of the study patients.   
 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
Title 
 
 
 
Address 
 
 
 
Signature / Date 
 
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STUDY SYNOPSIS 
 
 
 
PROTOCOL TITLE 
A Phase II, Double-blind, Randomized, Placebo-controlled, 
Multicenter Study to Assess the Safety and Efficacy of VM202 in 
Subjects with Critical Limb Ischemia 
STUDY PHASE 
II 
INVESTIGATIONAL AGENT 
VM202 
DOSE 
Two doses will be tested: 8 mg and 16 mg of VM202. 
POPULATION 
Patients aged ≥ 18 years to ≤ 90 years diagnosed with critical limb 
ischemia (CLI). 
STUDY DESIGN 
A phase II, double-blind, randomized, placebo-controlled, 
multicenter, 12-month study designed to assess the safety and 
efficacy of unilateral intramuscular injection in the calf of VM202 
in patients with critical limb ischemia (CLI).  Fifty (50) patients 
will be randomized in a 2:2:1 ratio to one of three treatment 
groups:  
• Low Dose: 8 mg VM202 – 20 patients 
• High Dose: 16 mg VM202 – 20 patients 
• Control – placebo (normal saline) – 10 patients 
Up to twenty sites will participate in the study.  Safety will be 
monitored throughout the study by a Data Safety Monitoring 
Board (DSMB). 
STUDY OBJECTIVES 
1. To evaluate the safety of IM administration of VM202 in 
subjects with moderate or high-risk CLI (Rutherford Clinical 
Severity Score equal to 4 or 5) who are poor or non- candidates 
for surgical or percutaneous revascularization. 
2. To evaluate potential bioactivity of IM administration of 
VM202 in subjects with CLI, when compared with placebo, on 
rest pain (as assessed by frequency of rest pain, pain medication 
use history, sleeping history, and intensity of rest pain) or leg 
ulcer healing (as assessed by ulcer surface area, time to 
complete healing), perfusion (MRA), hemodynamic assessment 
(ABI & TBI), tissue oxygenation (TcPO2) and the incidence and 
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extent of lower leg amputation or other surgical interventions 
 
INCLUSION CRITERIA 
1. Male or female, between 18 and 90 years of age; 
2. Diagnosis of critical limb ischemia (Rutherford Class 4 or 5), 
including:   
• A resting ankle systolic pressure (in either the dorsalis 
pedis or posterior tibial arteries) of ≤ 70 mmHg in the 
affected limb; or 
• A resting toe systolic pressure of ≤ 50 mmHg in the 
affected limb; or 
• For patients in which measurement of ankle systolic 
pressure is not feasible (e.g. vessel calcification and non-
compressibility), TcPO2 ≤ 30 mmHg; 
3. Poor or suboptimal candidate for bypass graft surgery or 
percutaneous angioplasty; 
4. Pain at rest, and/or ischemic ulcers, and/or focal gangrene (< 3 
cm2) for a minimum of 2 weeks,  
5. Significant stenosis (≥ 75%) of one or more of the following 
arteries: superficial femoral, popliteal, or two or more infra-
popliteal arteries as verified by angiography within 12 months 
prior to enrollment; 
6. Be willing to maintain current drug therapy for peripheral 
arterial disease throughout the course of the study including 
an anti-platelet, hypertension, and statin treatment unless not 
tolerated; 
7. Clinically stable on optimized medical regimen for >30 days; 
8. Be capable of understanding and complying with the protocol 
and signing the informed consent document prior to being 
subjected to any study related procedures; 
9. 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 urine pregnancy test result prior to study enrollment 
and must agree to repeat pregnancy screening tests during the 
study.  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. 
 
EXCLUSION CRITERIA 
1. 
Subjects who have undergone a successful revascularization 
procedure or sympathectomy within 12 weeks prior to study 
entry.  A clinically unsuccessful revascularization procedure is 
defined as one in which: 
•  the target vessel re-occludes (>50%, as verified by a 
second angiogram.  Duplex ultrasonography can be used 
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to determine vessel patency if the patient cannot tolerate a 
second angiogram), or 
• the target vessel remains patent, but there is no resolution 
of symptoms 6 weeks after the procedure (e.g. no evidence 
of ulcer healing, no improvement in pressures, no 
reduction in resting pain); 
2. 
Subjects that will require an amputation in the target leg 
within 4 weeks of randomization; 
3. 
Subjects with evidence of active infection (e.g., cellulitis, 
osteomyelitis) or deep ulceration exposing bone or tendon in 
the extremity planned for treatment; 
4. 
Heart Failure with a NYHA classification of III or IV; 
5. 
Stroke (NIH scale >2) or myocardial infarction within last 3 
months; 
6. 
Unstable angina 
7. 
Uncontrolled hypertension defined as sustained systolic blood 
pressure (SBP) > 200 mmHg or diastolic BP (DBP) > 110 
mmHg at baseline/screening evaluation; 
8. 
Ophthalmologic conditions pertinent to proliferative 
retinopathy or conditions that preclude standard 
ophthalmologic examination; 
9. 
Inflammatory disorder of the blood vessels (inflammatory 
angiopathy, such as Buerger’s disease); 
10. Subjects with advanced liver disease including 
decompensated cirrhosis, jaundice, ascites or bleeding varices; 
11. Subjects currently receiving immunosuppressive medications 
chemotherapy, or radiation therapy; 
12. Positive HIV or HTLV at Screening; 
13. Active Hepatitis B or C infection as determined by Hepatitis 
B surface antibody (HBsAb), Hepatitis B core antibody (IgG 
and IgM; HBcAb), Hepatitis B surface antigen (HBsAg) and 
Hepatitis C antibodies (Anti-HCV), at Screening; 
14. Specific laboratory values at screening including: Hemoglobin 
< 8.0 g/dL, WBC < 3,000 cells per microliter, platelet count 
<75,000/mm3, AST and/or ALT > 3 times the upper limit of 
normal or any other clinically significant lab abnormality 
which in the opinion of the investigator should be 
exclusionary; 
15. Patients with a recent history (< 5 years) of or new screening 
finding of malignant neoplasm except basal cell carcinoma or 
squamous cell carcinoma of the skin (if excised and no 
evidence of recurrence); patients with family history of colon 
cancer in any first degree relative are excluded unless they 
have undergone a colonoscopy in the last 12 months with 
negative findings; 
16. Elevated PSA unless prostate cancer has been excluded; 
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17. 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 
18. Subjects requiring > 81 mg daily of acetylsalicylic acid;  If > 
81 mg are taken at screening, subjects may be enrolled if 
willing/able to switch to another medication for the duration 
of the study; 
19. Subjects requiring regular COX-2 inhibitor drug(s) or high 
dose steroids (excepting inhaled steroids); 
20. Major psychiatric disorder in past 6 months; 
21. History of drug or alcohol abuse / dependence in the past 2 
years; 
22. Use of an investigational drug or treatment in past 12 months; 
concurrent participation in investigational protocol or 
unapproved therapeutics; and 
23. Unable or unwilling to give informed consent. 
 
STUDY PROCEDURES 
Patients will be screened for study eligibility after giving informed 
consent.  Screening should occur within the 60 days prior to Day 0 
(day of injection).  Screening will include assessment of study 
eligibility, a complete medical history, physical exam, cancer 
screening tests, viral screening, ABI & TBI, TcPO2, VAS, 12 lead 
EKG, retinal fundoscopy, clinical chemistry, hematology, 
urinalysis, and pregnancy test (women of childbearing potential 
only), and documentation of any ulcers or gangrenous areas. 
 
Patients will be treated with a final dose of 8 mg VM202, 16 mg 
VM202 or placebo by intramuscular injections in the affected calf 
on Day 0, Day 14, Day 28 and Day 42.  VM202 will be delivered 
in a solution of 0.5 mg VM202 / mL. 
 
TREATMENT 
GROUP 
FINAL 
DOSE 
VM202 
DOSE VM202 (MG) PER VISIT 
DAY 0 
DAY 14 
DAY 28 
DAY 42 
Low Dose 
8 mg 
4 
4 
0 
0 
High Dose 
16 mg 
4 
4 
4 
4 
Placebo 
0 
0 
0 
0 
0 
 
Patients in the Low Dose Group (8 mg VM202) will receive: 
• Day 0:    4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 14:  4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 28:  Placebo only (16 injection of 0.5 ml normal saline)  
• Day 42:  Placebo only (16 injection of 0.5 ml normal saline) 
Patients in the High Dose Group (16 mg VM202) will receive:  
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• Day 0:    4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 14:  4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 28:  4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 42:  4 mg of VM202 (16 injections of 0.5 ml of VM202) 
Patients in the placebo control group will receive 16 injections of 
0.5 ml normal saline at each visit. 
Determination of HGF serum levels will be made immediately pre-
treatment on Day 0, immediately pre-treatment on Day 42, Day 49 
and Day 90.   
The number of copies of VM202 in whole blood will be 
determined at Day 0 (pre-injection, and 2 hours post injection), 
Day 42 (pre-injection, and 2 hours post injection), Day 49, Day 90, 
and at 6 months.   
VAS assessment will be performed at Day 0 (pre-injection), Day 
14 (pre-injection), Day 28 (pre-injection), Day 42(pre-injection), 
Day 90, at 6 months, 9 months, and 12 months.  VascuQol will be 
administered on Day 0 (pre-injection), Day 90, at 9 months, and 12 
months.  .  Rutherford classification will be determined at 6 
months, 9 months, and 12 months.  ABI & TBI will be recorded at 
Day 0 (pre-injection), Day 28 (pre-injection), Day 90, at 6 months, 
9 months, and 12 months.  TcPO2 will be measured at Day 0 (pre-
injection), 6 months, 9 months, and 12 months. Measurement of 
ulcer(s) will be performed at Day 0, Day 14, Day 28, Day 42, Day 
49, Day 90, at 6 months, 9 months, and 12 months. Retinal 
fundoscopy will be conducted at 12 months.  Adverse events will 
be recorded throughout the one year follow-up period. 
MRA will be conducted as a sub-study at up to two sites on Day 0 
(pre-injection) and at 6 and 9 months.   
 
SCHEDULE OF 
EXAMINATIONS 
Screening (Day -60 to Day 0) 
Day 0 
Day 14 ± 3 days 
Day 28 ± 3 days 
Day 42 ±  3 days 
Day 49 ± 3 days  
Day 90 ± 7 days 
Month 6 ± 1 month 
Month 9 ± 1 month 
Month 12 ± 1 month 
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STUDY ENDPOINTS 
The primary study endpoint is to assess the difference in pain level 
between baseline and the 9 month follow-up as determined by 
VAS.  Active and placebo arms will be compared to determine 
treatment effect.  
Other secondary endpoints will include: 
• Difference in pain level between baseline and the 9 month 
follow-up as determined by VAS by sex and by comorbidities 
(esp. diabetes or renal dysfunction) 
• Change in tissue oxygenation (TcPO2) from baseline to 6, 9 and 
12 months following the first treatment 
• Change in hemodynamic measures (ABI and TBI) from 
baseline to Day 28, Day 90, 6 months, 9 months and 12 months 
following the first treatment 
• Change in perfusion (MRA) from baseline to 9 months 
following the first treatment 
• Wound healing (no ulcer: change of skin condition, one ulcer: 
change of ulcer size, multiple ulcer: change of ulcer number) 
from baseline to 9 months following the first treatment 
• Change in VAS score from baseline to Day 14, Day 28, Day 42, 
Day 90, at 6 months, 9 months, and 12 months. 
• Change in QOL score (VascuQol) at 90 Days, 9 months and 12 
months; 
• Major limb amputation rate at six months and twelve months 
following the first treatment 
• Mortality at six and twelve months after first treatment 
 
SAFETY 
Any patient who receives VM202 will be included in the safety 
analysis population.  Adverse events (including serious adverse 
events, and adverse events leading to treatment discontinuation) 
throughout the 12 month follow-up will be described according to 
severity and their relationship to the study drug and / or device and 
procedure.  Descriptive statistics (N, mean, median, SD, minimum 
and maximum values, where applicable) will be used to 
characterize safety parameters. 
All patients will undergo testing as presented in the American 
Cancer Society Cancer Screening Guidelines as part of their 
baseline testing to rule out cancer. 
 
 
 
 
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TABLE OF CONTENTS 
 
INVESTIGATOR’S AGREEMENT ......................................................................................................2 
STUDY SYNOPSIS .........................................................................................................................3 
TABLE OF CONTENTS ...................................................................................................................9 
GLOSSARY ................................................................................................................................. 13 
PERSONNEL AND FACILITIES ....................................................................................................... 15 
1. 
BACKGROUND ................................................................................................................... 18 
1.1. 
Peripheral Arterial Disease ................................................................................. 18 
1.2. 
Critical Limb Ischemia ....................................................................................... 18 
1.3. 
Treatment Options for CLI ................................................................................. 18 
1.3.1. 
Revascularization Options ..................................................................... 19 
1.3.2. 
Amputation ........................................................................................... 19 
1.3.3. 
Unmet Clinical Need ............................................................................. 19 
1.4. 
Therapeutic Angiogenesis in Ischemic Limb Disease ......................................... 19 
1.5. 
VM202 .............................................................................................................. 20 
1.6. 
Preclinical Data .................................................................................................. 21 
1.7. 
Clinical Data ...................................................................................................... 22 
1.8. 
Study and Dose Rationale .................................................................................. 23 
2. 
GOOD CLINICAL PRACTICES STATEMENT ........................................................................... 23 
3. 
INVESTIGATIONAL PLAN .................................................................................................... 24 
3.1. 
Study Objectives ................................................................................................ 24 
3.2. 
Study Design...................................................................................................... 24 
3.3. 
Patient Population .............................................................................................. 26 
3.3.1. 
Inclusion Criteria .................................................................................. 26 
3.3.2. 
Exclusion Criteria ................................................................................. 26 
3.4. 
Study Procedures ............................................................................................... 28 
3.4.1. 
Informed Consent.................................................................................. 28 
3.4.2. 
Patient Identification ............................................................................. 28 
3.4.3. 
Screening (Day -60 to Day 0) ................................................................ 28 
3.4.3.1. 
Screen Failures ...................................................................... 29 
3.4.4. 
Treatment Authorization ....................................................................... 29 
3.4.5. 
Randomization & Blinding.................................................................... 29 
3.4.6. 
Day 0 – 1st Injections ............................................................................ 30 
3.4.6.1. 
Pre-Injection (within 4 hrs prior to injections) ....................... 30 
3.4.6.2. 
1st Dose of VM202 / Placebo ................................................. 30 
3.4.6.3. 
Post-Injection ........................................................................ 30 
3.4.7. 
Day 14 ± 3 Day –2nd Injections ............................................................. 31 
3.4.7.1. 
Pre-Injection (within 4 hrs prior to injections) ....................... 31 
3.4.7.2. 
2nd Dose of VM202 / Placebo ................................................ 31 
3.4.7.3. 
Post-Injection ........................................................................ 31 
3.4.8. 
Day 28 ± 3 Day –3rd Injections .............................................................. 31 
3.4.8.1. 
Pre-Injection (within 4 hrs prior to injections) ....................... 31 
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3.4.8.2. 
3rd Dose of VM202 / Placebo ................................................ 31 
3.4.8.3. 
Post-Injection ........................................................................ 31 
3.4.9. 
Day 42 ± 3 Day – 4th Injections ............................................................. 32 
3.4.9.1. 
Pre-Injection (within 4 hrs prior to injections) ....................... 32 
3.4.9.2. 
4th Dose of VM202 / Placebo................................................. 32 
3.4.9.3. 
Post-Injection ........................................................................ 32 
3.4.10. Day 49 ± 3 Days ................................................................................... 32 
3.4.11. Day 90 ± 7 Days ................................................................................... 32 
3.4.12. 6 months  ± 1 month ............................................................................. 33 
3.4.13. 9 months  ± 1 month ............................................................................. 33 
3.4.14. 12 months  ± 1 month............................................................................ 33 
3.5. 
Study Completion .............................................................................................. 34 
3.5.1. 
Completed Patients ............................................................................... 34 
3.5.2. 
Discontinued Patients ............................................................................ 34 
3.5.3. 
Premature Study Termination ................................................................ 35 
3.6. 
Investigational Drug Product and Accountability ............................................... 35 
3.6.1. 
Investigational Drug Product ................................................................. 35 
3.6.2. 
Placebo ................................................................................................. 35 
3.6.3. 
Product Accountability .......................................................................... 35 
3.6.4. 
Dose and Administration ....................................................................... 36 
3.7. 
Prior and Concomitant Medication ..................................................................... 36 
4. 
EXAMINATIONS AND EVALUATIONS ................................................................................... 37 
4.1. 
Evaluations Conducted at Baseline Only ............................................................ 37 
4.1.1. 
Complete Medical History .................................................................... 37 
4.1.2. 
Complete Physical Exam....................................................................... 37 
4.1.3. 
Cancer Screening .................................................................................. 37 
4.1.4. 
Viral Screening ..................................................................................... 38 
4.1.5. 
Urinalysis.............................................................................................. 38 
4.1.6. 
12-Lead EKG ........................................................................................ 38 
4.1.7. 
Pregnancy Test (women of childbearing potential only) ........................ 38 
4.2. 
Evaluations Conducted Throughout the Study .................................................... 38 
4.2.1. 
Retinal Fundoscopy............................................................................... 38 
4.2.2. 
Concomitant Medications...................................................................... 38 
4.2.3. 
Vital Signs ............................................................................................ 39 
4.2.4. 
Serum Chemistry and Hematology ........................................................ 39 
4.2.5. 
Serum HGF ........................................................................................... 39 
4.2.6. 
Copies of VM202 in Whole Blood ........................................................ 40 
4.2.7. 
Visual Analog Scale (VAS) score ......................................................... 40 
4.2.8. 
Patient Questionnaire (VascuQol) ......................................................... 40 
4.2.9. 
Ankle Brachial Index (ABI) and Toe Brachial Index (TBI) ................... 40 
4.2.10. Transcutaneous Oxygen Pressure (TcPO2) ............................................ 41 
4.2.11. Photograph and measurement of ulcer ................................................... 41 
4.2.12. Injection Site Reaction Assessment ....................................................... 41 
4.2.13. MRA ..................................................................................................... 42 
5. 
EVALUATION OF ADVERSE EVENTS ................................................................................... 42 
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5.1. 
Definitions ......................................................................................................... 42 
5.2. 
Assessment of AEs ............................................................................................ 43 
5.2.1. 
AE Causality ......................................................................................... 44 
5.2.2. 
AE Intensity .......................................................................................... 44 
5.3. 
Reporting/Recording of AEs .............................................................................. 45 
5.4. 
Reporting / Recording of SAEs .......................................................................... 45 
5.4.1. 
Investigator’s Responsibility ................................................................. 45 
5.4.2. 
Sponsor’s Responsibility ....................................................................... 46 
6. 
STATISTICAL METHODS ..................................................................................................... 46 
6.1. 
General Methods ................................................................................................ 46 
6.2. 
Study Endpoints ................................................................................................. 47 
6.2.1. 
Primary Endpoint .................................................................................. 47 
6.2.2. 
Secondary Efficacy Endpoints ............................................................... 47 
6.2.3. 
Safety.................................................................................................... 47 
6.2.4. 
Data Safety Monitoring and Interim Analyses ....................................... 48 
6.3. 
Patient Categorization ........................................................................................ 48 
7. 
ACCESS TO STUDY DOCUMENTS AND STUDY MONITORING ................................................ 48 
8. 
QUALITY CONTROL AND ASSURANCE ................................................................................ 49 
9. 
INSTITUTIONAL REVIEW BOARD ........................................................................................ 49 
10. 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) .................................................................. 50 
11. 
INFORMED CONSENT PROCESS ........................................................................................... 50 
12. 
CONFIDENTIALITY ............................................................................................................. 51 
13. 
PROTOCOL AMENDMENTS ................................................................................................. 51 
14. 
DATA MANAGEMENT ........................................................................................................ 51 
15. 
RECORD KEEPING AND RETENTION .................................................................................... 52 
16. 
INVESTIGATOR FINAL REPORT ........................................................................................... 53 
17. 
STUDY REPORT AND PUBLICATION .................................................................................... 53 
18. 
REFERENCES ..................................................................................................................... 54 
 
FIGURES &TABLES 
 
Figure 1. 
VM202 construct .......................................................................................... 21 
 
Table 1. 
VM202 administration for each study arm .................................................... 25 
Table 2. 
Injection Reaction Assessment ..................................................................... 41 
Table 3. 
Single dose preparation and delivery, Day 0 and Day 14 .............................. 81 
Table 4. 
Single dose preparation and delivery, Day 28 and Day 42 ............................ 81 
 
 
 
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TABLE OF APPENDICES 
 
Appendix 1. 
Schedule of Evaluations and Visits ............................................................... 59 
Appendix 2. 
Sample Informed Consent ............................................................................ 61 
Appendix 3. 
MRA (select sites only) ................................................................................ 77 
Appendix 4. 
Test Article Administration .......................................................................... 80 
Appendix 5. 
VascuQol ..................................................................................................... 83 
Appendix 6. 
Guidelines for the Early Detection of Cancer ................................................ 87 
 
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GLOSSARY 
 
ABI 
Ankle brachial index 
AE / SAE 
Adverse event / serious adverse event 
ALT 
Alanine transaminase (SGPT) 
Anti-HCV 
Hepatitis C antibodies 
AST 
Aspartate transaminase (SGOT) 
AUC 
Area under the plasma concentration time curve 
BP 
Blood Pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
cDNA 
Complementary deoxyribonucleic acid 
CFR 
Code of Federal Regulation 
cm 
Centimeter(s) 
CRF 
Case report form 
CRO 
Clinical research organization 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EKG 
Electrocardiogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study Visual Acuity Chart 
FDA 
Food and Drug Administration 
FGF 
Fibroblast Growth Factor 
GCP 
Good Clinical Practices 
HBV 
Hepatits B Virus 
HBcAB 
Hepatitis B core antibody 
HBsAb 
Antibody to Hepatitis B antigen (IgG and IgM) 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatits C Virus 
HGF 
hepatocyte growth factor 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HTLV 
Anti-Human T-Cell Lymphotropic Virus 
IBC  
Institutional Biosafety Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
NIH 
National Institutes of Health  
O2 
Oxygen 
OBA 
Office of Biotechnology Activities 
PSA 
Prostate Specific Antigen 
RBC 
Red blood count 
RNA 
Ribonucleic acid 
SGPT 
Serum glutamic pyruvic transaminase (same as ALT) 
SOP  
Standard Operating Procedure 
TBI 
Toe-brachial index 
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TcPO2 
Transcutaneous pressure of oxygen 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood count 
WFI 
Water for Injection 
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1. 
BACKGROUND 
 
1.1. 
PERIPHERAL ARTERIAL DISEASE 
The term “peripheral arterial disease” (PAD) is widely used to refer to 
atherosclerotic disease that obstructs the blood supply to the lower limbs.  The 
clinical manifestations of PAD are a major cause of acute and chronic illness.  
Patients with PAD experience progressive decrements in functional capacity and 
quality of life.  PAD frequently coexists with coronary and / or cerebrovascular 
disease, likely due to a similar underlying pathology and shared risk factors (e.g., 
smoking, hyperlipidemia, hypertension, and diabetes).  Patients with PAD have a 
20% - 60% increased risk for myocardial infarction (MI), a two- to six-fold 
increased risk of cardiovascular death, and a 40% increased risk of stroke.1, 2  This 
higher level of morbidity and mortality occurs, in part, because many affected 
patients are asymptomatic and remain undiagnosed for years, allowing the disease to 
progress unchecked.  Clinical symptoms often only manifest when the disease state 
is advanced.3   
 
It is estimated that PAD now affects 8 to 12 million people in the United States.  The 
prevalence of symptomatic PAD increases with age and with number of risk factors.  
PAD occurs in 1% - 4% of the population over the age of 40, and is reported to be as 
high as 30% in patients over 70 or in patients older than 50 years with a history of 
diabetes, smoking, or both.4-6  As the population ages, this number will increase.  
 
 
1.2. 
CRITICAL LIMB ISCHEMIA 
Critical limb ischemia (CLI) is the end-stage manifestation of PAD.  One to three 
percent of newly diagnosed PAD patients initially present with CLI; 5%-10% of all 
other PAD patients eventually progress to CLI.  The natural history of CLI has been 
well documented to have an inexorable downhill course.  CLI patients experience 
ischemic rest pain (Rutherford category 4), ischemic skin lesions, and ulcers or 
gangrene (Rutherford category 5-6).  Amputation of the affected limb remains a 
common procedure and is likely to occur more frequently due to an aging 
population.7  The incidence of major amputations ranges from 120 to 
500/million/year.6  In patients with the comorbidities of diabetes mellitus or renal 
insufficiency, the rate of amputation can be much greater.7, 8 
 
 
1.3. 
TREATMENT OPTIONS FOR CLI 
The primary treatment goals in patients with CLI are to relieve ischemic pain, heal 
(neuro) ischemic ulcers, prevent limb loss, improve patient function and quality of 
life and prolong overall survival.  Therefore, reestablishing blood supply to the 
affected limb, when possible, is critical.  In addition to successful revascularization, 
the institution of lifestyle changes, atherosclerotic risk factor modification, and 
pharmacologic therapies are also used to reduce cardiovascular morbidity and 
mortality.  Narcotic medications are often used for analgesia and for assistance with 
sleeping.   
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1.3.1. 
REVASCULARIZATION OPTIONS 
Revascularization options for patients with CLI range from open surgical procedures 
(bypass grafts) to various endovascular procedures.  The treatment approach depends 
on a careful evaluation of a patient’s current medical condition (comorbidities), the 
location and extent of the lesion, and the availability of an autologous conduit (e.g. 
saphenous vein).9-11  Although arterial bypass surgery has long been considered the 
preferred first line treatment modality, many of the newer endovascular technologies 
can be used with similar success rates and with reduced morbidity.12, 13  
Percutaneous transluminal angioplasty (PTA) has been shown to be effective, with 
limb salvage rates comparable to surgical procedures.  Stents placement is usually 
attempted after failed PTA.  Adjunctive therapies such as lasers, thermal angioplasty 
and atherectomy devices have not yet demonstrated improved efficacy when 
compared with conventional lower extremity interventions.14, 15  
 
1.3.2. 
AMPUTATION 
Amputation is considered when revascularization is not feasible due to the location 
and extent of atherosclerosis, when a patients is unable to tolerate a procedure, or 
when a patient is unlikely to have a functional extremity despite restoration of distal 
flow (e.g. due to dementia, chronic illness, etc.).  While amputation does eliminate 
the source of pain at rest and all necrotic tissue,11 it is associated with a significantly 
elevated perioperative and one year mortality rate.1, 6, 16    
 
1.3.3. 
UNMET CLINICAL NEED 
In the absence of revascularization options, most patients with CLI require 
amputation within 6 months.  Patients requiring major amputation face a diminished 
quality of life, an unfavorable natural history and need extensive resources for their 
post-amputation rehabilitation and course.   The 1-year amputation-free survival rate 
for patients diagnosed with CLI is 45%; the mortality rate is approximately 25% and 
may be as high as 45% in those who have undergone amputation.1, 6, 16  Management 
of this end-stage disease process consumes a significant amount of healthcare 
resources.17, 18  Clearly, new therapeutic approaches are required. 
 
 
 
1.4. 
THERAPEUTIC ANGIOGENESIS IN ISCHEMIC LIMB DISEASE 
Two key processes determine the amount of blood flow to skeletal muscle in patients 
with CLI: 1) the degree of arterial occlusion, and 2) the degree to which an 
endogenous angiogenic response is mounted to compensate for the occlusion.  
Ischemic tissue injury causes the release of numerous mediators, including growth 
factors, transcription factors, and signaling molecules known to stimulate 
angiogenesis and growth of collateral vessels. 19, 20  However, this physiologic 
response to pathophysiologic processes is often inadequate to prevent clinical 
manifestations of ischemia.  
 
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A growing area of research has focused on elucidating the molecular mechanisms 
underlying angiogenesis.  The goal is to identify and harness the critical molecular 
players that initiate and / or regulate angiogenic growth.  A number of cytokines 
such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 
(FGF) have been studied intensively and early phase I/II studies have been 
conducted.  The data thus far have been mixed.21-26 
 
Hepatocyte growth factor (HGF) has been shown to be a potent angiogenic growth 
factor stimulating the growth of endothelial cells and migration of vascular smooth 
muscle cells.27, 28  It is a multi-functional mesenchyme-derived cytokine with potent 
angiogenic and anti-apoptotic effects 27-30  HGF stimulates DNA, RNA and protein 
synthesis by endothelial cells in a dose -dependent manner and attenuates high D-
glucose-induced endothelial cell death.  HGF has also been shown to upregulate 
VEGF expression, and has demonstrated greater mitogenic activity than that of 
VEGF alone in human aortic endothelial cells in vitro.31, 32  Recently, HGF 
gene transfer has been shown to produce significant augmentation of collateral 
formation in rabbit hind limb ischemia model.28  Furthermore, a significant increase 
in blood flow was achieved by HGF gene transfer both in rat diabetic and non-
diabetic hind limb ischemia models.30, 33   
 
Because of its pluripotent capabilities, increasing the availability of HGF in ischemic 
tissues to achieve therapeutic angiogenesis has been a growing area of research.  The 
challenge associated with delivering a targeted sustained dose of exogenous HGF to 
ischemic tissues is in overcoming the instability of HGF in blood circulation and its 
rapid clearance by the liver; HGF has an in vivo half-life of less than 15 minutes.34, 35  
 
One approach to increasing HGF in ischemic tissues is to develop a gene transfer 
strategy that would allow for persistent expression of HGF protein in vivo.  Although 
plasmid DNA is one of the least efficient gene transfer systems currently in use, the 
fact that it is associated with limited persistence and no propensity for genomic 
integration, (particularly in skeletal muscle tissue) makes it an attractive option for 
local targeted delivery in ischemic tissues. 
 
 
1.5. 
VM202 
The investigational agent being studied in this protocol is VM202.  VM202 is a 
DNA plasmid that contains novel genomic cDNA hybrid human hepatocyte growth 
factor (HGF) coding sequence (HGF-X7) expressing two isoforms of HGF, HGF728 
and HGF723. 
 
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 efficiently as in the human genome.  Because there is 
no change in the coding region of the HGF gene, HGF proteins generated from 
VM202 are identical to the wild-type human HGF proteins.  VM202 has been 
developed using the pCK DNA plasmid that has been safely used in previous 
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ViroMed-sponsored human clinical trials with VEGF165 as the therapeutic gene, 
known as VMDA-3601.   
 
 
Figure 1. VM202 construct 
 
Safety of VM202.  The use of plasmids for targeted delivery of angiogenic factors 
into muscle tissue is a particularly attractive and a relatively safe therapeutic 
approach, because plasmids have been shown to effectively transfect postmitotic 
cells such as skeletal and heart muscle and to successfully express angiogenic genes 
with very little dissemination and persistence at distant sites.  Following 
intramuscular injection, the plasmid that persists is extrachromosomal and 
integration into host DNA, if it occurs, is negligible.36-38  This local effect of 
conventionally injected naked plasmid DNA is well known.39, 40   
 
Potential Efficacy of VM202.  VM202 has demonstrated potential for stimulating 
angiogenesis in animal models.  The development of new blood vessels may 
improve blood flow to peripheral nerves and potentially replace damaged capillary 
bed.  VM202 may have the ability to increase perfusion and wound healing, as well 
as decrease pain due to neuropathy brought on by ischemia. 
 
 
1.6. 
PRECLINICAL DATA 
The non-clinical safety of VM202 has been evaluated for general toxicity following 
single intramuscular and intravenous doses in rats.  In addition, the general toxicity 
of VM202 following multiple intermittent (weekly or monthly) intramuscular doses 
has been evaluated in rabbits and rats, respectively.  The potential for genomic 
integration at the injection site as well as the potential for distribution to and 
persistence of VM202 in reproductive tissues was evaluated in rats. The ability of 
VM202 to induce humoral immune responses was evaluated following intramuscular 
administration with or without adjuvant in mice.  All species utilized for these 
studies (mouse, rat, and rabbit) were shown in in vivo experiments to be able to 
express the plasmid following intramuscular injection.  
 
An ischemic heart disease efficacy study in a Yorkshire swine model demonstrated 
that intrammyocardial administration of VM202 increased the capillary density and 
regional perfusion in ischemic myocardium and improved ischemic left ventricular 
function.  An ischemic heart disease efficacy study in rats demonstrated that 
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histologically identifiable capillaries increased following intramuscular 
administration of VM202 (versus pCK and pCK-VEGF165; p< 0.001). 
 
Collectively, VM202 has been well-tolerated in all studies conducted to date, with 
the only evidence of toxicity consisting of mild, transient injection site irritation in 
rats at a dose level 6-fold above the human clinical dose of 16 mg (0.23 mg/kg for a 
70 kg patient), the maximum dose administered on a single day in the phase I study.  
There has been no evidence of systemic toxicity in any study and human HGF has 
not been detected in the sera of rats or rabbits following intramuscular injection 
[lower limit of quantitation (LLOQ) = 125 pg/mL].  There is no evidence of genomic 
integration, potential germ cell transmission, or immunostimulatory effects 
following intramuscular administration of VM202 to animals.  
 
Therefore, the nonclinical efficacy and safety studies support the continued clinical 
investigation of VM202 in patients with critical limb ischemia.  
 
 
1.7. 
CLINICAL DATA 
VM202was evaluated for treatment of critical limb ischemia in a prospective, dose-
escalation Phase I study.  The study consisted of four (4) cohorts of three (3) ‘no-
option’ CLI patients.  Patients received either 2 mg, 4 mg, 8 mg, or 16 mg VM202.  
For each dose cohort, VM202 was administered as local intramuscular injections 
with half of the dose administered at Day 0 of the study and the second half 
administered 2 weeks later.  Preliminary efficacy (hemodynamic assessments), 
safety and tolerability were evaluated at Baseline (screening) and at designated time 
points throughout the study.  Clinical evaluations were to be conducted at baseline, 
Days 15, 28, 59, 91, 180, and 365.  All dose cohorts were followed for a year from 
the time of the first dose of study drug administration. 
 
Enrollment is now complete.  Between March of 2007 and October of 2008, twelve 
(12) patients participated in the study (median age, 72 years, 53% male and 75% 
were a current or former smoker).  No deaths occurred during the 12-month follow 
up, but one patient underwent a major amputation.  Median ABI and TBI 
significantly increased from 0.35 to 0.52 (P=0.005) and 0.15 to 0.24 (P=0.01) at 12 
months follow-up.  TCPO2 showed a trend of increase.  A significant reduction in 
pain was reported by nine of eleven patients, with median VAS decreasing from 58 
to 16 (P=0.03) at 6 months follow-up. VAS score reduction tracked well with the 
hemodynamic data.   
 
In general, there was more improvement over baseline in Cohort II (4 mg VM202) 
than in any other cohort.  Cohort I (2 mg of VM202) also experienced a significant 
reduction in pain and modest improvement in hemodynamic measurement.  
Interestingly, 2 patients in each of these cohorts (pt ID 001102, 001103, 001104, and 
001109) all had diabetes), possibly suggesting some benefit of VM202 in this 
subpopulation.  Doses of aspirin above 81 mg daily may have an inhibitory effect on 
the therapeutic activity of VM202.   
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VM202 appears to be well tolerated at doses as high as 16 mg.  There were no 
unexpected adverse events in the study.  None of the serious adverse events were 
directly attributable to VM202 (eight SAEs in five subjects, 5/12, 41.7%).  There 
was one amputation caused by osteomyelitis which was assessed as unrelated to 
VM202.   
 
Preliminary Conclusions.  These early data support the feasibility of intramuscular 
injections of VM202 in subjects with critical limb ischemia.  They suggest that this 
therapeutic approach may improve functional outcomes and provide symptomatic 
relief.  VM202 is rapidly eliminated from circulation, and appears to remain active 
only at the injection site.  The incidence of complications, while high, did not appear 
to be significantly different between treatment cohorts.  Continued study of VM202 
in patients with CLI and / or diabetes is warranted. 
 
 
1.8. 
STUDY AND DOSE RATIONALE  
Based on the promising results seen in the phase I study, two doses (8 mg and 16 mg 
final VM202 dose) will be tested and compared to placebo injections in this phase II 
study.  Patients will be treated with a final dose of 8 mg VM202, 16 mg VM202 or 
placebo by intramuscular injections in the affected calf on Day 0, Day 14, Day 28 
and Day 42.  VM202 will be delivered in a solution of 0.5 mg VM202 / mL. 
 
As there are currently no approved drugs that can reverse CLI and as most patients 
have exhausted surgical and endovascular intervention options, inducing 
angiogenesis in the affected limb with VM202 may result in an increase in tissue 
perfusion, which, in turn improve wound healing, reduce pain and improve limb 
salvage rates. 
 
 
 
2. 
GOOD CLINICAL PRACTICES STATEMENT 
This trial will be conducted in compliance with all applicable federal regulations pertaining 
to investigational drugs and devices including but not limited to: 21 CRF Part 50, Part 54, 
Part 56, Part 312, and Good Clinical Practice standards.  This trial will be conducted in 
compliance with the protocol as approved by an Institutional Review Board (IRB) and an 
Institutional Biosafety Committee (IBC).  Any deviations from the protocol will be 
immediately reported to the Sponsor and to the IRB and IBC per each institution’s 
guidelines. 
 
 
 
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3. 
INVESTIGATIONAL PLAN 
 
3.1. 
STUDY OBJECTIVES 
The objective of this Phase II study is to evaluate the safety of IM administration of 
VM202 in subjects with moderate or high-risk CLI (Rutherford Clinical Severity 
Score equal to 4 or 5) who are poor or non- candidates for surgical or percutaneous 
revascularization; and, to evaluate potential bioactivity of IM administration of 
VM202 in subjects with CLI, when compared with placebo, on rest pain (as assessed 
by frequency of rest pain, pain medication use history, sleeping history, and intensity 
of rest pain) or leg ulcer healing (as assessed by ulcer surface area, time to complete 
healing), perfusion (MRA), hemodynamic assessment (ABI & TBI), tissue 
oxygenation (TcPO2) and the incidence and extent of lower leg amputation or other 
surgical interventions. 
 
 
3.2. 
STUDY DESIGN 
This is a 12 month phase II, double-blind, randomized, placebo-controlled, 
multicenter study designed to assess the safety and efficacy of VM202 in subjects 
with critical limb ischemia.  Patients with critical limb ischemia will be screened for 
study eligibility after giving informed consent.  Screening will include assessment of 
study eligibility, a complete medical history, physical exam, cancer screening tests, 
viral screening, ABI & TBI, TcPO2, VAS, 12 lead EKG, retinal fundoscopy, clinical 
chemistry, hematology, urinalysis, and pregnancy test (women of childbearing 
potential only), and documentation of any ulcers or gangrenous areas.  With the 
exception of ulcer measurement, VAS, ABI & TBI and TcPO2 which will be 
repeated prior to first injection, procedures conducted during screening will 
represent the baseline reference values.  Screening/Baseline assessments should 
occur within the 60 days prior to Day 0 (day of injection).   
 
Patients who meet the eligibility criteria will be randomly assigned in a 2:2:1 fashion 
to one of the three treatment arms: Low Dose (8 mg VM202), High Dose (16 mg 
VM202), or placebo, respectively.  Assignment to a treatment arm will be 
centralized, using an independent predetermined randomization scheme in a double-
blinded fashion.  Blinding will be achieved by having the study medication (test and 
control products) prepared by the study pharmacist. Reconstituted VM202 is 
indistinguishable from saline solution. 
 
Prior to the first injection, vital signs, concomitant medications, serum chemistry and 
hematology, ulcer evaluation, VAS, ABI & TBI, TcPO2, VascuQol, serum HGF, 
and copies of VM202 will be determined.  MRA will also be conducted as a sub-
study at up to two sites.   
 
Patients will receive VM202 or placebo (normal saline) by intramuscular injections 
in the calf chosen for treatment on Day 0, Day 14, Day 28 and Day 42.  VM202 will 
be delivered in a solution of 0.5 mg VM202 / mL.  Study drug will only be 
administered unilaterally.   
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Patients in the Low Dose Group (8 mg VM202) will receive: 
 
• Day 0: 
4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 14: 4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 28: Placebo only (16 injection of 0.5 ml normal saline)  
• Day 42: Placebo only (16 injection of 0.5 ml normal saline) 
 
Patients in the High Dose Group (16 mg VM202) will receive:  
 
• Day 0: 
4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 14: 4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 28: 4 mg of VM202 (16 injections of 0.5 ml of VM202) 
• Day 42: 4 mg of VM202 (16 injections of 0.5 ml of VM202) 
 
Patients in the placebo control group will receive 16 injections of 0.5 ml normal 
saline at each visit. 
  
Table 1 lists the final dose and dose per visit to be administered by study arm. 
 
Table 1. 
VM202 administration for each study arm 
TREATMENT 
GROUP 
FINAL DOSE 
VM202 
DOSE VM202 (MG) PER VISIT 
DAY 0 
DAY 14 
DAY 28 
DAY 42 
Low Dose 
8 mg 
4 
4 
0 
0 
High Dose 
16 mg 
4 
4 
4 
4 
Placebo 
0 
0 
0 
0 
0 
 
Determination of HGF serum levels will be made immediately pre-treatment on Day 
0, immediately pre-treatment on Day 42, Day 49 and Day 90.  The number of copies 
of VM202 in whole blood will be determined at Day 0 (pre-injection, and 2 hours 
post injection), Day 42 (pre-injection, and 2 hours post injection), Day 49, Day 90, 
and at 6 months.  VAS assessment will be performed at Day 0 (pre-injection), Day 
14 (pre-injection), Day 28 (pre-injection), Day 42(pre-injection), Day 90, at 6 
months, 9 months, and 12 months.  VascuQol will be administered on Day 0 (pre-
injection), Day 90, at 9 months, and 12 months.  ABI & TBI will be recorded at Day 
0 (pre-injection), Day 28 (pre-injection), Day 90, at 6 months, 9 months, and 12 
months.  TcPO2 will be measured at Day 0 (pre-injection), 6 months, 9 months, and 
12 months.  Ulcer measurements will be performed at Day 0, Day 14, Day 28, Day 
42, Day 49, Day 90, at 6 months, 9 months, and 12 months.  MRA will be conducted 
as a sub-study at up to two sites on Day 0 (pre-injection) and at 6 and 9 months.  
Retinal fundoscopy will be conducted at 12 months.  Adverse events will be 
recorded throughout the one year follow-up period. 
 
A summary of the schedule of evaluations and visits from screening through the end 
of the study can be found in Appendix 1. 
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3.3. 
PATIENT POPULATION 
Fifty (50) patients meeting the following study entry criteria will be enrolled.  
 
3.3.1. 
INCLUSION CRITERIA 
1. Male or female, between 18 and 90 years of age; 
2. Diagnosis of critical limb ischemia (Rutherford Class 4 or 5), including:   
• A resting ankle systolic pressure (in either the dorsalis pedis or posterior 
tibial arteries) of ≤ 70 mmHg in the affected limb; or 
• A resting toe systolic pressure of ≤ 50 mmHg in the affected limb; or 
• For patients in which measurement of ankle systolic pressure is not feasible 
(e.g. vessel calcification and non-compressibility), TcPO2 ≤ 30 mmHg; 
3. Poor or suboptimal candidate for bypass graft surgery or percutaneous 
angioplasty; 
4. Pain at rest, and/or ischemic ulcers, and/or focal gangrene (< 3 cm2) for a 
minimum of 2 weeks; 
5. Significant stenosis (≥ 75%) of one or more of the following arteries: superficial 
femoral, popliteal, or two or more infra-popliteal arteries as verified by 
angiography within 12 months prior to enrollment; 
6. Be willing to maintain current drug therapy for peripheral arterial disease 
throughout the course of the study including an anti-platelet, hypertension and 
statin treatment unless not tolerated; 
7. Clinically stable on optimized medical regimen for >30 days; 
8. Be capable of understanding and complying with the protocol and signing the 
informed consent document prior to being subjected to any study related 
procedures; 
9. 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 urine 
pregnancy test result prior to study enrollment and must agree to repeat 
pregnancy screening tests during the study.  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. 
 
3.3.2. 
EXCLUSION CRITERIA 
1. Subjects who have undergone a successful revascularization procedure or 
sympathectomy within 12 weeks prior to study entry.  A clinically unsuccessful 
revascularization procedure is defined as one in which: 
•  the target vessel re-occludes (>50%, as verified by a second angiogram.  
Duplex ultrasonography can be used to determine vessel patency if the 
patient cannot tolerate a second angiogram), or 
• the target vessel remains patent, but there is no resolution of symptoms 6 
weeks after the procedure (e.g. no evidence of ulcer healing, no improvement 
in pressures, no reduction in resting pain); 
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2. Subjects that will require an amputation in the target leg within 4 weeks of 
randomization; 
3. Subjects with evidence of active infection (e.g., cellulitis, osteomyelitis) or deep 
ulceration exposing bone or tendon in the extremity planned for treatment; 
4. HF with a NYHA classification of III or IV; 
5. Stroke (NIH scale > 2) or myocardial infarction within last 3 months; 
6. Unstable angina 
7. Uncontrolled hypertension defined as sustained systolic blood pressure (SBP) > 
200 mmHg or diastolic BP (DBP) > 110 mmHg at baseline/screening evaluation; 
8. Ophthalmologic conditions pertinent to proliferative retinopathy or conditions 
that preclude standard ophthalmologic examination; 
9. Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as 
Buerger’s disease); 
10. Subjects with advanced liver disease including decompensated cirrhosis, 
jaundice, ascites or bleeding varices; 
11. Subjects currently receiving immunosuppressive medications chemotherapy, or 
radiation therapy; 
12. Positive HIV or HTLV at Screening; 
13. Active Hepatitis B or C infection as determined by Hepatitis B surface antibody 
(HBsAb), Hepatitis B core antibody (IgG and IgM; HBcAb), Hepatitis B surface 
antigen (HBsAg) and Hepatitis C antibodies (Anti-HCV), at Screening; 
14. Specific laboratory values at Screening including: Hemoglobin < 8.0 g/dL, WBC 
< 3,000 cells per microliter, platelet count <75,000/mm3, AST and/or ALT > 3 
times the upper limit of normal or any other clinically significant lab abnormality 
which in the opinion of the investigator should be exclusionary; 
15. Patients with a recent history (< 5 years) of or new screening finding of 
malignant neoplasm except basal cell carcinoma or squamous cell carcinoma of 
the skin (if excised and no evidence of recurrence); patients with family history 
of colon cancer in any first degree relative are excluded unless they have 
undergone a colonoscopy in the last 12 months with negative findings; 
16. Elevated PSA unless prostate cancer has been excluded; 
17. 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 
18. Subjects requiring > 81 mg daily of acetylsalicylic acid;  If > 81 mg are taken at 
screening, subjects may be enrolled if willing/able to switch to another 
medication for the duration of the study; 
19. Subjects requiring regular COX-2 inhibitor drug(s) or high dose steroids 
(excepting inhaled steroids); 
20. Major psychiatric disorder in past 6 months; 
21. History of drug or alcohol abuse / dependence in the past 2 years; 
22. Use of an investigational drug or treatment in past 12 months; concurrent 
participation in investigational protocol or unapproved therapeutics; and 
23. Unable or unwilling to give informed consent. 
 
 
 
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3.4. 
STUDY PROCEDURES 
Prior to recruitment of any patients into the study, written approval of the protocol 
and informed consent must be obtained from the Institutional Review Board (IRB). 
 
3.4.1. 
INFORMED CONSENT 
The investigator will explain the study purpose, procedures, and patient’s 
responsibilities to the potential participant.  The patient's willingness and ability to 
meet the follow-up requirements will be determined and written informed consent 
will be obtained (Appendix 2).  The patient will sign and date the informed consent 
form.  The person executing the consent will also sign and date the consent form.  
The original informed consent form will be retained with the patient records; a copy 
will be provided to the patient.   
 
Following is a detailed list of study visits from screening to final follow-up and the 
required procedures / tests.  Methodologies for specific tests/ procedures are 
described in Section 4. 
 
3.4.2. 
PATIENT IDENTIFICATION 
To maintain confidentiality, the patient’s name should not be recorded on any study 
document other than the informed consent form.  All patients that give informed 
consent (sign the informed consent form) will be assigned a unique identifier.   
 
3.4.3. 
SCREENING (DAY -60 TO DAY 0) 
Patient enrollment is subject to the rules established in Section 3.2 for 
randomization, but screening procedures can proceed provided the Investigator waits 
for enrollment confirmation from ViroMed or its Designee. 
 
The following procedures / evaluations will be conducted at screening: 
 
• Obtain informed consent prior to any study-related procedures  
• Evaluation of eligibility  
• Complete Medical History 
• Vital Signs 
• Complete Physical Exam 
• Concomitant Medications 
• Cancer screening – including cancer markers (carcinoembryonic antigen (CEA), 
alpha fetoprotein (AFP), CA19-9, and CA125 (females only)); pap smear and 
mammogram if not performed within past 12 months (females only); chest X-ray 
or CT scan of the chest (if the patient 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; PSA (males only); for patients ≥ 50 years old, colonoscopy within past 10 
years 
• Retinal Fundoscopy - fluorescein angiography may be conducted in cases where 
fundoscopy alone is deemed insufficient 
• Viral screening – HIV, Anti-Human T-Cell Lymphotropic Virus (HTLV) 
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• Positive Hepatitis B or C as determined by Hepatitis B core antibody (HBcAB), 
antibody to Hepatitis B antigen (IgG and IgM; HbsAB), Hepatitis B surface 
antigen (HBsAg) and Hepatitis C antibodies (Anti-HCV), at Screening 
• Serum chemistry and hematology 
• Urinalysis 
• Urine pregnancy test (for women of childbearing potential only) 
• Photograph and measurement of ulcer(s) – if present 
• ECG 
• Visual Analog Scale (VAS) score 
• ABI & TBI 
• TcPO2   
 
3.4.3.1. 
SCREEN FAILURES 
Patients not meeting all study entry criteria will be designated as a screen failures.  
End of study procedures will not be performed for these patients, but their reason for 
discontinuation will be recorded on the CRF.  Screen failures will be replaced. 
 
3.4.4. 
TREATMENT AUTHORIZATION 
After providing written informed consent, potential study participants will undergo 
Screening assessments.  The site will complete a Treatment Authorization Form 
(TAF) for patients determined to be eligible for study participation.  The TAF 
includes the patient identification number, demographic information (gender, date of 
birth) and indication that the patient meets all inclusion and exclusion criteria.  The 
completed TAF will be faxed to ViroMed or its designee.  ViroMed or its designee 
will confirm whether the patient can be treated, update the TAF with specific 
treatment instructions, and return it to the investigational site by fax. Upon receipt, 
the Investigator will schedule the patient to undergo the study treatment.  Note: 
adherence to this process is mandatory to track enrollment and to assure proper 
randomization. 
 
3.4.5. 
RANDOMIZATION & BLINDING 
A randomization schedule with subjects allocated to high dose, low dose or control 
in a 2:2:1 ratio will be sent to a centralized drug depot, which will prepare individual 
kits that are sequentially numbered and contain the appropriate treatment based on 
the randomization schedule.  When a site identifies a subject and treatment 
authorization is granted, the site will notify the drug depot.  
The drug depot will: 
 
1. Send the next kit in sequence to the site, labeled with the site number and subject 
number.  
2. Record which kit number was assigned to which site/subject and the date. 
3. Include in the kit, a sealed envelope that identifies the site number, subject 
number and kit number on the outside and the assigned treatment inside, to be 
opened by the Investigator or designee only in the case of a medical emergency. 
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4. Send another sealed envelope to the Sponsor with the site number, subject 
number and kit number on the outside and the assigned treatment inside, to be 
opened by the Sponsor or designee only in the case of a medical emergency.   
 
Blinding will be achieved by having the study medication (VM202) prepared by the 
study pharmacist. Reconstituted VM202 is indistinguishable from saline solution.. 
The site pharmacist prepares the vials according to the instructions in the kit (which 
vials to reconstitute with water for injection [WFI].  The drug depot, site pharmacist 
and select individuals at Synteract (but not including study monitors) will be 
unblinded to the treatment assignments. The subject and study personnel, including 
core lab, investigator and study coordinators, will remain blinded until all data has 
been entered into the database and the database is locked.  
 
IN CASE OF EMERGENCY ONLY, i.e. SERIOUS ADVERSE EVENT (SAE) 
AND ONLY WHEN THIS INFORMATION INFLUENCES THE PATIENT'S 
MANAGEMENT, the Investigator may open the sealed envelope to immediately 
start the appropriate treatment (to be recorded in the case report form [CRF]). 
 
For each opened envelope, the Investigator will provide the name of the person who 
opened the envelope, reason, date, and signature on the envelope.  At the end of the 
study, all (opened and unopened) envelopes will be returned with the study products 
to the Sponsor. 
 
3.4.6. 
DAY 0 – 1
ST INJECTIONS 
 
3.4.6.1. 
PRE-INJECTION (WITHIN 4 HRS PRIOR TO INJECTIONS) 
• Concomitant Medications 
• Vital Signs 
• Serum Chemistry and hematology 
• Serum HGF  
• Copies of VM202 in whole blood 
• Visual Analog Scale (VAS) score 
• VascuQol 
• ABI & TBI 
• TcPO2 
• Photograph and measurement of ulcer(s) – if present 
• MRA – sub-study to be only at designated site(s) –to be completed within 7 days 
prior to Day 0 
 
3.4.6.2. 
1
ST DOSE OF VM202 / PLACEBO 
• Intramuscular injections of VM202 in calf (unilateral) 
 
3.4.6.3. 
POST-INJECTION 
• Vital Signs 
• Copies of VM202 in whole blood (2 hours ± 1 hour post injection) 
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• Injection site assessment 
• Adverse event assessment 
 
 
3.4.7. 
DAY 14 ± 3 DAY –2
ND INJECTIONS  
 
3.4.7.1. 
PRE-INJECTION (WITHIN 4 HRS PRIOR TO INJECTIONS) 
• Concomitant Medications 
• Vital Signs 
• Serum Chemistry and hematology 
• Visual Analog Scale (VAS) score 
• Photograph and measurement of ulcer(s) – if present 
• Injection site assessment 
• Adverse event assessment 
 
3.4.7.2. 
2
ND DOSE OF VM202 / PLACEBO 
• Intramuscular injections of VM202 in calf (unilateral, same leg as 1st injection) 
 
3.4.7.3. 
POST-INJECTION 
• Vital Signs 
• Injection site assessment 
• Adverse event assessment 
 
 
3.4.8. 
DAY 28 ± 3 DAY –3
RD INJECTIONS  
 
3.4.8.1. 
PRE-INJECTION (WITHIN 4 HRS PRIOR TO INJECTIONS) 
• Concomitant Medications 
• Vital Signs 
• Serum Chemistry and hematology 
• Visual Analog Scale (VAS) score 
• ABI & TBI 
• Photograph and measurement of ulcer(s) – if present 
• Injection site assessment 
• Adverse event assessment 
 
3.4.8.2. 
3
RD DOSE OF VM202 / PLACEBO 
• Intramuscular injections of VM202 in calf (unilateral, same leg as 1st injection) 
 
3.4.8.3. 
POST-INJECTION 
• Vital Signs 
• Injection site assessment 
• Adverse event assessment 
 
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3.4.9. 
DAY 42 ± 3 DAY – 4
TH INJECTIONS 
 
3.4.9.1. 
PRE-INJECTION (WITHIN 4 HRS PRIOR TO INJECTIONS) 
• Concomitant Medications 
• Vital Signs 
• Serum Chemistry and hematology 
• Serum HGF  
• Copies of VM202 in whole blood 
• Visual Analog Scale (VAS) score 
• Photograph and measurement of ulcer(s) – if present 
• Injection site assessment 
• Adverse event assessment 
 
3.4.9.2. 
4
TH DOSE OF VM202 / PLACEBO 
• Intramuscular injections of VM202 in calf (unilateral, same leg as 1st injection) 
 
3.4.9.3. 
POST-INJECTION 
• Vital Signs 
• Copies of VM202 in whole blood (2 hours ± 1 hour post injection) 
• Injection site assessment 
• Adverse event assessment 
 
 
3.4.10. DAY 49 ± 3 DAYS 
• Concomitant Medications 
• Vital Signs 
• Serum Chemistry and hematology 
• Copies of VM202 in whole blood 
• Serum HGF 
• Photograph and measurement of ulcer(s) – if present 
• Injection site assessment 
• Adverse event assessment 
 
 
3.4.11. DAY 90 ± 7 DAYS 
• Concomitant Medications  
• Vital Signs 
• Serum Chemistry and hematology 
• Serum HGF 
• Copies of VM202 in whole blood 
• Visual Analog Scale (VAS) score 
• VascuQol 
• ABI & TBI 
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• Photograph and measurement of ulcer – if present 
• Adverse event assessment 
 
 
3.4.12. 6 MONTHS  ± 1 MONTH 
• Concomitant Medications  
• Vital Signs 
• Serum Chemistry and hematology 
• Photograph and measurement of ulcer – if present 
• Visual Analog Scale (VAS) score 
• Copies of VM202 in whole blood 
• ABI & TBI  
• TcPO2 
• MRA  – sub-study to be only at designated site(s) - to be completed within 7 
days of the Month 6 Visit 
• Rutherford Classification 
• Adverse event assessment 
 
3.4.13. 9 MONTHS  ± 1 MONTH 
• Concomitant Medications 
• Vital Signs 
• Serum Chemistry and hematology 
• Visual Analog Scale (VAS) score 
• VascuQol 
• ABI & TBI 
• Photograph and measurement of ulcer(s) – if present 
• TcPO2 
• MRA – sub-study to be only at designated site(s) ) - to be completed within  days 
of the Month 9 Visit 
• Rutherford Classification 
• Adverse event assessment 
 
3.4.14. 12 MONTHS  ± 1 MONTH 
• Retinal fundoscopy 
• Concomitant Medications 
• Vital Signs 
• Serum Chemistry and hematology 
• Visual Analog Scale (VAS) score 
• VascuQol 
• ABI & TBI 
• Photograph and measurement of ulcer(s) – if present 
• TcPO2 
• Rutherford Classification 
• Adverse event assessment 
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3.5. 
STUDY COMPLETION 
 
3.5.1. 
COMPLETED PATIENTS 
Each patient in the study will be considered completed when all assessments through 
12 months have been performed in accordance with the study protocol. 
 
3.5.2. 
DISCONTINUED PATIENTS 
Any patient may voluntarily discontinue the study at any time without prejudice.  
The investigator may discontinue a patient from the study at any time if (s)he 
considers that remaining in the study compromises the patient’s health or the patient 
is not sufficiently cooperative. In either event, reason(s) for discontinuation should 
be recorded on the CRF. 
 
Possible reasons for study discontinuation include the following: 
 
• AEs necessitating discontinuation from the study (pre-treatment). 
• The patient is lost to follow-up. 
• Patient decision (specify). 
• Investigator decision (specify). 
• Other reason (specify). 
 
The reasons for any patient discontinuation will be recorded on the study completion 
form of the CRF. 
 
Discontinued patient(s) will be replaced in any treatment arm if discontinuation 
occurs prior to the 90 Day follow-up; 
 
Patients discontinued for AE(s) will be followed-up after patient’s discontinuation 
until the event is resolved or considered medically stable by the investigator.   
 
Subjects that withdraw prior to study completion will undergo the following if 
possible: 
 
• 
Retinal Fundoscopy 
• 
Concomitant Medications 
• 
Serum Chemistry and hematology 
• 
Photograph and measurement of ulcer(s) if present at baseline 
• 
Vital Signs 
• 
Serum HGF if discontinued prior to Day 90 
• 
Copies of VM202 in whole blood if discontinued prior to Day 90 
• 
Injection site reaction assessment if discontinued prior to Day 49 
• 
Adverse Events 
 
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In case of a patient lost-to-follow-up, the investigator must do his/her best to contact 
the patient (by phone or letter) at least twice.  If no response is obtained from the 
patient, the investigator is encouraged to contact one of the patient’s relatives or 
his/her general practitioner.  The evidence of these contacts must be recorded in the 
patient medical chart.  It can be, for instance, the acknowledgement of receipt of a 
letter sent to the patient.   
 
3.5.3. 
PREMATURE STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study for any safety, ethical or 
administrative reason at any time. 
 
 
3.6. 
INVESTIGATIONAL DRUG PRODUCT AND ACCOUNTABILITY 
 
3.6.1. 
INVESTIGATIONAL DRUG PRODUCT 
VM202 is a DNA plasmid containing a novel genomic cDNA hybrid human 
hepatocyte growth factor (HGF) coding sequence (HGF-X7) expressing two 
isoforms of HGF, HGF728 and HGF723.  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 efficiently as in 
the human genome.  Because there is no change in the coding region of the HGF 
gene, HGF proteins generated from VM202 are identical to the wild-type human 
HGF proteins.   
 
The plasmid has 7,377 base pairs, a HCMV enhancer / promoter, a growth hormone 
polyadenylation terminator sequence, ColEl originator, and the Kanamycin 
resistance gene, on a pCK backbone.   
 
VM202 is supplied in a sterile glass vial containing 2.2 mg of lyophilized study 
product.  VM202 should be stored in a refrigerator at temperatures between 2oC and 
8oC in an appropriately locked room accessible only to the pharmacist or a duly 
designated person.  Since VM202 does not contain preservatives, opened vials of 
VM202 and VM202 reconstituted with water for injection (WFI) must be used 
within 6 hours when stored at room temperature. VM202 should never be frozen.  A 
complete description of test article administration can be found in Appendix 4. 
 
3.6.2. 
PLACEBO 
The placebo will be sterile normal saline.  Sodium Chloride Injection, USP is a 
sterile, nonpyrogenic solution for fluid and electrolyte replenishment.  It contains no 
antimicrobial agents.  The nominal pH is 5.5 (4.5 to 7.0) and it contains 9.0 g/L 
Sodium Chloride, USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). 
Visually, normal saline is indistinguishable from reconstituted VM202. 
 
3.6.3. 
PRODUCT ACCOUNTABILITY 
In accordance with federal regulations (21CFR 312.62), all Investigators are required 
to keep accurate records showing final disposition of all investigational drugs.   
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Investigational drugs are to be used only in accordance with this protocol and under 
supervision of the Principal Investigator.  The Principal Investigator or his designee 
will maintain an accurate record of the receipt of the test drug as shipped by the 
Sponsor/Designee, including the date received.  In addition, an accurate drug 
disposition record will be kept, specifying the amount dispensed to each patient and 
the date of dispensation.  This inventory record must be available for inspection at 
any time.  Copies of this record will be provided to the Sponsor by the Principal 
Investigator at the conclusion of the study. 
 
After the study is completed, the Principal Investigator must account for all drug 
used, unused and partially used.  Unused study medication from the study site will 
be returned to the Sponsor/Designee as directed in writing by the Sponsor for gross 
reconciliation. 
 
3.6.4. 
DOSE AND ADMINISTRATION 
VM202 is supplied in a sterile glass vial containing 2.2 mg of lyophilized study 
product.  Before administration, it will be reconstituted with 4.4 mL of water for 
injection (WFI) by the study pharmacist for a final VM202 concentration of 0.5 mg / 
mL.  Each reconstituted vial is only to be used for one subject.  Patients assigned to 
either the placebo arm or the Low Dose arm will receive normal saline injections.  
The placebo group will receive only normal saline injections; the Low Dose arm will 
receive VM202 for the first two injection visits (Day 0 and Day 14), and then normal 
saline for the next two injection visits (Day 28 and Day 42).   Visually, normal saline 
is indistinguishable from reconstituted VM202.  A complete description of test 
article administration can be found in Appendix 4. 
 
 
 
3.7. 
PRIOR AND CONCOMITANT MEDICATION 
All concomitant medications (taken within 60 days of the first injection) will be 
recorded on the CRF at each study visit.   
 
For each medication taken, the following information will be collected: 
• Medication trade name; 
• Indication for which the medication was given; 
• Dose/strength, route, and frequency of administration; 
• Date started and 
• Date stopped (or continuation). 
 
 
 
 
 
 
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4. 
EXAMINATIONS AND EVALUATIONS 
 
4.1. 
EVALUATIONS CONDUCTED AT BASELINE ONLY 
 
4.1.1. 
COMPLETE 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 and prior to the first study drug administration (Day 
0) will be considered to be part of the medical history and will not be recorded as an 
adverse event. 
 
The Investigator will perform an especially detailed assessment of past peripheral 
arterial disease history to include all events and interventions for critical limb 
ischemia and to excluded other (e.g. structural abnormalities such as fibromuscular 
dysplasia or connective tissue disorders, inflammatory conditions, thromboembolic 
disease, impingement/entrapment, venous claudication, etc.).  
 
4.1.2. 
COMPLETE PHYSICAL EXAM 
A complete physical exam will be performed at Baseline.  The exam will include the 
following: head, eyes, ears, nose, and throat (HEENT), heart, lungs, abdomen, 
extremities, lymph nodes, musculoskeletal, neurological, gastrointestinal and 
dermatological systems. Any clinically significant abnormalities should be recorded 
in the patient’s CRF. 
 
4.1.3. 
CANCER SCREENING 
All patients 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. 
For patients ≥ 50 years old, colonoscopy within past 10 years 
2. 
Chest X-ray or CT scan of the chest (if the patient 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 
 
The cancer screening tests performed at baseline for this protocol are consistent with 
the American Cancer Society “Guidelines for the Early Detection of Cancer” dated: 
3/28/07 (see Appendix 6). 
 
 
 
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4.1.4. 
VIRAL SCREENING 
Each site will be responsible for Screening Viral Testing.  Assays will include: 
HIV1, HIV2, HTLV, HBV and HCV as determined by screening for the HBsAg, 
HBsAB, HBcAb (IgM plus IgG), and Anti-HCV.. 
 
4.1.5. 
URINALYSIS 
Specific gravity, pH, color, protein, sugar, and byproducts will be evaluated at 
baseline. 
 
4.1.6. 
12-LEAD EKG 
A 12 lead electrocardiogram (EKG) will be conducted at screening.  The EKG 
recording will be printed out in duplicate, and one copy will be placed with patient 
records.  Any clinically meaningful changes from baseline will be recorded as 
adverse events.  
 
4.1.7. 
PREGNANCY TEST (WOMEN OF CHILDBEARING POTENTIAL ONLY) 
For women of childbearing potential, a urine beta human chorionic gonadotropin (β-
HCG) test will be performed at Screening.  Results of the test must be negative and 
effective contraception documented.  Acceptable methods of contraception include: 
 
• Barrier type devices (e.g., female condom, diaphragm and contraceptive sponge) 
used only in combination with a spermicide; 
• Intrauterine device; 
• Oral contraceptive agents; 
• Depo-provera (medroxyprogesterone acetate); 
• Levonorgestrel implants; 
 
Abstention, the rhythm method or contraception by a partner are not acceptable 
methods of contraception. 
 
 
 
4.2. 
EVALUATIONS CONDUCTED THROUGHOUT THE STUDY 
 
4.2.1. 
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 will be assessed by retinal fundoscopy at 
Screening/Baseline patients for eligibility and repeated at 12 months.  Retinal 
fundoscopy must be performed by an ophthalmologist within 3 months of Screening. 
 
4.2.2. 
CONCOMITANT MEDICATIONS 
Concomitant medications will be recorded at each visit using the trade name or 
generic name as described in Section 3.7. 
 
 
 
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4.2.3. 
VITAL SIGNS 
The vital signs of blood pressure (while patient is sitting), temperature , body weight, 
heart rate, and respiratory rate will be measured and recorded at screening and at 
every visit through the 12 month follow-up and recorded in the patients CRF. 
 
4.2.4. 
SERUM CHEMISTRY AND HEMATOLOGY 
Evaluation of serum chemistry and hematology will be conducted at Baseline and at 
every study visit though the 12 month follow-up.  Evaluations will be conducted 
locally at each site. 
 
Serum chemistry evaluations will include: calcium, phosphorus, glucose, sodium, 
potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline 
phosphatase, gamma glutamyl transpeptidase (GGT), lactic dehydrogenase (LDH), 
uric acid, albumin, and globulin. 
 
Hematology evaluations will include: complete blood count (CBC): red blood cells 
(RBC); hemoglobin (HgB), HCT, mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration 
(MCHC), platelets and white blood cells (WBC) with differential; and, neutrophils 
or polymorphonuclear cells (polys), lymphocytes (lymphs), monocytes or 
macrophages (monos), eosinophils (eos) and basophils (bas).  Abnormal readings do 
not necessarily constitute an adverse event; the reading needs to be reviewed in the 
context of the patient’s health. 
 
4.2.5. 
SERUM HGF 
Serum HGF will be determined by ELISA at the following follow-up visits: 
immediately pre-treatment on Day 0, immediately pre-treatment on Day 42, on Day 
49, and Day 90.  A minimum 2 cc blood draw will be taken at each time point.   
Allow blood to clot for 30 minutes then centrifuge for 10 minutes at 1000 x g. Serum 
should be collected and transferred into plastic vials of 0.2 cc aliquots each.  The 
plastic vials will be snap frozen in LN2 or an alcohol dry ice bath.  Samples will be 
maintained in a cooler containing dry ice and then placed in a ≤ -65°C freezer until 
shipped for analysis.  Samples should be labeled with subject ID, draw date, study 
number and visit interval (i.e., Day 0, 14, 30 or 60). All sample packages will be sent 
in a single batch, including VM202 samples, with a temperature tracking recorder.  
Analysis will be conducted by Charles River Laboratories in accordance with good 
laboratory practices (GLP).  Samples should be sent to: 
 
Charles River Laboratories 
Preclinical Services Nevada 
6995 Longley Lane 
Reno, NV  89511 
Phone:  (775) 682-2079 
 
 
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4.2.6. 
COPIES OF VM202 IN WHOLE BLOOD 
The number of copies of VM202 in whole blood will be determined by PCR at Day 
0 (pre-injection, and 2 hours post injection), Day 42 (pre-injection, and 2 hours post 
injection), Day 49, Day 90, and 6 months.  Whole blood will be collected in EDTA-
coated tubes, inverted >5 times and transferred to plastic sterile and or RNase and 
DNase free vials of ~0.6 cc aliquots each.  Collect 5 cc of whole blood per patient 
per timepoint (meaning a transfer to a minimum of 5 vials containing 0.6cc – 1cc 
aliquots).  The vials will be snap frozen in LN2 or an alcohol dry ice bath.  These 
will be maintained in a ≤ -65°C freezer until shipped for analysis.  Samples should 
be labeled with subject ID, draw date and time, study number, and visit interval (i.e., 
Day 0, 14, 21, 30, 60 or 90).  All sample packages will be sent in a single batch, 
including serum HGF samples) with a temperature tracking recorder.  Analysis will 
be conducted by Charles River Laboratories in accordance with good laboratory 
practices (GLP).  Samples should be sent to: 
 
Charles River Laboratories 
Preclinical Services Nevada 
6995 Longley Lane 
Reno, NV  89511 
Phone:  (775) 682-2079 
 
4.2.7. 
VISUAL ANALOG SCALE (VAS) SCORE 
Pain will be measured using the visual analog scale (VAS) at screening, before the 
first treatment (injection) on Day 0, pretreatment on Days 14, 28 and 42, Day 90, 6 
months, 9 months and 12 months.  The VAS scoring instrument is a 10-cm line, 
oriented horizontally, with the left end indicating “no pain” and the right end 
representing “pain as bad as it can be”.  The patient is asked to mark a place on the 
line corresponding to the current pain intensity.  The distance along the scale is then 
converted into a numeric reading as detailed in the study manual. 
 
4.2.8. 
PATIENT QUESTIONNAIRE (VASCUQOL) 
The VascuQol patient questionnaire was specifically developed for use in patients 
with lower limb ischemia.42   This questionnaire has 25 questions that review five 
domains: activity level, symptoms, pain, emotional status and social items.  
VascuQol was found to be better at detecting improvement in symptoms, disease 
severity than SF-36 in CLI patients and correlated well with the Rutherford 
classification.43  This test will be administered pre-injection on Day 0, at Day 90, 9 
months, and 12 months.  The VascuQol can be found in Appendix 5. 
 
4.2.9. 
ANKLE BRACHIAL INDEX (ABI) AND TOE BRACHIAL INDEX (TBI) 
Ankle-Brachial Index (ABI) and Toe Brachial Index (TBI) will be determined at 
screening, before the first treatment (injection) on Day 0, before the third injection 
on Day 28, on Day 90, 6 months, 9 months and 12 months.  ABI and TBI will be 
determined as described in the Study Manual. 
 
 
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4.2.10. TRANSCUTANEOUS OXYGEN PRESSURE (TCPO2) 
Transcutaneous oxygen pressure (TcPO2) will be measured at screening, before the 
first treatment (injection) on Day 0, at 6, 9 and at 12 months.  TcPO2 measurement 
sites will include the anterior and posterior calf and dorsum of the foot.  Because 
TcPO2 measurements are instrument dependent, investigators should use the same 
instrument for all TcPO2 assessments and follow the standard procedures defined by 
their instrument’s manufacturer.  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 TcPO2 value of zero pressure (“0 mmHg”).  Hard copy 
instrumentation printout will be included in the source documentation to support the 
TcPO2 data. The limb/chest TcPO2 index will be calculated by using the lesser of the 
lower limb measurements.   
 
4.2.11. PHOTOGRAPH AND MEASUREMENT OF ULCER 
Two photographs of any ulcerations or gangrenous areas will be taken for 
documentation purposes only if present at screening or immediately before treatment 
on Day 0.  If present prior to the first injection, two photographs of each 
ulceration/gangrene area will be obtained pretreatment on Days 14, 28 and 42, on 
Day 49, Day 90, 6 months, 9 months and 12 months.  A metric ruler (cm and mm) 
will be photographed in the lower right hand corner of the frame to allow for scale 
determination.  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, patient’s initials, and the patient’s study number 
assignment.  Ulcer dimensions will be measured and recorded as detailed in the 
Study Manual.  
 
4.2.12. INJECTION SITE REACTION ASSESSMENT 
Local injection sites reactions will be assessed on Day 0 post injection, pre and post 
injection on Days 14, 28 and 42, and on Day 49 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 as described in 
Table 2. 
 
Table 2. Injection Reaction Assessment 
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. 
Life-
threatening 
consequences; 
major invasive 
intervention 
indicated (e.g., 
complete 
Death 
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ADVERSE 
EVENT 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
GRADE 5 
hyperbaric 
oxygen) 
resection , 
tissue 
reconstruction, 
flap, or 
grafting 
Alergic reaction 
/ 
hypersensitivity 
Transient 
flushing or 
rash; drug 
fever < 38oC 
(<100.4oF) 
Rash; flushing 
; urticaria; 
dyspnea; drug 
fever ≥38oC 
(≥100.4oF) 
Symptomatic 
bronchospasm, 
with or without 
urticaria; 
parenteral 
medications(s) 
indicated; allergy-
related edema/ 
angioedema; 
hypotension 
Anaphylaxis 
Death 
 
 
4.2.13. MRA 
MRA will be conducted as a sub-study at up to two sites on Day 0 (pre-injection) 
and at 6 and 9 months (see Appendix 3).   
 
 
 
 
5. 
EVALUATION OF ADVERSE EVENTS 
 
5.1. 
DEFINITIONS 
An Adverse Event (AE) is the development of an untoward medical occurrence or 
the deterioration of a pre-existing medical condition following or during exposure to 
an investigational product, whether or not considered causally related to the product.   
 
An untoward medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver) or clinically significant abnormal results of an 
investigation (e.g., laboratory findings, electrocardiogram). 
An adverse reaction means any adverse event caused by a drug.  Adverse reactions 
are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For the purposes of 
IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
 
A serious adverse event (SAE) is any untoward medical occurrence which: 
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• Results in death; 
• Is life-threatening; 
• Requires inpatient hospitalization or prolongation of hospitalization which is not 
specifically required by the protocol or is elective; 
• Results in permanent impairment of a body function or permanent damage to a 
body structure; or 
• Requires medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure. 
 
Additionally, important medical events that may not result in death, be life-
threatening or require hospitalization may be considered SAEs when they jeopardize 
the patient or require medical or surgical intervention to prevent one of the serious 
outcomes listed above.  Examples of such medical events include: allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse.  Medical and scientific judgment 
must be exercised when classifying events as serious. 
 
Life-threatening means that the patient is, in the view of the investigator, at 
immediate risk of death from the AE as it occurred.  It does not include an AE 
which, had it occurred in a more serious form, might have caused death.  
Persistent or significant disability/incapacity means that the event resulted in 
permanent or significant and substantial disruption of the patients’ ability to carry 
out normal life functions.   
 
An unexpected AE is an AE, the nature or severity of which is not consistent with 
the applicable product information (e.g. Investigator Brochure for an unapproved 
product).  Expected means that the event has been previously observed with the test 
article and is identified and/or described in the applicable product information.  It 
does not mean that the event is expected with the underlying disease(s) or 
concomitant medications.  It is expected that certain disease states will have 
reoccurring adverse events some of which may be considered expected over time. 
 
 
5.2. 
ASSESSMENT OF AES 
All AEs, regardless of severity, occurring following the first study drug 
administration and the 12 month follow-up visit of the study by a patient must be 
recorded on the AE form provided with the CRF.  This will include the following 
information: 
 
• Description of the AE 
• Date of onset 
• Duration 
• Frequency 
• Severity 
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• Seriousness (yes/no) 
• Treatment 
• Outcome 
• Relationship to study medication, injection procedure  and/or  underlying disease  
 
All AEs and SAEs must be followed until resolution, or the condition stabilizes.  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 its designee may request that the Investigator perform or 
arrange for the conduct of supplemental measurements and/or evaluations. 
 
5.2.1. 
AE CAUSALITY 
The study investigator will determine whether an AE is related or unrelated to study 
medication, the procedure (intramuscular injection) and / or the underlying disease 
using the following criteria: 
 
Not related: An adverse event that is not related to the use of the test article or 
administration procedure.   
 
Possibly related: An adverse event that might be due to the use of the test article or 
administration procedure. An alternative explanation, e.g., concomitant study 
product(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, a causal relationship cannot be excluded.   
 
Probably related: An adverse event that might be due to the use of the test article or 
administration procedure. The relationship in time is suggestive. An alternative 
explanation is less likely, e.g., concomitant drug(s), concomitant disease(s). 
 
Definitely related: An AE that is due to the use of the test article or administration 
procedure. The event cannot be reasonably explained by an alternative explanation – 
e.g., concomitant drug(s), concomitant disease(s).  
 
5.2.2. 
AE INTENSITY 
The intensity of the AE/SAE will be defined by the following criteria: 
Mild: 
The AE is noticeable to the patient but does not interfere with 
routine activity. 
Moderate: 
The AE is discomforting and interferes with routine activity. 
Severe: 
The AE significantly limits the patient’s ability to perform 
routine activities despite symptomatic therapy. 
 
 
 
 
 
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5.3. 
REPORTING/RECORDING OF AES 
Throughout the course of the study, all efforts will be made by the investigator to 
remain alert to possible AEs.  The first concern will be the safety of the patient, and 
for providing appropriate medical intervention.  The period of observation for 
collection of AEs starts during the first intramuscular injection procedure (Day 0) 
until the 12 month follow-up visit.  Any AE should be recorded on the appropriate 
CRF page(s). 
 
 
5.4. 
REPORTING / RECORDING OF SAES 
 
5.4.1. 
INVESTIGATOR’S RESPONSIBILITY 
SAES will be recorded following the first study drug administration and the 12 
month follow-up visit.  Any serious adverse event that occurs during this 
investigation, whether or not related to the study medication, must be reported 
immediately (within 48 hours) to the study sponsor and / or Synteract, the designated 
CRO.   
 
Each SAE must be followed with appropriate medical management until resolved or 
assessed as chronic or stable regardless of whether or not, in the opinion of the 
Investigator, the event is thought to be related to the study medication.   
 
The Investigator will be required to provide complete information concerning each 
SAE to the CRO and Sponsor within 5 calendar days of the event.  This information 
must be recorded in the patient’s medical record and then transcribed onto the SAE 
Form.  The completed SAE Form (including the Investigator’s opinion of the 
relationship of the SAE to the study medication), copies of related results/reports, 
consultant report(s), and other relevant information will be faxed and mailed to the 
CRO. 
 
In the event of an SAE leading to hospitalization, every effort will be made by the 
investigational site to obtain medical records, including 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.  Any follow-up information 
obtained must be recorded on an SAE follow-up report form. 
 
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), Institutional Biosafety Committee (IBC).  Upon receipt from 
ViroMed of an initial or follow-up IND Safety Report or other safety information, 
the Investigator must promptly notify his or her IRB, IBC. 
 
 
 
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5.4.2. 
SPONSOR’S RESPONSIBILITY 
All AEs and SAEs will be reported on and annual basis to FDA in accordance with 
the IND regulation (21 CFR Part 312).  Per the 2010 FDA Guidance Document for 
Industry and Investigators “Safety Reporting Requirements for  
INDs and BA/BE Studies,” events categorized as ‘possibly’ or ‘probably’ related 
will be treated as ‘suspected adverse reactions.’  Events categorized as ‘definitely’ 
related will be treated as an ‘adverse reaction.’ 
 
All serious, unexpected adverse reactions and suspected adverse reactions will be 
reported to FDA and to all participating investigators as an IND Safety Report 
within 15 calendar days of the event after the sponsor determines that the suspected 
adverse reaction qualifies for reporting (21 CFR §312.32).  Any unexpected fatal or 
life-threatening AEs will be reported to the Agency within 7 calendar days after the 
sponsor’s initial receipt of the information. 
 
Any incidents of neoplasia or retinopathy will be reported to FDA in an expedited 
report (within 7 days of occurrence). 
 
ViroMed will notify all participating investigators of any new safety information that 
alters the current risk-benefit assessment of the study medication or that would be 
sufficient to consider changes in VM202 administration or in the overall conduct of 
the trial. 
 
 
 
 
6. 
STATISTICAL METHODS 
The objective of this Phase II study is to evaluate the safety of IM administration of 
VM202 in subjects with moderate or high-risk CLI (Rutherford Clinical Severity Score 
equal to 4 or 5) who are poor or non- candidates for surgical or percutaneous 
revascularization; and, to evaluate potential bioactivity of IM administration of VM202 in 
subjects with CLI, when compared with placebo, on rest pain (as assessed by frequency of 
rest pain, pain medication use history, sleeping history, and intensity of rest pain) or leg 
ulcer healing (as assessed by ulcer surface area, time to complete healing), perfusion 
(MRA), hemodynamic assessment (ABI & TBI), tissue oxygenation (TcPO2) and the 
incidence and extent of lower leg amputation or other surgical interventions. 
 
6.1. 
GENERAL METHODS 
Means, standard deviations (SD), medians and minimum and maximums will be 
presented for continuous variables, the number and percentage of patients in each 
category will be presented for nominal and ordered categorical variables.  Statistical 
tests with a p value <0.05 will be considered statistically significant, unless 
otherwise stated.   
 
 
 
 
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6.2. 
STUDY ENDPOINTS 
 
6.2.1. 
PRIMARY ENDPOINT 
The primary study endpoint is to assess the difference in pain level between baseline 
and the 9 month follow-up as determined by VAS.  Active and placebo arms will be 
compared to determine treatment effect.  The primary analysis will be conducted in 
the efficacy analysis dataset.  A secondary analysis will be conducted in the ITT 
analysis dataset, and further analyses conducted as necessary to explore any 
inconsistency between the two results. 
 
6.2.2. 
SECONDARY EFFICACY ENDPOINTS 
Other secondary endpoints will include: 
 
• Difference in pain level between baseline and the 9 month follow-up as 
determined by VAS by sex and by comorbidities (esp. diabetes or renal 
dysfunction) 
• Change in tissue oxygenation (TcPO2) from baseline to 6, 9 and 12 months 
following the first treatment 
• Change in hemodynamic measures (ABI and TBI) from baseline to Day 28, Day 
90, 6 months, 9 months and 12 months following the first treatment 
• Change in perfusion (MRA) from baseline to 9 months following the first 
treatment 
• Wound healing (no ulcer: change of skin condition, one ulcer: change of ulcer 
size, multiple ulcer: change of ulcer number) from baseline to 9 months 
following the first treatment 
• Change in VAS score from baseline to Day 14, Day 28, Day 42, Day 90, at 6 
months, 9 months, and 12 months. 
• Change in QOL score (VascuQol) at 90 Days, 9 months and 12 months; 
• Major limb amputation rate at six months and twelve months following the first 
treatment 
• Mortality at six and twelve months after first treatment 
 
6.2.3. 
SAFETY 
Any patient who receives VM202 will be included in the safety analysis population.  
Adverse events (including serious adverse events, and adverse events leading to 
treatment discontinuation) throughout the 12 month follow-up will be described 
according to severity and to their relationship with the study drug and / or device and 
procedure.  Descriptive statistics (N, mean, median, SD, minimum and maximum 
values, where applicable) will be used to characterize safety parameters. 
 
All patients will all undergo testing as presented in the American Cancer Society 
Cancer Screening Guidelines as part of their baseline testing to rule out cancer. 
 
 
 
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6.2.4. 
DATA SAFETY MONITORING AND INTERIM ANALYSES 
For ethical reasons, and to ensure study integrity, an interim examination of key 
safety data will be performed when approximately half of the patients (n=25) have 6 
months data.   The primary objective of this analysis will be to evaluate the 
accumulating data for an unacceptably high frequency of negative clinical outcomes 
in either active treatment arm.  An independent data safety monitoring board 
(DSMB) will perform the review.  The DSMB Chair will review a limited set of 
unblinded tables and listings, including all reported SAEs, monthly through to the 
full DSMB interim analysis (at 25-patients) and then every three months thereafter.  
The DSMB chair may request additional data for review and/or additional meetings 
of the committee as he / she sees fit. 
 
 
 
6.3. 
PATIENT CATEGORIZATION 
Screen Failure - Any patient who was consented and entered into the screening 
process appropriately, but subsequently did not meet the entry criteria in order to be 
treated.  Patients who fail screening will not be followed for safety or efficacy 
assessment, and no other study procedures will be performed. 
 
Evaluable Patient - Any patient who received the study drug. 
 
Lost to follow-up - A patient deemed to be lost to follow-up is any patient who 
received treatment, but who does not complete scheduled study visits.  This includes 
those patients who withdraw consent and refuse further study participation and all 
attempts to contact the patient are deemed unsuccessful. 
 
 
 
 
 
7. 
ACCESS TO STUDY DOCUMENTS AND STUDY MONITORING 
ViroMed has designated Synteract to monitor the progress of this study.  The clinical 
monitor, as a representative of ViroMed, has the obligation to follow this study closely.  In 
addition to conducting a site visit prior to initiation of enrollment, the clinical monitor will 
visit the study facilities regularly, and utilize telephone and written communications on an 
ongoing basis to maintain current knowledge of the study.   
 
During periodic visits to the study site, the monitor will review the source documents used 
in the preparation of the CRFs to verify the accuracy and completeness of the information 
contained in those reports in preparation for retrieval.  All source documents must be dated 
and signed by the person who performed the assessment or procedure, and must contain all 
information required by the CRF.  All data generated during this study and the source 
documents from which they originated are patient to inspection by ViroMed or its 
representative, the FDA and other regulatory agencies. 
 
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Upon completion of the study, the clinical monitor will conduct a final visit (close-out) to 
the site.  The objectives of this visit are to ascertain that all regulatory records and reports 
are complete, verify that study drug and other supplies have been accounted for and ensure 
that the investigator is aware of his/her responsibilities post-study. 
 
 
 
8. 
QUALITY CONTROL AND ASSURANCE 
ViroMed employees and/or their contracted representatives utilize Standard Operating 
Procedures (SOP) designed to ensure that research procedures and documentation are 
consistently conducted/prepared to the highest quality standards.  These SOPs also require 
compliance with Health Authority regulations and Good Clinical Practice guidance. 
 
A Quality Assurance audit may be conducted by ViroMed or its designee at any time 
during or after completion of a study.  The Investigator will be given adequate notice if 
he/she is selected for an audit.  The audit will include, but is not limited to, a review of all 
informed consent forms, a review of CRFs, associated source documents and medical 
records, a review of regulatory documentation, an assessment of study conduct and 
protocol compliance, and a review of the investigational drug accountability.  At the 
conclusion of an audit, the auditor will conduct a brief meeting with the Investigator to 
review the findings of the audit. 
 
 
 
9. 
INSTITUTIONAL REVIEW BOARD 
Prior to the initiation of the study, the protocol, the informed consent form and 
investigator’s brochure will be submitted to the IRB for approval.  By signing the 
"Statement of Investigator" form (form FDA 1572), the investigator is assuring that an IRB 
which complies with the requirements set forth in 21 CFR Part 56 will be responsible for 
the initial and continuing review of the proposed clinical study.  A copy of the IRB 
approval letter for the protocol, the informed consent, and the protocol signature page must 
be submitted to ViroMed or its designee, prior to release of investigational supplies to the 
study site.  The approval letter must refer to the specific protocol and the informed consent 
form.  The study site must maintain an accurate and complete record of all reports, 
documents and other submissions made to the IRB concerning this protocol.  A list of the 
IRB members, their titles or occupations, and their institutional affiliation, or an IRB 
assurance number must be provided to ViroMed or its designee prior to release of study 
supplies. 
 
FDA/relevant health authority regulations require that all advertisements for patient 
recruitment be approved by an IRB prior to implementation.  The complete text and format 
must be submitted to ViroMed or its designee for approval prior to IRB submission. 
 
The investigator is responsible for notifying the IRB of any serious adverse events as 
required by the IRB.  A copy of the notification must be forwarded to ViroMed and to 
Synteract.   
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Status reports must be submitted to the IRB at least once a year (or more frequently as 
required by the IRB) and the IRB must be notified of completion or termination of the 
study.  A final report must be provided to the IRB and ViroMed within 1 month of study 
completion or termination.  This report should include: any deviations from the protocol, 
the number of participants evaluated, the number of participants who withdrew or were 
withdrawn and the reasons for withdrawal, any significant adverse events and the 
investigator's summation of the study. 
 
 
 
10. 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 patient 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. 
 
 
 
11. INFORMED CONSENT PROCESS 
It is the responsibility of the investigator to inform each patient, prior to the screening 
evaluation, of the purpose of this clinical trial, including possible risks and benefits and 
document the informed consent process in the patient’s chart.  A sample informed consent 
form containing the required elements of informed consent is provided in Appendix 2.  Any 
changes made to this sample must be approved by ViroMed or its designee, prior to 
submission to an IRB.  After approval by ViroMed or its designee, the informed consent 
must be submitted to and approved by an IRB.  Prior to entry into the study or initiation of 
any study-related procedures, the patient must read, sign and date the informed consent 
form.  The person executing the consent must also sign and date the final consent form 
page.  Patients will be asked to initial each page of the informed consent form to 
acknowledge awareness of its contents.  One original informed consent form is to be 
retained by the study site and a copy is to be given to the patient.  The informed consent 
process must be documented in the patient’s medical record. 
 
The informed consent must be written in a language in which the patient is fluent.  If a 
foreign language translation is required, a statement of certification of the translation must 
be issued.  Regulations require that foreign language informed consent forms be submitted 
to the IRB for approval.  The investigator must forward a copy of the consent form, the 
certified foreign language translation and an IRB approval letter to ViroMed Co., Ltd. 
 
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12. CONFIDENTIALITY 
In accordance with GCP and with the national data protection laws, all information 
concerning the patients in the study must be treated as strictly confidential by all persons 
involved in the study. 
 
The investigator acknowledges that any and all information acquired from the Sponsor or 
its designee or developed or acquired in connection with the study are strictly confidential.  
The investigator will not disclose any confidential information to any third party nor use 
confidential information for any purpose without first obtaining the consent of Sponsor in 
writing.  Such consent shall be deemed to have been given for disclosure to any person for 
whom the investigator is responsible at his/her center, but only so far as required for the 
purposes of the study, and, in the case of disclosures to staff, only if such staff are bound by 
obligations of confidentiality no less strict than those set out herein. 
 
 
 
13. PROTOCOL AMENDMENTS 
The Sponsor will document modifications to the protocol in the form of a written 
amendment.  Protocol modifications that impact patient safety or the validity of the study 
must be approved by the IRB before implementation.  In the case of a medical emergency, 
to remove immediate apparent hazard to patients, a change may be made preferably after 
discussion with ViroMed or its designee.  In these instances, the IRB and FDA will be 
notified as soon as possible.  
 
 
 
14. DATA MANAGEMENT 
All data relating to study procedures will be entered into CRFs provided by ViroMed or its 
designee.  All requested information must be entered on the CRF.  If an item is not 
available or not applicable this fact should be indicated.   
 
Obvious errors (self evident corrections) will be corrected and documented by ViroMed or 
its designee.  Other errors or omissions will result in queries which will be sent to the 
investigational site on Data Clarification Forms (DCF) for resolution.  A copy of the signed 
DCF is to be kept by the site with the CRFs.  Once the original is received by ViroMed or 
is designee, the resolutions will be reviewed and entered into the database.   
 
Data will be entered into a computer database developed specifically for this trial.  Access 
to the database will be restricted to personnel responsible for data entry and to data 
management and statistics personnel who are directly involved in the management or 
analysis of this trial.  During the course of the trial, data queries will be generated for data 
items that are potentially erroneous and require appropriate clarification or correction.  
Prior to database lock, statistical verification of the data will be undertaken in order to 
further assure data quality. 
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15. RECORD KEEPING AND RETENTION 
Data generated for the study should be stored in a limited-access file area and be accessible 
only to representatives of the study site, ViroMed and its representatives and FDA/relevant 
health authorities/regulatory agencies.  All reports and communications relating to study 
patients will identify patients only by initials and patient identification number.  Complete 
patient identification will be kept by the investigator.  This information will be treated with 
strict adherence to professional standards of confidentiality. 
 
An investigator must in reasonable time, upon request from any properly authorized officer 
or employee of FDA/relevant health authority or regulatory agency, permit such officer or 
employee to have access to requested records and reports, and copy and verify any records 
or reports made by the investigator.  Upon notification of a visit by the FDA/relevant health 
authority or regulatory agency, the investigator will contact ViroMed or its designee 
immediately.  The investigator will also grant ViroMed representatives the same privileges 
offered to FDA/relevant health authority or regulatory agents/officers/employees. 
 
The Investigator must provide Viromed or its designee with the following documents prior 
to study initiation and retain a copy in the study file: 
 
• 
A completed and signed Form FDA 1572.  If during the course of the study any 
changes occur that are not reflected on the 1572, a new 1572 form must be completed 
and returned to Sponsor/CRO for submission to the FDA. 
• 
Current signed curriculum vitae and medical licenses (within 2 years) for the Principal 
Investigator and all co-investigators listed on the 1572. 
• 
A copy of the original approval for conducting the study by the IRB.  Renewals, with 
continuance of the study, must be submitted at yearly intervals or as required by IRB 
policy. 
• 
A copy of the IRB approved informed consent form. 
• 
IRB member list and DHHS General Assurance Number (if IRB has an Assurance 
number). 
• 
Signed Financial Disclosure Form for all personnel listed on the 1572 with a statement 
of non-voting by study staff.   
• 
The signature page of this protocol signed and dated by the Principal Investigator. 
 
In addition to the documents listed above, the study site will also retain the following 
items: 
 
• Certifications and laboratory reference ranges for all local laboratories used for this 
study. 
• All original informed consent forms with required signatures 
• All IRB correspondence (i.e., informed consent [including any approved revisions], 
protocol, AE, advertisements, newsletters) 
• Copy of the Study Monitoring Log Sheet 
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• 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 
• Copies of all SAEs reports submitted to ViroMed and Synteract 
• Copies of all IND Safety Reports submitted to the site by ViroMed 
• Copies of approved package labeling 
• Study personnel signature log 
 
All study-related records must be maintained for at least 2 years after a marketing 
application (NDA/BLA) is approved for the drug; or if an application is not approved for 
the drug, until at least 2 years after shipment and delivery of the drug for investigational 
use is discontinued and FDA/health authorities or regulatory agencies have been notified.  
ViroMed will notify the principal investigator when records are no longer needed.  The 
investigator will not discard any records without notifying ViroMed.  If the principal 
investigator moves from the current investigational site, ViroMed should be notified of the 
name of the person who will assume responsibility for maintenance of the records at the 
investigational site or the new address at which the records will be stored.  The investigator 
will notify ViroMed as soon as possible in the event of accidental loss or destruction of any 
study documentation. 
 
 
 
16. INVESTIGATOR FINAL REPORT 
The investigator shall provide the IRB and ViroMed with an accurate final report within 2 
months after completion, termination or discontinuation of the study.  The final report may 
not precede retrieval of CRFs which have not been monitored. 
 
 
 
17. STUDY REPORT AND PUBLICATION 
The data resulting from this study will be the proprietary information of ViroMed and may 
be made public after all data have been analyzed and the study results are available.  None 
of the data resulting from this study will be allowed to be presented or published in any 
form, by the investigator or any other person, without the prior written approval of 
ViroMed.  At the end of the study, a clinical study report will be written by the Sponsor or 
its designee.   
 
 
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18. REFERENCES 
 
1. 
Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the 
management of patients with peripheral arterial disease (lower extremity, renal, 
mesenteric, and abdominal aortic): a collaborative report from the American Association 
for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular 
Angiography and Interventions, Society for Vascular Medicine and Biology, Society of 
Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing 
Committee to Develop Guidelines for the Management of Patients With Peripheral 
Arterial Disease): endorsed by the American Association of Cardiovascular and 
Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for 
Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease 
Foundation. Circulation 2006;113:e463-654. 
2. 
Criqui MH, Ninomiya JK, Wingard DL, Ji M, Fronek A. Progression of peripheral 
arterial disease predicts cardiovascular disease morbidity and mortality. J Am Coll 
Cardiol 2008;52:1736-42. 
3. 
Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the 
United States: results from the National Health and Nutrition Examination Survey, 1999-
2000. Circulation 2004;110:738-43. 
4. 
Belch JJ, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection 
and management: a call to action. Arch Intern Med 2003;163:884-92. 
5. 
Sethi A, Arora RR. Medical management and cardiovascular risk reduction in peripheral 
arterial disease. Exp Clin Cardiol 2008;13:113-9. 
6. 
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Inter-Society 
Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 
2007;45 Suppl S:S5-67. 
7. 
Malmstedt J, Leander K, Wahlberg E, Karlstrom L, Alfredsson L, Swedenborg J. 
Outcome after leg bypass surgery for critical limb ischemia is poor in patients with 
diabetes: a population-based cohort study. Diabetes Care 2008;31:887-92. 
8. 
Abou-Zamzam AM, Jr., Gomez NR, Molkara A, et al. A prospective analysis of critical 
limb ischemia: factors leading to major primary amputation versus revascularization. Ann 
Vasc Surg 2007;21:458-63. 
9. 
Taylor SM, Kalbaugh CA, Blackhurst DW, et al. Determinants of functional outcome 
after revascularization for critical limb ischemia: an analysis of 1000 consecutive 
vascular interventions. J Vasc Surg 2006;44:747-55; discussion 55-6. 
10. 
Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in severe ischaemia of 
the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005;366:1925-34. 
11. 
Beard JD. Which is the best revascularization for critical limb ischemia: Endovascular or 
open surgery? J Vasc Surg 2008;48:11S-6S. 
12. 
Shah AP, Klein AJ, Sterrett A, et al. Clinical outcomes using aggressive approach to 
anatomic screening and endovascular revascularization in a veterans affairs population 
with critical limb ischemia. Catheter Cardiovasc Interv 2008. 
13. 
Fowkes F, Leng GC. Bypass surgery for chronic lower limb ischaemia. Cochrane 
Database Syst Rev 2008:CD002000. 
14. 
Arain SA, White CJ. Endovascular therapy for critical limb ischemia. Vasc Med 
2008;13:267-79. 
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15. 
Zeller T, Sixt S, Rastan A. New techniques for endovascular treatment of peripheral 
artery disease with focus on chronic critical limb ischemia. Vasa 2009;38:3-12. 
16. 
Schanzer A, Mega J, Meadows J, Samson RH, Bandyk DF, Conte MS. Risk stratification 
in critical limb ischemia: derivation and validation of a model to predict amputation-free 
survival using multicenter surgical outcomes data. J Vasc Surg 2008;48:1464-71. 
17. 
Margolis J, Barron JJ, Grochulski WD. Health care resources and costs for treating 
peripheral artery disease in a managed care population: results from analysis of 
administrative claims data. J Manag Care Pharm 2005;11:727-34. 
18. 
Hirsch AT, Hartman L, Town RJ, Virnig BA. National health care costs of peripheral 
arterial disease in the Medicare population. Vasc Med 2008;13:209-15. 
19. 
Silvestre JS, Levy BI. Angiogenesis therapy in ischemic disease. Arch Mal Coeur Vaiss 
2002;95:189-96. 
20. 
Tang GL, Chang DS, Sarkar R, Wang R, Messina LM. The effect of gradual or acute 
arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat 
hindlimb ischemia. J Vasc Surg 2005;41:312-20. 
21. 
Sellke FW, Ruel M. Vascular growth factors and angiogenesis in cardiac surgery. Ann 
Thorac Surg 2003;75:S685-90. 
22. 
Fuchs S, Dib N, Cohen BM, et al. A randomized, double-blind, placebo-controlled, 
multicenter, pilot study of the safety and feasibility of catheter-based intramyocardial 
injection of AdVEGF121 in patients with refractory advanced coronary artery disease. 
Catheter Cardiovasc Interv 2006;68:372-8. 
23. 
Kastrup J, Jorgensen E, Ruck A, et al. Direct intramyocardial plasmid vascular 
endothelial growth factor-A165 gene therapy in patients with stable severe angina 
pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial. J 
Am Coll Cardiol 2005;45:982-8. 
24. 
Shah PB, Losordo DW. Non-viral vectors for gene therapy: clinical trials in 
cardiovascular disease. Adv Genet 2005;54:339-61. 
25. 
Attanasio S, Snell J. Therapeutic angiogenesis in the management of critical limb 
ischemia: current concepts and review. Cardiol Rev 2009;17:115-20. 
26. 
Kuhlmann MT, Klocke R, Nikol S. Therapeutic angiogenesis for peripheral artery 
disease: cytokine therapy. Vasa 2007;36:253-60. 
27. 
Bussolino F, Di Renzo MF, Ziche M, et al. Hepatocyte growth factor is a potent 
angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 
1992;119:629-41. 
28. 
Nakagami H, Kaneda Y, Ogihara T, Morishita R. Hepatocyte growth factor as potential 
cardiovascular therapy. Expert Rev Cardiovasc Ther 2005;3:513-9. 
29. 
Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J 
Biochem 1996;119:591-600. 
30. 
Jayasankar V, Woo YJ, Pirolli TJ, et al. Induction of angiogenesis and inhibition of 
apoptosis by hepatocyte growth factor effectively treats postischemic heart failure. J Card 
Surg 2005;20:93-101. 
31. 
Gille J, Khalik M, Konig V, Kaufmann R. Hepatocyte growth factor/scatter factor 
(HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured 
keratinocytes. J Invest Dermatol 1998;111:1160-5. 
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32. 
Morishita R, Aoki M, Yo Y, Ogihara T. Hepatocyte growth factor as cardiovascular 
hormone: role of HGF in the pathogenesis of cardiovascular disease. Endocr J 
2002;49:273-84. 
33. 
Jayasankar V, Woo YJ, Bish LT, et al. Gene transfer of hepatocyte growth factor 
attenuates postinfarction heart failure. Circulation 2003;108 Suppl 1:II230-6. 
34. 
Kawaida K, Matsumoto K, Shimazu H, Nakamura T. Hepatocyte growth factor prevents 
acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci U S A 
1994;91:4357-61. 
35. 
Liu ML, Mars WM, Zarnegar R, Michalopoulos GK. Uptake and distribution of 
hepatocyte growth factor in normal and regenerating adult rat liver. Am J Pathol 
1994;144:129-40. 
36. 
Wolff JA, Dowty ME, Jiao S, et al. Expression of naked plasmids by cultured myotubes 
and entry of plasmids into T tubules and caveolae of mammalian skeletal muscle. J Cell 
Sci 1992;103 ( Pt 4):1249-59. 
37. 
Wolff JA, Budker V. The mechanism of naked DNA uptake and expression. Adv Genet 
2005;54:3-20. 
38. 
Malecki M, Kolsut P, Proczka R. Angiogenic and antiangiogenic gene therapy. Gene 
Ther 2005;12 Suppl 1:S159-69. 
39. 
Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events. In: 
CBER, ed. Rockville; 2006. 
40. 
Considerations for Plasmid DNA Vaccines for Infectious Disease Indications. In: CBER, 
ed. Rockville; 2007. 
41. 
Aboyans V, Criqui MH, Denenberg JO, Knoke JD, Ridker PM, Fronek A. Risk factors 
for progression of peripheral arterial disease in large and small vessels. Circulation 
2006;113:2623-9. 
42. 
Morgan MB, Crayford T, Murrin B, Fraser SC. Developing the Vascular Quality of Life 
Questionnaire: a new disease-specific quality of life measure for use in lower limb 
ischemia. J Vasc Surg 2001;33:679-87. 
43. 
de Vries M, Ouwendijk R, Kessels AG, et al. Comparison of generic and disease-specific 
questionnaires for the assessment of quality of life in patients with peripheral arterial 
disease. J Vasc Surg 2005;41:261-8. 
 
 
 
 
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APPENDICES 
 
 
 
 
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TABLE OF APPENDICES 
 
 
Appendix 1. 
Schedule of Evaluations and Visits ............................................................... 59 
Appendix 2. 
Sample Informed Consent ............................................................................ 61 
Appendix 3. 
MRA (select sites only) ................................................................................ 77 
Appendix 4. 
Test Article Administration .......................................................................... 80 
Appendix 5. 
VascuQol ..................................................................................................... 83 
Appendix 6. 
Guidelines for the Early Detection of Cancer ................................................ 87 
 
 
 
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Appendix 1. 
Schedule of Evaluations and Visits 
 
 
 
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SCHEDULE OF EVALUATIONS AND VISITS 
 
PROCEDURE 
Screening / 
Baseline 
(-60 – 0 D) 
1st Injection 
Day 0 
2nd Injection 
Day 14 ± 3 D 
3rd Injection 
Day 28 ± 3 D 
4th Injection 
Day 42 ± 3 D 
Day 49 
± 3 D 
Day 90 
± 7 D 
6 mo 
± 1 mo 
9 mo 
± 1 mo 
12 mo 
± 1 mo 
Early 
Withdrawal 
Pre-
dose 
Post-
dose 
Pre-
dose 
Post-
dose 
Pre-
dose 
Post-
dose 
Pre-
dose 
Post-
dose 
Baseline Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer screening† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral screening – HIV, HTLV, 
HBV, HCV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety and Efficacy Parameters 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retinal Fundoscopy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry and hematology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copies of VM202 in whole blood 
 
 
** 
 
 
 
 
 
** 
 
 
 
 
 
1 
Serum HGF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Visual Analog Scale (VAS) score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VascuQol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABI & TBI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TcPO2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Photograph and measurement of 
ulcer(s)†† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rutherford Classification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRA (at designated site(s) only) ††† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection site reaction assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
† 
Includes: cancer markers (carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), CA19-9, and CA125 (females only)); chest X-ray or CT scan of the chest (if patient has a previous history 
of tobacco use, a CT scan will be performed instead of the chest X-ray) within 3 months; pap smear and mammogram if not performed within past 12 months (females only); PSA (males 
only); for patients ≥ 50 years old, colonoscopy within past 10 years 
†† If present prior to first study drug administration 
††† 7 days prior to Day 0; ±7 days to Month 6 and Month 9 
** 2 hours after injection (± 1 hour) 
1 
If withdrawal occurred before Day 90 Visit 
2 
If withdrawal occurred before Day 49 Visit 
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Appendix 2. 
Sample Informed Consent 
 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
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TITLE:  A Phase II, Double-blind, Randomized, Placebo-controlled, Multicenter Study to 
Assess the Safety and Efficacy of VM202 in Subjects with Critical Limb Ischemia  
Protocol #: VMCLI-II-09-002 
 
SPONSOR:  
ViroMed Co., Ltd.  
2221 Peachtree Rd. NE Suite D258  
Atlanta GA 30309  USA 
www.viromed.co.kr/eng/index.asp  
Worldwide Headquarters: 
D203 Inter-University Research Bldg. 5th Fl 
Seoul National University 
599 Gwanak-ro, Gwanak-gu 
Seoul 151-742 Korea 
 
 
PRINCIPAL 
INVESTIGATOR: 
[INSERT NAME AND TITLE] 
 
 
INSTITUTION: 
 
[INSERT INSTITUTION NAME AND ADDRESS] 
 
 
SUBJECT INITIALS: 
[INSERT SUBJECT’S INITIALS] 
SUBJECT NUMBER: 
[INSERT SUBJECT’S UNIQUE STUDY NUMBER] 
 
 
You are being asked to participate in a research study sponsored by ViroMed Co., Ltd.  Before 
you decide whether to participate, it is important for you to know why the research is being done, 
and what it will involve.  Please take your time to read the following information carefully, and 
feel free to discuss your decision with your family, friends, and your primary care doctor.  Please 
ask your study doctor to explain if there is anything that is not clear or if you would like more 
information.  If you agree to take part in this study, you need to sign this consent form.  Your 
signature on this form means that you have been told about and understand the purpose of the 
study, procedures to be followed, and any benefits or risks.  Your signature on this form also 
means that you want to take part in this study if you meet the criteria, based on the results of 
your medical tests, which must be done before you are asked to continue your participation in the 
study.  After you agree, you will be provided with a copy of this signed form for your records.   
 
Do I have to take part? 
Taking part in this study is entirely voluntary, and you may refuse to participate or withdraw 
from the study at any time without influencing your regular medical treatment and without 
giving a reason.  A decision to withdraw at any time, or a decision not to take part, will not affect 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
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Page 63 of 90 
the standard of care you receive.  Regardless of your decision, you will still be treated for your 
medical condition.   
 
Why is this study being done? 
You are being considered to participate in this research study because you have critical limb 
ischemia and are not a good candidate for a revascularization procedure.  
 
Because the blood vessels in your body have narrowed or become blocked, not enough blood 
flows to your legs, causing pain, swelling, and possibly an infection that is slow to heal.  The 
growth of new blood vessels to supply blood to your limbs would help increase blood flow that 
may reduce pain, swelling, and infection.  Stimulating the growth of new blood vessels may also 
stimulate growth or regeneration of nerves and may reduce pain. Researchers have discovered 
that a protein called hepatocyte growth factor (HGF) that your body naturally produces in small 
amounts can cause the growth of new blood vessels and protect nerves.  Unfortunately, your 
body only makes a small amount of this protein and not always in the areas where you need it.  
Researchers have found a way to increase the amount of HGF in your legs.  They have isolated 
the genes responsible for directing the production of HGF, and have designed a product that can 
be injected into your leg. 
 
In the research study the HGF gene will be injected into your calf muscle cells to evaluate if it 
changes your pain related to critical limb ischemia.  The product being used in this study is 
called VM202.  VM202 is an experimental drug that is not yet approved by regulatory authorities 
(the US Food and Drug Administration [FDA]).  VM202 is a plasmid (a small piece of DNA), 
which includes the HGF genes.  VM202 has been used in a study in Korea in patients with 
coronary artery disease and in another study in the United States in patients with critical limb 
ischemia (decreased blood flow to the legs).  VM202 has also been tested in people undergoing 
coronary bypass surgery.  It is hoped that VM202 injected into your calf muscle will increase the 
blood flow to your foot ant reduce pain.  This study will examine whether VM202 injected into 
your leg is safe and tolerable at either low or high dose, and also will collect preliminary 
information about whether the plasmid increases HGF and relieves your critical limb ischemia. 
This study is intended to help determine: 
• The safety and tolerability of a low and high dose of VM202; and, 
• if VM202 can improve your critical limb ischemia and reduce your pain.   
 
VM202 will be injected into your calf muscle using a syringe with a fine needle.  Only one leg 
will be treated in this study.   
 
Who is in charge of this study? 
The Principal Investigator is [INSERT PRINCIPAL INVESTIGATOR NAME].  This study is 
sponsored and funded by ViroMed Co., Ltd.  [insert PRINCIPAL INVESTIGATOR NAME] is 
being paid by ViroMed Co., Ltd. to conduct this study.  Together with your doctor, ViroMed 
Co., Ltd. will also use a specialized research company, called a contract research organization, in 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
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Page 64 of 90 
addition to specialized laboratories to manage some parts of the detailed requirements of the 
study.   
 
How many people will take part in this research study? 
A total of 50 patients will take part in this study at up to 20 hospitals in the United States.   
 
What happens if I agree to be in this research study? 
After you sign this consent form indicating you want to participate in this study, you will need to 
undergo some tests done to see if you qualify for the study.  The list of the tests that will be done 
are listed below.  If you do not meet all of the study entry criteria, you will not be able to 
participate in the study and your doctor will discuss with you other options that you may have for 
treatment of your medical condition.  The study doctor will tell you whether you are able to 
participate in this study after the initial test results are received and reviewed.   
 
This study is a double-blind, placebo-controlled, randomized clinical study.  If you agree and are 
medically eligible to participate you will be “randomly” assigned (like drawing numbers out of a 
hat or flipping a coin) to one of three groups as listed below.  “Double-blind” means that you and 
your doctor will not know the treatment you are getting in the study.  However, your doctor can 
find out if needed.  “Placebo controlled” means not all participants will be assigned to a 
treatment group that will receive the study drug.  Some participants may only receive saline 
injections.  What group you are assigned to is done by a computer and is not known by your 
doctor until the study is completed.   
 
You will be randomly assigned to one of three possible study groups:   
 
• Low Dose VM202 Treatment Group – if you are selected for this group, you will receive 8 
mg of VM202 over the course of the first two injection visits (4 mg of VM202 at the Day 0 
visit and 4 mg of VM202 at the Day 14 visit).  Each individual injection contains 0.5 mL of 
fluid with 0.25mg VM202.  You will receive 16 injections for a total of 8 milliliters (8 mL) 
of VM202 (which is about a teaspoon and a half of fluid) at the first two injection visits.  On 
the next two injection visits (Day 28 and Day 42) you will receive saline injections (sixteen 
0.5 mL injections for a total of 8 mL at each injection visit).  Approximately forty percent of 
patients will be selected for this group.   
 
• High Dose VM202 Treatment Group – if you are selected for this group, you will receive 16 
mg of VM202 over the course of the four injection visits (4 mg of VM202 at the Day 0 visit, 
4 mg of VM202 at the Day14 visit, 4 mg of VM202 at the Day 28 visit, and 4 mg of VM202 
at the Day 42 visit).  Each individual injection contains 0.5 mL of fluid with 0.25mg VM202.  
You will receive a total of 8 milliliters (8 mL) of VM202 (which is about a teaspoon and a 
half of fluid) at each of the four injection visits.  Approximately forty percent of patients will 
be selected for this group.   
 
• Placebo Control Group – if you are selected for this group, you will not receive VM202.  
You will only receive injections of saline.  At each of the four injection visits, you will 
receive sixteen injections of 0.5 mL of saline for a total of 8 milliliters (8 mL) of saline 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
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Page 65 of 90 
(which is about a teaspoon and a half of fluid).  Approximately twenty percent of patients 
will be selected for this group.   
 
All patients (regardless of which group they assigned to) will receive sixteen 0.5 mL injections at 
each of the four injection visits.   
 
 
What tests, procedures, and diagnostic studies will be done during this study?  
There are 10 visits which span 12 months total time from visit #2 to visit #10.  Depending on the 
visit, different tests will be done.  Visit #1 may actually take more than one visit to accomplish 
depending on how many tests can be scheduled on that first day, but is usually completed within 
a few weeks before the first injection procedure (Visit #2).  Below is a detailed description of 
each of the required visits and the laboratory tests, procedures, and evaluations that will be done 
during the visits.   
 
Description of the tests, procedures, and diagnostic studies to be done  
 
Medical history – Discussion with your doctor of your medical history, including diabetes 
history and any changes that have happened.   
 
Physical exam – Your doctor will examine you.  This exam includes taking your sitting blood 
pressure, temperature, and heart rate (vital signs).   
 
Photograph and Measurement of Ulcer – any ulcerations or gangrenous areas present prior to 
the first injection will be photographed. 
 
Medication Review – Discussion with your doctor of what medications and dietary supplements 
you have taken or are currently taking.   
 
Assessment of critical limb ischemia – Assessment by your doctor of the condition of your feet 
and legs, your reflexes, and sensitivity to touch. 
 
Injection site reaction assessment – Assessment by your doctor of any pain or other reaction at 
the locations where VM202 was injected. 
 
Assessment of side effects – Assessment by your doctor of any unpleasant medical experiences, 
side effects, or discomforts that may have happened to you.   
 
Questionnaire – You will be asked to fill in a short questionnaire about feeling in your legs and 
feet at Screening.  You will be asked to complete brief questionnaires about pain in your feet and 
legs at some visits. 
 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
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Cancer Screening – Cancer screening includes testing for cancer markers; pap smear and 
mammogram if not performed within past 12 months (females only); PSA (males only); for 
patients ≥ 50 years old, colonoscopy within past 10 years; and x-ray or CT scan of chest. 
 
Retinal Fundoscopy – An ophthalmologist may dilate your pupils and perform a retinal 
examination with retinal photographs at Screening.  If your ophthalmologist determines that a 
more detailed image of the blood vessels in your eye is necessary to determine if you are eligible 
for study participation, he / she may conduct another test called fluorescein angiography.   This 
involves injecting a dye into a vein in your arm; the dye then circulates through the bloodstream 
and to the blood vessels of your eye.  Retinal photographs of the back of your eye will be taken 
again at 12 months, but the fluorescein angiography will not be repeated.  If dilating eye drops 
are used, they may impair focusing of the eyes for several hours. Therefore, arrangements should 
be made for someone else to drive after the examination. Wearing sunglasses or tinted lenses 
may make dilated pupils more comfortable.  You should tell the examiner if you are allergic to 
any medications, are taking any medications, or have glaucoma or a family history of glaucoma.   
 
Pregnancy test – If you are a female of child bearing age, you will have a urine pregnancy test 
done to confirm that you are not pregnant.  You cannot participate if you are pregnant or plan to 
become pregnant during the course of the trial.   
 
12 Lead ECG – An electrocardiogram (ECG) is a measurement of your heart’s electrical activity 
that is traced and sent to a machine, which can be read by your doctor.  This procedure is not 
painful and involves lying as still as possible for a few minutes with sticky pads (electrodes) on 
your chest, arms and legs which are connected through wires to the ECG machine.  This test 
typically takes approximately 15 to 20 minutes. 
 
Urine and blood tests – Routine urine and blood tests will be done at certain visits.  Laboratory 
tests will also include testing for VM202 and HGF levels in the blood at certain visits.  The 
screening evaluation laboratory tests will include viral tests for various diseases including HIV 
(the AIDS virus), HTLV (human T-cell lymphotropic virus), hepatitis B (HBV), and hepatitis C 
(HCV).  
 
Measuring blood pressure in your leg (ABI & TBI) – The ankle-brachial index (ABI) and the 
toe-brachial (TBI) index is the ratio of the blood pressure in the lower legs to the blood pressure 
in the arms. Compared to the arm, lower blood pressure in the leg is a symptom of blocked 
arteries.  Blood pressure measurements are taken at the arms and ankles or toes. You may 
experience some minor discomfort associated with compressing the artery with the cuff.  It will 
last only a few seconds. 
 
Transcutaneous oxygen pressure (TcPO2) – Transcutaneous oxygen pressure (TcPO2) is a 
measurement of how much oxygen reaches your skin.  It requires that a small device be placed 
on the skin for 15 – 20 minutes.  There is no pain or risk associated with this procedure. 
 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 67 of 90 
Additional imaging study – One to two hospitals in this study will be conducting an additional 
imaging test called magnetic resonance angiogram (MRA).  This study is being done to 
determine how well blood is flowing through your legs.  An MRA is a type of magnetic 
resonance imaging (MRI) scan that uses a magnetic field and pulses of radio wave energy to 
provide pictures of blood vessels inside the body.  With MRA, both the blood flow and the 
condition of the blood vessel walls can be seen.  You will lie on your back on a table that is part 
of an MRI scanner.  Your leg may be held with straps to help you remain still.  The table will 
slide into a space that contains the magnet.  Some MRI machines (open MRI) are now made so 
that the magnet does not surround the person being tested. Open MRI is less confining than a 
standard MRI but may not provide the same quality of image.  Inside the scanner, you may hear 
a fan and feel air moving.  You may also hear tapping or thumping noises as the MRA scans are 
taken.  You may want to ask for ear plugs to reduce the noise.  If contrast material is needed, the 
technologist will put it in an IV in your arm. The material may be given over 1 to 2 minutes. 
Then more MRI scans are done.  An MRA test usually takes 30 to 90 minutes but can take as 
long as 2 hours. 
 
Visit # 1: Screening/Baseline Evaluations 
Screening is a process of evaluating your initial health status and assessing the status of your 
critical limb ischemia.  Screening is usually completed within one month before the first study 
injections if you qualify for this study.  If you agree to take part in this research study, you will 
first sign this consent form, and then undergo screening.  Screening will involve the following 
procedures:  medical history, physical exam, medication review, questionnaire, assessment of 
critical limb ischemia, cancer screening, retinal fundoscopy; urine and blood tests including a 
viral screen; ABI & TBI, TcPO2, photograph and measurement of ulcer, pregnancy test (if you 
are a female), and 12 lead ECG. 
 
Please note:  If any of your viral test results are positive you may need to have a second test done 
to make sure the results are the same.  The doctor or his/her nurse will tell you how to find 
medical help and counseling as needed, and you will not be able to take part in this study.  The 
study sponsor will not pay for the cost of the repeat tests, or any other follow-up medical care, or 
counseling for a positive or abnormal test result.   
 
It takes approximately one to two weeks to get all of the initial test results.  After your doctor has 
reviewed the results of these tests he/she will determine whether you are eligible for participation 
in the study.  If you are eligible for the study and you do wish to continue, you will be assigned 
by chance (randomly) to either one of the groups to receive VM202 (low or high dose) or the 
placebo control group.  You will then be scheduled for the first set of injections which will be 
done at your next visit (Visit #2). 
 
Visit # 2 – First Injection Procedure (injection of VM202 or Placebo into the calf muscle) 
 
Before Injection Procedure:  
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 68 of 90 
The following tests will be performed before you have your injection procedure done:  
medication review, questionnaires, ABI & TBI, TcPO2, vital signs, photograph and measurement 
of ulcer, MRA (only if your hospital is participating in the small sub-study), and blood tests 
including HGF and VM202. 
 
VM202 Injection Procedure:   
The injection procedure will be done in your doctor’s office.  The doctor will use a syringe with 
a fine needle to inject 0.5 mL of VM202 solution or placebo at 16 sites evenly distributed over 
your calf muscle. 
 
Each injection will take 20 – 30 seconds.  Each site will be marked with an indelible marker.  
The entire injection procedure is expected to take 30 – 60 minutes. 
 
After Injection Procedure:  
After the injection procedure is performed, the following tests and/or evaluations will be done:  
vital signs, injection site reaction assessment, VM202 blood test, blood tests including HGF and 
VM202, and assessment of side effects. 
 
Before you go home detailed discharge instructions about what you need to do to take care of 
yourself, what medications you should take, and who to call if you have a problem after you 
leave the clinic, will be reviewed with you by the nurse and/or doctor. 
 
Research personnel will be on call anytime to answer any questions that you may have and 
respond to reports you may have of any symptoms.   
 
 
Visit # 3 – Second Injection Procedure (14 Days After the First Injection Procedure) 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  
medication review, questionnaire, vital signs, photograph and measurement of ulcer, injection 
site reaction assessment, and assessment of side effects, and blood tests. 
 
VM202 Injection Procedure:   
The injection procedure will be done in your doctor’s office.  The doctor will use a syringe with 
a fine needle to inject 0.5 mL of VM202 solution or placebo at 16 sites evenly distributed over 
your calf muscle.  If the marks made to identify the first injection sites are still visible, they will 
guide the doctor to inject at locations that were not injected previously.   
 
Each injection will take 20 – 30 seconds.  Each site will be marked with an indelible marker.  
The entire injection procedure is expected to take 30 – 60 minutes. 
 
After Injection Procedure:  
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 69 of 90 
After the injection procedure is performed, the following tests and/or evaluations will be done:  
vital signs, injection site reaction assessment, and assessment of side effects. 
 
Before you go home you will receive detailed discharge instructions.  
 
 
Visit # 4 – Third Injection Procedure – Day 28 (14 Days After the Second Injection 
Procedure) 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  
medication review, questionnaire, vital signs, photograph and measurement of ulcer, ABI & TBI, 
injection site reaction assessment, and assessment of side effects, and blood tests. 
 
VM202 Injection Procedure:   
The injection procedure will be done in your doctor’s office.  The doctor will use a syringe with 
a fine needle to inject 0.5 mL of VM202 solution or placebo at 16 sites evenly distributed over 
your calf muscle.  If the marks made to identify the second injection sites are still visible, they 
will guide the doctor to inject at locations that were not injected previously.   
 
Each injection will take 20 – 30 seconds.  Each site will be marked with an indelible marker.  
The entire injection procedure is expected to take 30 – 60 minutes. 
 
After Injection Procedure:  
After the injection procedure is performed, the following tests and/or evaluations will be done:  
vital signs, injection site reaction assessment, and assessment of side effects. 
 
Before you go home you will receive detailed discharge instructions.  
 
 
Visit # 5 – Fourth/Last Injection Procedure – Day 42 (14 Days After the Third Injection 
Procedure) 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  
medication review, questionnaire, vital signs, photograph and measurement of ulcer, injection 
site reaction assessment, and assessment of side effects and blood tests including HGF and 
VM202. 
 
VM202 Injection Procedure:   
The injection procedure will be done in your doctor’s office.  The doctor will use a syringe with 
a fine needle to inject 0.5 mL of VM202 solution or placebo at 16 sites evenly distributed over 
your calf muscle.  If the marks made to identify the second injection sites are still visible, they 
will guide the doctor to inject at locations that were not injected previously.   
 
VM BioPharma 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 70 of 90 
Each injection will take 20 – 30 seconds.  Each site will be marked with an indelible marker.  
The entire injection procedure is expected to take 30 – 60 minutes. 
 
After Injection Procedure:  
After the injection procedure is performed, the following tests and/or evaluations will be done:  
vital signs, VM202 blood test, injection site reaction assessment, and assessment of side effects. 
 
Before you go home you will receive detailed discharge instructions.  
 
Visit # 6 –Day 49 (7 days after the fourth/last injection procedure) 
At this visit, the following tests or evaluations will be done:  medication review, vital signs, 
photograph and measurement of ulcer, blood tests including HGF and VM202, injection site 
reaction assessment, and assessment of side effects. 
 
Visit # 7 – Day 90 
At this visit, the following tests or evaluations will be done:  medication review, vital signs, 
questionnaires, ABI & TBI, photograph and measurement of ulcer, blood tests including HGF 
and VM202, and assessment of side effects. 
 
Visit # 8 – 6 months 
At this visit, the following tests or evaluations will be done:  medication review, vital signs, 
questionnaire, ABI & TBI, TcPO2, MRA (if applicable to your hospital), photograph and 
measurement of ulcer, blood tests including VM202, and assessment of side effects. 
 
Visit # 9 – 9 months 
At this visit, the following tests or evaluations will be done:  medication review, vital signs, 
questionnaires, ABI & TBI, TcPO2, MRA (if applicable to your hospital), photograph and 
measurement of ulcer, MRA (only if your hospital is participating in the small sub-study), blood 
tests, and assessment of side effects. 
 
Visit # 10 – 12 months – Final Visit 
At this visit, the following tests or evaluations will be done:  medication review, vital signs, 
questionnaires, ABI & TBI, TcPO2, photograph and measurement of ulcer, blood tests, and 
assessment of side effects. 
 
After you have completed your 12-month follow-up visit, you do not have to return for any more 
visits. 
 
How long will I be in this research study? 
Your last follow up visit will be approximately 12 months after your first injection procedure.  
After this visit, you will have completed this study. 
 
What do I have to do as a participant in this study? 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 71 of 90 
Participation in this study requires you to make sure that you are available to attend all your 
scheduled visits.   
 
During your participation in the study you will be asked to report any unpleasant medical 
experiences that you may have.   
 
You must not use any additional prescription medication during the treatment period without 
first checking with your study doctor.  If you use any non-prescription medication you should 
inform your doctor of the details (medication, dose, etc.) at each study visit.   
 
You also must not participate in any other clinical trial while participating in this study.   
 
What about my rights to decline participation or withdraw from the study? 
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw 
from the study at any time.  If you withdraw from the study, no new data about you will be 
collected for study purposes unless the data pertain to a side effect related to the study.  If such 
an event occurs, we may need to review your entire medical record.   
 
Your decision not to participate or to withdraw from the study will not involve any penalty or 
loss of benefits to which you are entitled, and will not affect your access to health care.  If you do 
decide to stop your participation in the study, you should talk to your doctor immediately so 
he/she can advise you of any additional tests that may be needed for your safety.  Your doctor 
may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if he/she determines that it is no longer in your best interest to continue.  The Sponsor 
or regulatory agencies may stop this study at anytime without your consent.  If this occurs, you 
will be notified and your study doctor will discuss with you other options you may have.   
 
What are the risks of this research study? 
There are known risks and discomforts involved in some of the tests and evaluations.  There are 
also unknown risks.  Below is a description of these risks.   Your doctor will discuss the risks 
and procedures with you before you start in the study.   
 
Risks from Injection Procedures 
VM202 will be injected into the calf muscles using a fine needle.  There may be some pain at the 
injection site at the time of injection.  There may be swelling, bruising or inflammation near the 
injection site.  You may experience an increase in the level of pain in the treated leg.  There may 
be a risk of an allergic reaction (anaphylaxis), fever or tissue damage from the injection 
(ulceration, necrosis).  Because HGF has the potential to create new blood vessels 
(angiogenesis), there may be risk of promoting tumor growth (cancer) or of increasing the 
number of blood vessels in the back of your eye and damaging your retina (retinopathy).   
 
Risks to women who can get pregnant or are breastfeeding 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 72 of 90 
Being a part of this study while pregnant may expose the unborn child to significant risks.  
Therefore, pregnant women cannot take part in this study.  If you are a woman who can get 
pregnant, a urine pregnancy test will be done and it must show that you are not pregnant before 
you can participate in this study.  You must also agree not to become pregnant during this study.  
You may not take part in this study if you are breastfeeding.  If sexually active, you must agree 
to use an acceptable method of birth control for the whole study.   
 
The following birth control measures are acceptable:  
• Barrier type devices (examples are condom, diaphragm, and contraceptive sponge) used only 
in combination with a spermicide; 
• Intrauterine device (IUD); 
• Birth control pills 
• Depo-provera (medroxyprogesterone acetate); 
• Levonorgestrel implants; 
 
Abstention, the rhythm method, and/or contraception by the partner are not acceptable methods 
of contraception.   
 
If you do become pregnant during this study or think that you might be pregnant, you must 
inform your study doctor immediately.  If this happens, the study doctor will discuss with you 
what you should do.  If you get pregnant, you will be asked to stop taking part in the study and 
you will be asked for information about the pregnancy and the baby.   
 
Risks from taking a blood sample 
You will have routine blood samples taken from a vein in your arm by a needle stick.  Risks 
associated with drawing blood from your arm include slight discomfort and/or bruising.  
Infection, bleeding, clotting, or fainting are also possible, although unlikely.  The number of 
times that you will have a blood sample drawn for this study totals about 12 times over 
approximately 13 months.  Each time your blood is drawn roughly 1 to 2 tablespoons of blood 
will be taken.   
 
Risks from cancer screening 
Cancer screening includes testing for cancer markers; pap smear and mammogram if not 
performed within past 12 months (females only); PSA (males only); for patients ≥50 years old, 
colonoscopy within past 10 years; current fecal occult blood test; and x-ray or CT scan of chest.  
Possible risks include  a small amount of radiation exposure from a chest x-ray (or chest CT 
scan, if you have a history of smoking) and mammogram (if you are female), discomfort 
associated with pap smear and mammography (if you are female), and risks associated with 
taking a blood sample (as described above).  Possible risks from colonoscopy may include:  
bowel perforation (a hole or tear in the wall of the colon) requiring a repair operation (fewer than 
1 out of 1,000 tests), heavy or persistent bleeding from biopsy or polyp-removal sites (1 out of 
1,000 tests), adverse reaction to sedative medication causing breathing problems or low blood 
VM BioPharma 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 73 of 90 
pressure (4 out of 10,000 tests), infection requiring antibiotic therapy (very rare), and nausea, 
vomiting, bloating, or rectal irritation caused by medicines taken by mouth to cleanse the bowel. 
 
Risks from Retinal Fundoscopy  
The test itself involves no risk.  If dilating eye drops are used, they may produce a brief stinging 
sensation when put in the eyes and a medicinal taste in the mouth caused by the medication 
draining from the tear ducts into the throat.  Dilating eye drops rarely produce nausea, vomiting, 
dryness of the mouth, flushing, dizziness, or an attack of narrow-angle glaucoma.  If glaucoma is 
suspected, drops generally are not used.  
 
Risks from Fluorescein Angiography(if deemed necessary by the ophthalmologist)  
Side effects associated with injection of fluorescein dye into a vein in the arm include nausea 
and/or vomiting (approximately 5% of patients) hives and itching (approximately 0.5% of 
patients) and rarely, a life threatening allergic reaction, consisting of possible seizures and 
difficulty in breathing (less than 0.01%).  There may be a local temporary discomfort at the site 
of injection. 
 
Risks from ECG  
In rare circumstances, a rash or irritation at the location of the electrocardiogram electrode 
placement can occur due to the adhesive.  If this should occur it will be assessed and treated 
using clinical standards of care with appropriate medication(s) and/or compresses. 
 
Unknown risks 
In addition to the risks already described, there may be other discomforts or risks from this study 
drug and/or procedures that we do not know about.  You will be watched for signs and symptoms 
of any side effects and you should tell your doctor if you do not feel well or experience any 
unusual symptoms.   
 
 
Are there benefits to taking part in this research study? 
There may be no direct benefit to you by participating in this study.  However, it is possible that 
the pain related to your critical limb ischemia will improve. Knowledge from this study may help 
us better understand how to treat people with critical limb ischemia.     
 
What if new information becomes available? 
If additional data regarding potential safety risks become available during the study, your 
research doctor will tell you about it and discuss with you whether you want to continue in the 
study.  If you decide to withdraw from the study, your research doctor will make arrangements 
for your care to continue.  If you decide to continue in the study you may be asked to sign an 
updated consent form which will explain the new information clearly.   
 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 74 of 90 
Also, on receiving new information your research doctor might consider it to be in your best 
interests to withdraw you from the study.  He/she will explain the reasons and arrange for your 
care to continue.   
 
Will I need to pay for the tests and procedures? 
Participation in this study will be of no cost to you.  All medical exams, urine and blood tests, 
and study evaluations and procedures that are required for this research study are provided to you 
at no cost to you.  You will also not need to pay for the VM202 product injections.  ViroMed 
Co., Ltd. pays for this research.  However, if taking part in this study leads to procedures or care 
not included in this study, it may lead to added costs for you or your insurance company.   
 
What happens if I am injured because I took part in this research study? 
In the event of an injury resulting from your participation in this study, you will be provided with 
appropriate medical care.  However the costs incurred may, ultimately, be borne by your medical 
insurance.  Further information concerning this and your rights as a research subject can be 
obtained from [INSERT NAME OF PRINCIPAL INVESTIGATOR] or by phone [INSERT 
PHONE NUMBER] or by mail [INSERT MAILING ADDRESS].   
 
What are my rights if I take part in this research study? 
You have the right to refuse to sign this consent.  Taking part in this research study does not take 
away any other rights or benefits you might have if you did not take part in the study.  Taking 
part in this study does not give you any special privileges.  You will not be penalized in any way 
if you decide not to take part or if you stop after you start the study.  Specifically, you do not 
have to be in this study to receive or continue to receive medical care from your doctor.  If you 
stop the study you would still receive medical care for your condition although you would not be 
able to get the VM202 product.   
 
For any questions pertaining to your rights as a research subject, you may contact [PROVIDE 
CONTACT NAME] of the Institutional Review Board [PROVIDE NAME OF IRB AND 
CONTACT PHONE NUMBER].   
 
What about confidentiality? 
The personal information obtained about you during the course of this study will remain 
confidential.  When recording the results of the study you will be referred to only by a unique 
patient identifier code number and your initials.  Except when required by law, you will not be 
identified by name, social security number, address, telephone number, or any other direct 
personal identifier in study records.   
 
Your records may be reviewed in order to meet Federal Food and Drug Administration (US 
FDA) regulations, or other national and/or local health regulatory authorities.  Your records may 
be copied by, or for these groups.  If your research record is reviewed by any of these groups, 
they may also need to review your entire medical record.  Copies of the study records that do not 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 75 of 90 
include your name, but may be traced back to you may also be given to the groups listed below.  
The Sponsor may send a copy of the records to the FDA or other regulatory agencies.   
 
By agreeing to participate in this research study, you consent to give representatives of the 
following entities access to your research-related medical records to ensure the proper conduct of 
the research and verify the accuracy of the collected data.  Clinical monitors, auditors, IRB 
members, and regulatory authorities will be granted access to your original medical records for 
verification of clinical trial procedures and/or data, without violating your confidentiality, to the 
extent permitted by the applicable laws and regulations.   
 
Reviewers for the study may include the Sponsor (ViroMed Co., Ltd.), or its representatives such 
as members of the Steering Committee, Executive Committee or Data Monitoring Committee, 
the Contract Research Organization identified as, Synteract and the IRB or other Research 
Committee(s) that approve and oversee research in the hospitals and clinics.  Additionally, 
representatives of national regulatory authorities (for example the Food and Drug Administration 
in the USA), representatives of the central laboratory facilities appointed by the Sponsor 
responsible for analyzing the urine and blood tests, and other representatives as designated by the 
Sponsor who will have a role in the handling and analysis of the study data or in trial operations.   
 
Complete confidentiality cannot be promised because information needs to be shared as 
described.  However, information will be collected and shared following professional standards 
of confidentiality.   
 
What will happen to the results of this study? 
The results of this research study will be used to support an application to regulatory agencies 
that approve drugs for use on prescription.  In addition, the results may be used in scientific 
publications or presented at medical meetings.  Your identity as a participant will not be 
revealed.   
 
Who has reviewed this study? 
The study has been reviewed by the FDA, an IRB and/or research ethics committee(s). 
 
Who can answer my questions? 
You may talk to the study doctor or IRB at any time about any questions or concerns you have 
on this study.  A copy of this form will be placed in your medical record.  A copy of this form 
will also be given to you.   
 
What alternatives are there to participation in this study?   
You do not have to take part in this study to receive treatment for critical limb ischemia.  If you 
decide not to take part in this study, there are other treatments for critical limb ischemia, which 
include surgery, angioplasty, amputation, skin grafting, and medications such as aspirin, 
clopidogrel (Plavix), and cholesterol-lowering agents such as atorvastatin (Lipitor).  Your doctor 
will discuss these other treatments with you. 
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SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE II, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
(PROTOCOL VMCLI-II-09-002) 
 
 
Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 76 of 90 
. 
STATEMENT OF CONSENT 
 
I confirm that I have read and understand this consent form.  I confirm that the purpose of this 
study, procedures to be followed, risks and benefits have been explained to me.  I have been 
allowed to ask questions, and my questions have been answered to my satisfaction.  I have 
decided of my own free will to agree to take part in this study.   
 
I understand that my participation is voluntary and that I am free to withdraw at any time, 
without giving any reason, and without my medical care or legal rights being affected.   
 
I understand that sections of any or all of my medical records may be reviewed by 
representatives of the Sponsor, ViroMed Co., Ltd., its subcontractors, or by regulatory authorities 
where it is relevant to my taking part in this research.  I give permission for these individuals to 
have access to my records.  I understand that I will not be referred to by name in any report 
concerning the study.  I agree to disclosure of such records and any results to the regulatory 
authorities.   
 
I understand that I will be provided clinically appropriate medical care and that I have access to 
my doctor in case of any injury or deterioration in my health or well-being caused directly by my 
participation in this study.   
 
 
 
 
 
 
 
(Printed Name of Participating Subject) 
 
 
 
 
 
 
 
 
 
 
: 
(Signature of Participating Subject) 
 
Date 
 
Time 
 
 
 
 
 
 
(Printed Name of Physician or his/her 
Representative Obtaining Consent 
 
 
 
 
 
 
 
 
 
 
: 
(Signature of Physician or his/her Representative 
Obtaining Consent) 
 
Date 
 
Time 
 
 
 
 
 
Original copy for researcher/site file; 1 copy for subject; 1 copy to be kept with hospital record.   
 
 
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Protocol VMCLI-II-09-002/E 
CONFIDENTIAL 
VM BioPharma 
 
 
Page 77 of 90 
 
 
 
 
 
Appendix 3. 
MRA (select sites only) 
 
 
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Protocol VMCLI-II-09-002/E 
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VM BioPharma 
 
 
Page 78 of 90 
MRI Measurements 
 
Magnetic Resonance Imaging (MRI): MRI will be used to quantify the changes in the blood flow 
and muscle mass of the treated leg. Both large vessel (>500 Mm) and capillary level blood flow 
(perfusion) will be evaluated.  
 
Safety screening: All participants who undergo MRI scans that include contrast agent injections 
will be required to have normal kidney function. A measurement of glomerular filtration rate 
(GFR) taken no earlier than 24 hrs prior to the contrast injection will be used to determine kidney 
function. No subject with GFR < 60 mL/min/1.73 m2 will be administered contrast agent. The 
staff nurse of the Northwestern University MRI research facility (CAMRI) where these scan are 
performed will perform point-of-care (iSTAT) to determine GFR on the same day as the MRI 
scan. MRI scans that do not required the administration of MRI contrast agent may be evaluated 
using the non-contrast MRI scans (i.e. to evaluate muscle mass). Prior to the visit, participants 
will be interviewed to ensure they do not have contraindications to MRI testing (presence of 
metal or electrical devices in their body, such as a cardiac pacemaker, defibrillation wires, or 
metal foreign objects).   
 
MRI Scan Protocol: Participants will be positioned on the MRI table. An intravenous catheter 
will be inserted into the arm for infusion of the gadolinium-based MRI contrast agent. A signal-
reception coil will be placed to cover the low leg of the participant. Cross-sectional images will 
be acquired along the length of the participant’s legs. These images will be acquired to cover 
from the knee to the mid-leg, covering the entire calf muscle.  
 
Calf Muscle Area 
2D T1 weighted single slice acquired at the mid-calf. The localization will be kept consistent by 
measuring a 2D slice located at a fixed distant from the top of the tibia. A 2.5 mm thick 
transverse image will be acquired at the point of maximal muscle cross-sectional area. The distal 
end of the tibia will be used to scan a point located 66% of the distance from the distal to the 
proximal tibial. This point represents maximum muscle area on > 95% of individuals.  
 
Perfusion 
Calf muscle will be calculated using a standard imaging technique. A multi-phase interleaved, 
multi-echo MRI pulse sequence (SR-FLASH) and (IR-FLASH) will be acquired in conjunction 
with an injection of MRI contrast agent (0.1 mmol/kg b.w.). Two slices will be prescribed for 
this scan. They will be separated by 5 cm with the lower of the two sliced co-localized at the 
level of the muscle mass image. Immediately prior to the images acquisitions participants will be 
asked to perform 50 heel-rises in the MRI scanning area. They will do this by balancing against 
the wall with their fingertips and raising up and down on their toes once per second until they 
have complete 50 heel-rises, or are too tired to continue (whichever comes first).  
  
Angiography (Collateralization) 
Time-resolved MRA images will be acquired, following the perfusion scans in conjunction with 
a second, single dose injection of contrast agent (Gd-DTPA or equivalent). These will be 
acquired as a second, single dose (0.1 mmol/kg b.w.) contrast injection. A time-series of T1 
weighted, 3D Fast Low Angle Shot gradient-recalled will be acquired of the peripheral 
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vasculature from the knee to the ankle. This region will cover the region of interest for analysis 
of collateral formation. The size and number collaterals will be counted and scored.  
 
 
 
 
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Appendix 4. 
Test Article Administration 
 
 
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1. 
Test article preparation  
 
VM202 - VM202 is supplied in a sterile glass vial containing 2.2 mg of lyophilized study 
product.  Before administration, it will be reconstituted with 4.4 mL of water for injection 
(WFI) for a final VM202 concentration of 0.5 mg / mL.  Each reconstituted vial is only to be 
used for one subject.  For the Low Dose treatment arm, the final doses of 8 mg of VM202 
will be divided evenly between the Day 0 administration and the Day 14 administration, 
with the Day 28 and Day 42 injections consisting of normal saline (see description of 
normal saline below).  The High Dose treatment arm will receive final doses of 16 mg of 
VM202 divided evenly between the Day 0, Day 14, Day 28 and Day 42 administrations.  
Individual injections will be 0.5 mL.  All injections will be 0.5 mL administered by 
intramuscular injections. 
 
Placebo - Patients assigned to either the placebo arm or the Low Dose arm will receive 
normal saline injections.  The placebo group will receive only normal saline injections; the 
Low Dose arm will receive VM202 for the first two injection procedures (Day 0 and Day 
14), and then normal saline for the next two injection visits (Day 28 and Day 42).   Visually, 
normal saline is indistinguishable from reconstituted VM202.    
 
Table 3. Single dose preparation and delivery, Day 0 and Day 14 
TREATMENT 
ARM 
NUMBER OF VIALS 
RECONSTITUTED 
TOTAL 
VOLUME TO 
BE INJECTED 
NUMBER OF 
INJECTIONS 
VOLUME / 
SINGLE 
INJECTION 
Low Dose 
8 mg VM202 
2 Vials VM202, reconstituted 
with WFI 
8 mL 
16 
0.5 mL 
High Dose 
16 mg VM202 
2 Vials VM202, reconstituted 
with WFI 
8 mL 
16 
0.5 mL 
Placebo – 
Normal Saline 
NA 
8 mL 
16 
0.5 mL 
 
Table 4. Single dose preparation and delivery, Day 28 and Day 42 
TREATMENT 
ARM 
NUMBER OF VIALS 
RECONSTITUTED 
TOTAL 
VOLUME TO 
BE INJECTED 
NUMBER OF 
INJECTIONS 
VOLUME / 
SINGLE 
INJECTION 
Low Dose 
8 mg VM202 
NA – Normal Saline 
8 mL 
16 
0.5 mL 
High Dose 
16 mg VM202 
2 Vials VM202, reconstituted 
with WFI 
8 mL 
16 
0.5 mL 
Placebo – 
Normal Saline 
NA 
8 mL 
16 
0.5 mL 
 
 
2. Test material administration – Patients will receive injections of VM202 or placebo on Day 
0, Day 14, Day 28, and Day 42.  A fine needle (e.g. 27 gauge, 1”) suitable for IM injections 
will be used.  Only one leg will be treated in this study.  Distribute injection sites evenly over 
the calf muscle, carefully avoiding fascia. 
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3. Inject the entire amount of the drug per each injection in about 3-5 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.  An indelible marker should be used to 
identify each injection site. 
 
4. Subsequent administrations – Subsequent administrations should also be distributed evenly 
over the calf, and, as much as is possible, at different injection sites.  If marks made to 
identify previous injection sites are visible, every effort should be made to inject at alternate 
locations. 
 
 
 
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Appendix 5. 
VascuQol 
 
 
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Appendix 6. 
Guidelines for the Early Detection of Cancer 
 
 
 
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American Cancer Society Guidelines for the Early Detection of 
Cancer 
 
The following cancer screening guidelines are recommended for those people at average risk for cancer (unless 
otherwise specified) and without any specific symptoms.  
People who are at increased risk for certain cancers may need to follow a different screening schedule, such as 
starting at an earlier age or being screened more often. Those with symptoms that could be related to cancer should 
see their doctor right away.  
Cancer-related Checkup  
For people aged 20 or older having periodic health exams, a cancer-related checkup should include health 
counseling, and depending on a person's age and gender, might include exams for cancers of the thyroid, oral cavity, 
skin, lymph nodes, testes, and ovaries, as well as for some non-malignant (non-cancerous) diseases.  
Special tests for certain cancer sites are recommended as outlined below.  
Breast Cancer  
 
Yearly mammograms are recommended starting at age 40 and continuing for as long as a woman 
is in good health.  
 
Clinical breast exam (CBE) should be part of a periodic health exam, about every 3 years for 
women in their 20s and 30s and every year for women 40 and over.  
 
Women should know how their breasts normally feel and report any breast change promptly to 
their health care providers. Breast self-exam (BSE) is an option for women starting in their 20s.  
 
Women at high risk (greater than 20% lifetime risk) should get an MRI and a mammogram every 
year. Women at moderately increased risk (15% to 20% lifetime risk) should talk with their doctors about 
the benefits and limitations of adding MRI screening to their yearly mammogram. Yearly MRI screening is 
not recommended for women whose lifetime risk of breast cancer is less than 15%. 
Colon and Rectal Cancer  
Beginning at age 50, both men and women should follow 1 of these 5 testing schedules:  
 
yearly fecal occult blood test (FOBT)* or fecal immunochemical test (FIT)  
 
flexible sigmoidoscopy every 5 years  
 
yearly FOBT* or FIT, plus flexible sigmoidoscopy every 5 years**  
 
double-contrast barium enema every 5 years  
 
colonoscopy every 10 years  
*For FOBT, the take-home multiple sample method should be used. **The combination of yearly FOBT or 
FIT flexible sigmoidoscopy every 5 years is preferred over either of these options alone.  
All positive tests should be followed up with colonoscopy.  
People should talk to their doctor about starting colorectal cancer screening earlier and/or undergoing screening 
more often if they have any of the following colorectal cancer risk factors:  
 
a personal history of colorectal cancer or adenomatous polyps  
 
a strong family history of colorectal cancer or polyps (cancer or polyps in a first-degree relative 
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[parent, sibling, or child] younger than 60 or in 2 first-degree relatives of any age)  
 
a personal history of chronic inflammatory bowel disease  
 
a family history of an hereditary colorectal cancer syndrome (familial adenomatous polyposis or 
hereditary non-polyposis colon cancer)  
Cervical Cancer  
 
All women should begin cervical cancer screening about 3 years after they begin having vaginal 
intercourse, but no later than when they are 21 years old. Screening should be done every year with the 
regular Pap test or every 2 years using the newer liquid-based Pap test.  
 
Beginning at age 30, women who have had 3 normal Pap test results in a row may get screened 
every 2 to 3 years. Another reasonable option for women over 30 is to get screened every 3 years (but not 
more frequently) with either the conventional or liquid-based Pap test, plus the HPV DNA test. Women 
who have certain risk factors such as diethylstilbestrol (DES) exposure before birth, HIV infection, or a 
weakened immune system due to organ transplant, chemotherapy, or chronic steroid use should continue to 
be screened annually.  
 
Women 70 years of age or older who have had 3 or more normal Pap tests in a row and no 
abnormal Pap test results in the last 10 years may choose to stop having cervical cancer screening. Women 
with a history of cervical cancer, DES exposure before birth, HIV infection or a weakened immune system 
should continue to have screening as long as they are in good health.  
 
Women who have had a total hysterectomy (removal of the uterus and cervix) may also choose to 
stop having cervical cancer screening, unless the surgery was done as a treatment for cervical cancer or pre-
cancer. Women who have had a hysterectomy without removal of the cervix should continue to follow the 
guidelines above.  
Endometrial (Uterine) Cancer  
The American Cancer Society recommends that at the time of menopause, all women should be informed about the 
risks and symptoms of endometrial cancer, and strongly encouraged to report any unexpected bleeding or spotting to 
their doctors. For women with or at high risk for hereditary non-polyposis colon cancer (HNPCC), annual screening 
should be offered for endometrial cancer with endometrial biopsy beginning at age 35.  
Prostate Cancer  
Both the prostate-specific antigen (PSA) blood test and digital rectal examination (DRE) should be offered annually, 
beginning at age 50, to men who have at least a 10-year life expectancy. Men at high risk (African-American men 
and men with a strong family of one or more first-degree relatives [father, brothers] diagnosed before age 65) should 
begin testing at age 45. Men at even higher risk, due to multiple first-degree relatives affected at an early age, could 
begin testing at age 40. Depending on the results of this initial test, no further testing might be needed until age 45.  
Information should be provided to all men about what is known and what is uncertain about the benefits, limitations, 
and harms of early detection and treatment of prostate cancer so that they can make an informed decision about 
testing.  
Men who ask their doctor to make the decision on their behalf should be tested. Discouraging testing is not 
appropriate. Also, not offering testing is not appropriate.  
References  
American Cancer Society. Cancer Facts & Figures 2007. Atlanta, Ga: American Cancer Society; 2007.  
Saslow D, Boetes C, Burke W, et al for the American Cancer Society Breast Cancer Advisory Group. American 
Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 
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2007;57:75-89. [Free full text article available at: http://caonline.amcancersoc.org/cgi/content/full/57/2/75]. 
Accessed March 28, 2007.  
Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer, 2006. CA 
Cancer J Clin. 2006;56:11-25.  
Revised: 03/28/2007  
 
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