A Phase I/II, Open Label, Dose-Escalation Study to Assess the Safety and Tolerability of Engensis (VM202) in Patients With Painful Diabetic Peripheral Neuropathy
Phase: PHASE1
Conditions: Painful Diabetic Peripheral Neuropathy
Sponsor: Helixmith Co., Ltd.



 
 
 
Protocol VMDN-001/G 
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ViroMed, 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, Inc. 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 I/II, Open Label, Dose-Escalation Study to Assess the 
Safety and Tolerability of VM202 in Patients with Painful Diabetic 
Peripheral Neuropathy 
 
 
 
STUDY PHASE 
I/II 
 
INVESTIGATIONAL AGENT 
VM202 
 
DOSE 
Three doses will be tested: 4 mg, 8 mg and 16 mg VM202. 
 
POPULATION 
Patients aged ≥ 18 years to ≤ 75 years diagnosed with painful 
diabetic neuropathy in both lower extremities. 
 
STUDY DESIGN 
A phase I/II, open label, dose-escalation, multicenter, 12-month 
study designed to assess the safety and tolerability of unilateral 
intramuscular injection in the calf of VM202 in patients with 
painful diabetic peripheral neuropathy (DPN).  The study will 
consist of three (3) cohorts with a total of 4 patients enrolled in 
each cohort.  
 
A Data Safety Monitoring Board (DSMB) will monitor patient 
safety throughout the study.  After the first patient in a dose cohort 
completes the Day 30 follow-up evaluation and the other three 
patients enrolled in the same cohort complete at least the Day 14 
follow-up (second dosing), an interim safety evaluation will be 
performed by the DSMB.  If the DSMB recommends proceeding, 
the next dose cohort will be treated.  This process will be repeated 
between the second and third dose cohort.  All three dose cohorts 
will be followed for one year from the time of the first dose of 
study drug administration.  If a dose limiting toxicity (DLT) is 
observed in one patient in any dose group, two additional patients 
will be added to the dose cohort in which the toxicity was 
observed.  If no additional DLTs are observed in the 6 patients at 
this dose level, it will be considered the Maximum Tolerated Dose 
(MTD).  If a DLT occurs in 2 patients at any dose level, then the 
preceding dose level will be considered the MTD.  The study will 
be stopped in the event that 2 DLTs occur at any point in the study. 
 
NUMBER OF PATIENTS 
12 to a maximum of 14 

 
 
 
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INCLUSION CRITERIA 
 
1. Age ≥ 18 years to ≤ 75 years; 
2. Documented history of Type I or II diabetes with current 
treatment control (glycosylated hemoglobin A1c of ≤ 10.0%); 
3. Diagnosis of painful diabetic peripheral neuropathy in both 
lower extremities;  
4. The  physical examination component of the Michigan 
Neuropathy Screening Instrument Score (MNSI) is ≥ 3 at 
Screening; 
5. Visual analog scale (VAS) score of ≥ 4 cm at Screening (0 cm 
= no pain – 10 cm worst imaginable pain); 
6. Stable treatment of diabetes for at least 3 months with no 
anticipated changes in medication regimen, and no new 
symptoms associated with diabetes; 
7. Lower extremity pain for at least 6 months; and 
8. If female of childbearing potential, negative pregnancy test at 
screening and using acceptable method of birth control during 
the study. 
 
EXCLUSION CRITERIA 
1. Peripheral neuropathy caused by condition other than diabetes; 
2. Other pain more severe than neuropathic pain; 
3. Progressive or degenerative neurological disorder; 
4. Myopathy; 
5. Inflammatory disorder of the blood vessels (inflammatory 
angiopathy, such as Buerger’s disease); 
6. Active infection; 
7. Chronic inflammatory disease (e.g. Crohn’s, Rheumatoid 
Arthritis)  
8. Positive HIV or HTLV at Screening 
9. 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 or known 
immunosuppression or on chronic treatment with 
immunosuppressive drugs, chemotherapy or radiation therapy; 
10. Stroke or myocardial infarction within last 6 months; 
11. Ophthalmologic conditions pertinent to proliferative 
retinopathy or conditions that preclude standard 
ophthalmologic examination: 
 
• Cataract surgery within 6 months of trial;  
• Vascular lesions of the anterior segment of the eye 
(infection or ulceration of the cornea, rubeotic glaucoma, 
etc);  
• Vascular lesions of the posterior segment of the eye or 
proliferative retinopathy, macular edema, s/p 

 
 
 
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photocoagulation for macular edema or proliferative 
retinopathy; sickle cell retinopathy, ischemic retinopathy 
due to retinal venous stasis or carotid artery disease;  
• Choroidal angiogenesis; and  
• Large elevated choroidal nevi, choroidal vascular tumors 
(choroidal hemangioma), or melanomas. 
 
12. Specific laboratory values at Screening including: Hemoglobin 
< 9.0 g/dL, WBC < 3,000 cells per microliter, platelet count 
<75,000/mm3, Creatinine > 2.0 mg/dL; GFR < 50, AST and/or 
ALT > 2 times the upper limit of normal or any other clinically 
significant lab abnormality which in the opinion of the 
investigator should be exclusionary; 
13. Use of gamma-linolenic acid (GLA), alpha lipoic acid or any 
other high dose dietary antioxidant supplement for 
symptomatic relief of DPN; 
14. Uncontrolled hypertension as defined as sustained systolic 
blood pressure (SBP) > 200 mmHg or diastolic BP (DBP) > 
110 mmHg at baseline/screening evaluation; 
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); 
16. Malignant tumors or abnormal screening test suspicious for 
cancer, or patients in whom screening exams indicate possible 
occult malignancy unless malignancy has been ruled out.  
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; 
17. Elevated PSA unless prostate cancer has been excluded;  
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; 
19. Major psychiatric disorder in past 6 months; 
20. History of drug or alcohol abuse / dependence in the past 2 
years; 
21. History of recent tobacco abuse (within past 5 years); 
22. BMI > 45 kg/m2; 
23. Use of an investigational drug or treatment in past 12 months; 
and 
24. 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, vital signs, physical exam, 

 
 
 
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STUDY ENDPOINTS 
The primary study endpoint is to evaluate safety and tolerability of 
intramuscular injection in the calf of VM202 in patients with 
painful DPN.  Secondary endpoints include the assessment of the 
potential of VM202 to reduce the pain associated with DPN. 
 
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. 
 
PHARMACOKINETICS Determination of HGF serum levels will be determined 
immediately pre-treatment on Day 0, immediately pre-treatment on 
Day 14, Day 30, and Day 60.  The number of copies of VM202 in 
whole blood will be determined at Day 0 (pre-injection, and 2 
hours post injection), at Day 14 (pre-injection, and 2 hours post 
injection), Day 21, Day 30, Day 60 and Day 90. 
 
EFFICACY 
This is a phase I /II study, not powered to assess efficacy.  
However, descriptive statistics (N, mean, median, SD, minimum 
and maximum values, where applicable) of clinically meaningful 
endpoints will be tabulated.  Change in pain level, as measured by 
the VAS, SF-MPQ and BPI-DPN will be recorded.  The status of 
preexisting ulcers will also be reported. 
 
 
 

 
 
 
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TABLE OF CONTENTS 
 
INVESTIGATOR’S AGREEMENT ......................................................................................................... 2 
STUDY SYNOPSIS ............................................................................................................................. 3 
TABLE OF CONTENTS ....................................................................................................................... 8 
GLOSSARY ..................................................................................................................................... 12 
PERSONNEL AND FACILITIES .......................................................................................................... 14 
1. 
BACKGROUND .......................................................................................................................15 
1.1. 
Diabetes..................................................................................................................15 
1.1.1. 
Diabetic Peripheral Neuropathy ...............................................................15 
1.1.2. 
Pathophysiology of Diabetic Peripheral Neuropathy ...............................15 
1.2. 
Current Treatment Options ....................................................................................17 
1.2.1. 
Preventive Treatment ...............................................................................17 
1.2.2. 
Medical Management ...............................................................................17 
1.2.3. 
Other Treatment Options ..........................................................................18 
1.2.4. 
Unmet Clinical Need ................................................................................18 
1.3. 
HGF for the Treatment of Diabetic Neuropathy ....................................................19 
1.4. 
VM202 ...................................................................................................................19 
1.5. 
Preclinical Data ......................................................................................................20 
1.6. 
Clinical Data ..........................................................................................................21 
1.7. 
Study and Dose Rationale ......................................................................................22 
2. 
GOOD CLINICAL PRACTICES STATEMENT ..............................................................................23 
3. 
INVESTIGATIONAL PLAN ........................................................................................................23 
3.1. 
Study Objectives ....................................................................................................23 
3.2. 
Study Design ..........................................................................................................23 
3.3. 
Patient Population ..................................................................................................26 
3.3.1. 
Inclusion Criteria ......................................................................................26 
3.3.2. 
Exclusion Criteria .....................................................................................27 
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. 
Day 0 – 1st Injections ................................................................................30 
3.4.5.1. 
Pre-Injection (within 4 hrs prior to injections) ........................30 
3.4.5.2. 
1st Dose of VM202 ...................................................................30 
3.4.5.3. 
Post-Injection ...........................................................................30 
3.4.6. 
Day 14 ± 1 Days – 2nd Injections .............................................................30 
3.4.6.1. 
Pre-Injection (within 4 hours prior to the injections) ...............30 
3.4.6.2. 
2nd Dose of VM202 ..................................................................30 
3.4.6.3. 
Post-Injection ...........................................................................30 
3.4.7. 
Day 21 ± 3 Days .......................................................................................31 

 
 
 
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3.4.8. 
Day 30 ± 3 Days .......................................................................................31 
3.4.9. 
Day 60 ± 7 Days .......................................................................................31 
3.4.10.  Day 90 ± 7 Days .......................................................................................31 
3.4.11.  6 months ± 1 month ..................................................................................32 
3.4.12.  12 months ± 1 month ................................................................................32 
3.5. 
Study Completion ..................................................................................................32 
3.5.1. 
Completed Patients ...................................................................................32 
3.5.2. 
Discontinued Patients ...............................................................................32 
3.5.3. 
Premature Study Termination ..................................................................33 
3.6. 
Investigational Drug Product and Accountability ..................................................34 
3.6.1. 
Investigational Drug Product ....................................................................34 
3.6.2. 
Product Accountability .............................................................................34 
3.6.3. 
Dose and Administration ..........................................................................34 
3.7. 
Prior and Concomitant Medication ........................................................................35 
4. 
EXAMINATIONS AND EVALUATIONS ......................................................................................35 
4.1. 
Evaluations Conducted at Baseline Only ...............................................................35 
4.1.1. 
Complete Medical History .......................................................................35 
4.1.2. 
Complete Physical Exam ..........................................................................35 
4.1.3. 
Cancer Screening ......................................................................................36 
4.1.4. 
Viral Screening .........................................................................................36 
4.1.5. 
Urinalysis ..................................................................................................36 
4.1.6. 
Michigan Neuropathy Screening Instrument ...........................................36 
4.1.7. 
12-Lead EKG ...........................................................................................36 
4.1.8. 
Pregnancy Test (women of childbearing potential only) .........................37 
4.2. 
Evaluations Conducted Throughout the Study ......................................................37 
4.2.1. 
Retinal Fundoscopy ..................................................................................37 
4.2.2. 
Concomitant Medications .........................................................................37 
4.2.3. 
Vital Signs ................................................................................................37 
4.2.4. 
Serum Chemistry and Hematology ..........................................................37 
4.2.5. 
Serum HGF ...............................................................................................38 
4.2.6. 
Copies of VM202 in Whole Blood ...........................................................38 
4.2.7. 
Photograph and measurement of ulcer .....................................................39 
4.2.8. 
Visual Analog Scale (VAS) score ............................................................39 
4.2.9. 
Short Form McGill Pain Questionnaire (SF-MPQ) .................................39 
4.2.10.  Brief Pain Inventory for Patients with Diabetic Peripheral Neuropathy 
(BPI-DPN) ................................................................................................40 
4.2.11.  Injection Site Reaction Assessment .........................................................40 
5. 
EVALUATION OF ADVERSE EVENTS .......................................................................................41 
5.1. 
Definitions..............................................................................................................41 
5.2. 
Assessment of AEs ................................................................................................42 
5.2.1. 
AE Causality .............................................................................................42 
5.2.2. 
AE Intensity ..............................................................................................43 
5.3. 
Reporting/Recording of AEs ..................................................................................43 
5.4. 
Reporting / Recording of SAEs .............................................................................43 
5.4.1. 
Investigator’s Responsibility ....................................................................43 

 
 
 
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5.4.2. 
Sponsor’s Responsibility ..........................................................................44 
6. 
STATISTICAL METHODS .........................................................................................................44 
6.1. 
Patient Categorization ............................................................................................44 
6.2. 
Study Endpoints .....................................................................................................45 
6.2.1. 
Safety ........................................................................................................45 
6.2.2. 
Pharmacodynamics ...................................................................................45 
6.2.3. 
Efficacy ....................................................................................................45 
7. 
ACCESS TO STUDY DOCUMENTS AND STUDY MONITORING...................................................45 
8. 
QUALITY CONTROL AND ASSURANCE ....................................................................................46 
9. 
INSTITUTIONAL REVIEW BOARD ............................................................................................46 
10. 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) .....................................................................47 
11. 
INFORMED CONSENT PROCESS ...............................................................................................47 
12. 
CONFIDENTIALITY .................................................................................................................48 
13. 
PROTOCOL AMENDMENTS .....................................................................................................48 
14. 
DATA MANAGEMENT .............................................................................................................48 
15. 
RECORD KEEPING AND RETENTION .......................................................................................49 
16. 
INVESTIGATOR FINAL REPORT ...............................................................................................50 
17. 
STUDY REPORT AND PUBLICATION ........................................................................................50 
18. 
REFERENCES ..........................................................................................................................51 
 
FIGURES &TABLES 
 
Figure 1. 
The neurodestructive effects of hyperglycemia .............................................. 16 
Figure 2. 
VM202 construct ............................................................................................ 20 
Figure 3. 
Study flowchart ............................................................................................... 25 
 
Table 1. 
First and second tier recommendations for pain management in DPN .......... 18 
Table 2. 
VM202 administration for each cohort ........................................................... 24 
Table 3. 
Injection Reaction Assessment ....................................................................... 40 
Table 4. 
Single dose preparation and delivery of VM202 ............................................ 79 
Table 5. 
 ................................................................. 93 
Schedule of laboratory evaluations
 

 
 
 
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TABLE OF APPENDICES 
 
Appendix 1. 
Schedule of Evaluations and Visits................................................................. 56 
Appendix 2. 
Sample Informed Consent............................................................................... 58 
Appendix 3. 
Michigan Neuropathy Screening Instrument .................................................. 73 
Appendix 4. 
Test Article Administration ............................................................................ 78 
Appendix 5. 
Short Form McGill Pain Questionnaire .......................................................... 80 
Appendix 6. 
Brief Pain Inventory for Patients with Diabetic Peripheral Neuropathy (BPI-
DPN) ............................................................................................................... 82 
Appendix 7. 
Guidelines for the Early Detection of Cancer ................................................. 86 
Appendix 8. 
Visual Analog Scale ........................................................................................ 90 
Appendix 9. 
Laboratory Tests by Visit ................................................................................ 92 
 

 
 
 
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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) 
BP 
Blood Pressure 
BPI-DPN 
Brief Pain Inventory for Diabetic Peripheral Nephropathy 
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 
DCF 
Data Clarification Form 
DLT 
Dose Limiting Toxicities 
DNA 
Deoxyribonucleic Acid 
DPN 
Diabetic Peripheral Neuropathy 
DSMB 
Data Safety Monitoring Board 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FOBT 
Fecal occult blood test 
GCP 
Good Clinical Practices 
HBV 
Hepatitis B Virus 
HBcAB 
Hepatitis B core antibody 
HBsAb 
Antibody to Hepatitis B antigen (IgG and IgM) 
HBsAg 
Hepatitis B surface antigenHCV 
Hepatitis C Virus 
HGF 
Hepatocyte Growth Factor 
HIV 
Human Immunodeficiency Virus 
HTLV 
Anti-Human T-Cell Lymphotropic Virus 
IBC  
Institutional Biosafety Committee 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MTD 
Maximum Tolerated Dose 
NIH 
National Institutes of Health  
OBA 
Office of Biotechnology Activities 
PSA 
Prostate Specific Antigen 
RBC 
Red Blood Cell Count 
RNA 
Ribonucleic Acid 
SF-MPQ 
Short Form version of the McGill Questionnaire 
SGPT 
Serum Glutamic Pyruvic Transaminase (same as ALT) 
SOP  
Standard Operating Procedure 
TBI 
Toe-Brachial Index 

 
 
 
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TCA 
Tricyclic Antidepressants 
TCPO2 
Transcutaneous pressure of oxygen 
VAS 
Visual Analog Scale (Pain Scores) 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell Count 
WFI 
Water for Injection 

 
 
 
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1. 
BACKGROUND 
 
1.1. 
DIABETES 
Approximately 23.6 million adults in the United States have diabetes mellitus, a 
metabolic disorder of multiple causes characterized by chronic hyperglycemia and 
disorders of carbohydrate, fat, and protein metabolism.†  Diabetes can result from 
defects in insulin secretion (type 1), insulin action (type 2), or a combination of these 
factors, and is associated with a high level of morbidity and mortality.  The total 
estimated cost of diabetes in 2007 was $174 billion, including $116 billion in excess 
medical expenditures and $58 billion in reduced national productivity.1 
 
1.1.1. 
DIABETIC PERIPHERAL NEUROPATHY 
Diabetic peripheral neuropathy (DPN) is one of the most commonly encountered 
neuropathic pain syndromes in clinical practice, and is a particularly debilitating 
complication of diabetes.  When symptomatic, it is associated with continuous or 
paroxysmal pain described by patients as shooting, stabbing, or electric in nature.2  
The pain can either be triggered by an external stimulus or be independent of 
external input.  Unlike other painful sensations which signal a warning in response to 
a harmful stimulus, neuropathic pain is maladaptive.  DPN accounts for significant 
morbidity by predisposing the foot to ulceration and lower extremity amputation.3, 4   
 
According to both the American Diabetes Association and the National Institute of 
Diabetes and Digestive and Kidney Disease (NIDDK), 60 to 70 percent of diabetics 
will eventually develop some form of diabetic neuropathy.  Today, 3.9 million 
diabetics over the age of 40 already have symptomatic DPN.5  The total annual cost 
of DPN and its complications in the U.S. is estimated to be between $4.6 and $13.7 
billion.6, 7  If current health trends persist unabated, the costs associated with diabetic 
neuropathy will rise sharply over the coming decades. 
 
1.1.2. 
PATHOPHYSIOLOGY OF DIABETIC PERIPHERAL NEUROPATHY 
DPN manifests as three broad categories: sensory, motor and autonomic.  The most 
prevalent form is somatic or sensorimotor neuropathy.  Symptoms often exhibit a 
distal symmetric pattern, beginning distally at the base of the toes and ascending 
proximally up the lower leg as the disease progresses.  Symptoms are described as 
burning, tingling, stabbing and a pins-and-needles sensation in a stocking and glove 
distribution.  Patients may also display muscle weakness, lack of coordination and 
ataxia, and loss of pain perception.  Loss of protective sensation can lead to the 
formation of foot ulcerations, infections, and amputations.  
 
Despite being the focus of current research, the sequence of physiological events that 
result in this condition is poorly understood.  The pathogenesis of diabetic 
neuropathy likely involves the interplay of hyperglycemia, ischemia, and oxidative 
                                                 
† 
CDC. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 
2007. Atlanta, GA: US Department of Health and Human Services, CDC; 2008. Available 
at http://www.cdc.gov/diabetes/pubs/factsheet07 htm#contents.  
 

 
 
 
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stress.8  Vascular dysfunction, driven by metabolic change, is thought to play a 
crucial role in the progression of diabetic neuropathy.9-12  Figure 1 portrays the 
relationship of hyperglycemia to oxidative stress, metabolic alterations, vascular 
dysfunction and neural damage.  
 
 
Figure 1. The neurodestructive effects of hyperglycemia 
 
Increased polyol pathway flux. Hyperglycemia causes increased levels of 
intracellular glucose in nerves, leading to saturation of the normal glycolytic 
pathway.  Extra glucose is shunted into the polyol pathway and converted to sorbitol 
and fructose by the enzymes aldose reductase and sorbitol dehydrogenase. 
Accumulation of sorbitol and fructose lead to reduced nerve myoinositol, decreased 
membrane Na+/K+-ATPase activity, impaired axonal transport, and structural 
breakdown of nerves, causing abnormal action potential propagation.13 
 
Non-enzymatic protein glycation. Advanced glycation end products are the result of 
nonenzymatic addition of glucose or other saccharides to proteins, lipids, and 
nucleotides.  In diabetes, excess glucose accelerates advanced glycation end product 
generation that leads to intracellular and extracellular protein cross-linking and 
protein aggregation.  Activation of the advanced glycation end product receptor 
alters intracellular signaling and gene expression, releases proinflammatory 
molecules, and results in an increased production of reactive oxygen species that 
contribute to diabetic microvascular complications. 
 
Oxidative Stress. Hyperglycemia induces an increased presence of markers of 
oxidative stress, such as superoxide and peroxynitrite ions, and decreases antioxidant 
defense moieties in patients with DPN.  It is associated with the development of 
apoptosis in neurons and supporting glial cells 14 

 
 
 
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Vascular Damage. Nervous tissue depends on adequate blood flow to deliver 
nutrients and remove metabolic waste.  Normally, the capillary basement membrane 
allows the passage of nutrients into the cell and permits the removal of waste 
products.  In patients with prolonged hyperglycemia, glucose is more likely to be 
deposited in the basement membrane, thus decreasing its permeability.  Decreased 
permeability results in the buildup of toxic metabolites, resulting in poor cellular 
metabolism, further free radical formation, apoptosis and a decline in vascularization 
of nervous tissues. 
 
 
1.2. 
CURRENT TREATMENT OPTIONS 
Currently, there are no approved drugs or interventional strategies known to halt or 
reverse the progression of DPN.  Treatments target pain reduction, physical function 
improvement, reduction of psychological distress, and quality of life 
improvements.15 
 
1.2.1. 
PREVENTIVE TREATMENT  
Glycemic control. It is generally agreed that long-term complications of both type 1 
and type 2 diabetes can be reduced by tight glycemic control.  To date, this is the 
only intervention specifically shown to arrest or postpone the onset and severity of 
peripheral neuropathy.16-18   
 
Modifiable risk factors. The incidence of neuropathy is also associated with 
potentially modifiable cardiovascular risk factors, including an elevated triglyceride 
level, a high body mass index, smoking, and hypertension.19   
 
Foot care. Patients with diabetes also need to be educated about foot care and 
footwear, and about protection of hyposensitive areas and pressure points, to prevent 
the occurrence of ulcers and to decrease the risk of bone infection.20   
 
1.2.2. 
MEDICAL MANAGEMENT  
There are only two drugs approved by FDA specifically for the treatment of the 
symptoms of DPN: Cymbalta – (duloxetine), a serotonin and norepinephrine 
reuptake inhibitor; and Lyrica - (pregabalin), an anticonvulsant drug.  Both are 
prescribed for the management of pain associated with diabetic peripheral 
neuropathy.  Table 1 presents the Diabetic Peripheral Neuropathic Pain Consensus 
Treatment Guidelines Advisory Board’s recommendations for first- and second-tier 
agents to treat DPN based on the level of evidence available from clinical trials and 
the committee’s clinical experience.2 

 
 
 
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1.3. 
HGF FOR THE TREATMENT OF DIABETIC NEUROPATHY 
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.24, 25  It is a multi-functional mesenchyme-derived cytokine with potent 
angiogenic and anti-apoptotic effects 24-27  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.28, 29  Recently, HGF 
gene transfer has been shown to produce significant augmentation of collateral 
formation in the rabbit hind limb ischemia model.25  Furthermore, a significant 
increase in blood flow was achieved by HGF gene transfer both in rat diabetic and 
non-diabetic hind limb ischemia models.27, 30   
 
Recent research also indicates that HGF can function as a neurotrophic factor.31  
Sympathetic neurons co-express bioactive HGF and its cognate receptor, the Met 
receptor, and localized exogenous HGF has been shown to promote the growth (but 
not survival) of sympathetic neurons.32-35  It is proposed that administration of HGF 
may promote axonal growth and regeneration.  As loss of microvasculature in 
diabetic neuropathy has also been implicated in acceleration of neuronal loss and 
pain symptoms,36 HGF may be an ideally suited candidate for the treatment this 
condition.  Exogenous VEGF has been studied in this patient population, but with 
limited success.37-40 
 
The challenge associated with delivering a targeted sustained dose of exogenous 
HGF 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.41, 42  
 
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. 
 
 
1.4. 
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, HGF 
728 and HGF 723. 
 
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 

 
 
 
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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 
ViroMed-sponsored clinical trials with VEGF as the therapeutic gene, known as 
VMDA-3601.   
 
 
Figure 2. 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.43-45  This local effect of 
conventionally injected naked plasmid DNA is well known.46, 47   
 
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.  As there is some overlap in the pathology of critical limb ischemia and diabetic 
neuropathy,48 VM202 may have the ability to decrease neuropathic pain, and 
improve patient quality of life and exercise capacity. 
 
 
1.5. 
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 intramyocardial administration of VM202 increased the capillary density and 

 
 
 
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regional perfusion in ischemic myocardium and improved ischemic left ventricular 
function.  An ischemic heart disease efficacy study in rats demonstrated that 
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 11 times the clinical dose of 8 mg (0.11 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 clinical 
investigation of VM202 in patients with painful diabetic peripheral neuropathy.  
 
 
1.6. 
CLINICAL DATA 
VM202 is being evaluated for treatment of critical limb ischemia in a prospective, 
dose-escalation Phase I study.  The study consists of four (4) cohorts of three (3) 
patients.  Patients received 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.  
All 4 dose cohorts were followed for one year from the time of the first dose of study 
drug administration. 
 
Enrollment and follow-up are 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 ankle 
brachial index (ABI) and toe brachial index (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.  
Transcutaneous pressure of oxygen (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.   
 
To date, data indicate that VM202 treatment is safe and well-tolerated.  HGF levels 
remained unchanged and there was no HGF plasmid detectable via biodistribution 
studies after 59 days even at the highest dose cohort (16 mg).  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 

 
 
 
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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.   
 
Preliminary Conclusions.  These early data support the feasibility of intramuscular 
injections of VM202 in patients with critical limb ischemia.  Results 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.   
 
 
1.7. 
STUDY AND DOSE RATIONALE  
This is a dose escalating study.  For each cohort, VM202 will be administered as 
unilateral intramuscular injections in the calf of 4 mg, 8 mg, or 16 mg of VM202.  
Only the right leg will be treated in this study, unless medically contraindicated.  
VM202 will be delivered 2 divided doses with a 2-week interval between injections.  
Each injection will contain 0.25mg VM202.  Individual injections will be of 0.5 mL. 
 
The first cohort of patients will receive a total dose of 4 mg of study product in 8 mL 
of solution (eight injections on Day 0, and eight injections on Day 14).  The second 
cohort of patients will receive a total dose of 8 mg of study product in 16 mL of 
solution (sixteen injections on Day 0, and sixteen injections on Day 14).  The third 
cohort of patients will receive a total dose of 16 mg of study product in 32 mL of 
solution (thirty-two injections on Day 0, and thirty-two injections on Day 14).   
 
These doses were chosen because no toxicity was detected in rabbit, rat and mouse 
toxicity studies and safety was demonstrated at doses that were approximately 5 
(80mg/70kg) to 60 (960mg/70kg) times the maximum cumulative clinical dose (16 
mg in Cohort III) proposed in this study: 
 
1. Single intramuscular or intravenous doses in rat: 1.2mg/kg that is approximately 
5 times the maximum cumulative clinical dose. 
2. Repeated dose toxicity in rabbit (IM): 6mg/kg that is approximately 26 times the 
maximum cumulative clinical dose. 
3. Repeated dose toxicity in rat (IM): 13.68mg/kg that is approximately 60 times 
the maximum cumulative clinical dose.  
4. Single dose toxicity in rat (IM): 6.84mg/kg that is approximately 30 times the 
maximum cumulative clinical dose. 
5. Immunotoxicity in mice (IM): 1.14mg/kg that is approximately 5 times the 
maximum cumulative clinical dose. 
6. Genomic integration / reproductive tissue distribution in rat (IM): 6.84 mg/kg 
that is approximately 30 times of the maximum cumulative clinical dose. 

 
 
 
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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 CFR 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. 
 
 
 
3. 
INVESTIGATIONAL PLAN 
 
3.1. 
STUDY OBJECTIVES 
The objective of this Phase I/II study is to evaluate the safety and tolerability of 
intramuscular injection in the calf of VM202 in patients with diabetic peripheral 
neuropathy.  Secondarily, the potential role of VM202 to reduce pain in patients with 
diabetic peripheral neuropathy will be explored.  Efficacy parameters include 
changes in the sensory portion of the Short Form McGill Pain Questionnaire (SF-
MPQ), the Brief Pain Inventory (BPI-DPN), and the VAS Pain score. 
 
 
3.2. 
STUDY DESIGN 
This is a phase I/II, open label, dose-escalation, multicenter, 12 month study.  
Patients with painful DPN will be screened for study eligibility after giving informed 
consent.  Patients will be treated with 4 mg, 8 mg or 16 mg of VM202 by 
intramuscular injections in the right calf on Day 0 and again on Day 14.  Study drug 
will only be administered unilaterally.  If injection in the right leg is medically 
contraindicated, the left leg may be treated and noted on the appropriate case report 
form. 
 
VM202 will be delivered in a solution of 0.5 mg VM202 / mL.  Individual injections 
will be 0.5 mL.  Patients in Cohort I will receive 2 mg of VM202 on Day 0 and Day 
14 for a final dose of 4 mg; Cohort II will receive 4 mg of VM202 on Day 0 and Day 
14 for a final dose of 8 mg; and Cohort III will receive 8 mg of VM202 on Day 0 
and Day 14 for a final dose of 16 mg VM202.  Table 2 lists the final dose and 
number of injections to be administered by study cohort.  Patients will be followed 
for a period of 12 months.   

 
 
 
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second and third dose cohort (if applicable).  The DSMB will monitor patient safety 
throughout the 12 month follow-up period.   
 
 
 
Figure 3. Study flowchart 

 
 
 
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Screening/Baseline assessments should occur within the 60 days prior to Day 0 (day 
of injection).  Baseline assessments include assessment of study eligibility, a 
complete medical history, vital signs, complete physical exam, photograph and 
measurement of ulcers (if any), cancer screening tests, viral screening, MNSI Score, 
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 8, 16 or 32 – 0.5 mL intramuscular injections in the 
right calf of VM202 on Day 0 and again on Day 14.  Each injection will contain 0.25 
mg VM202.  The first cohort of patients will receive a total dose of 4 mg of study 
product in 8 mL of solution (eight injections on Day 0, and eight injections on Day 
14).  The second cohort of patients will receive a total dose of 8 mg of study product 
in 16 mL of solution (sixteen injections on Day 0, and sixteen injections on Day 14).  
The third cohort of patients will receive a total dose of 16 mg of study product in 32 
mL of solution (thirty-two injections on Day 0, and thirty-two injections on Day 14).  
 
Adverse events will be recorded throughout the one year follow-up period.  HGF 
serum levels will be determined immediately pre-treatment on Day 0, immediately 
pre-treatment on Day 14, on Day 30, and Day 60.  The number of copies of VM202 
in whole blood will be determined at Day 0 (pre-injection, and 2 hours post 
injection), Day 14 (pre-injection, and 2 hours post injection), Day 21, Day 30, Day 
60 and Day 90.  VAS score, the SF-MPQ and BPI-DPN will be recorded on Day 0, 
Day 30, Day 60, Day 90, at 6 months and 12 months.  Retinal fundoscopy will be 
conducted at screening and at 12 months. 
 
 
3.3. 
PATIENT POPULATION 
Up to 14 evaluable patients with DPN meeting the following study entry criteria will 
be enrolled.  
 
3.3.1. 
INCLUSION CRITERIA 
1. Age ≥ 18 years to ≤ 75 years; 
2. Documented history of Type I or II diabetes with current treatment control 
(glycosylated hemoglobin A1c of ≤ 10.0%); 
3. Diagnosis of painful diabetic peripheral neuropathy in both lower extremities;  
4. The  physical examination component of the Michigan Neuropathy Screening 
Instrument Score (MNSI) is ≥ 3 at Screening; 
5. Visual analog scale (VAS) score of ≥ 4 cm at screening (0 cm = no pain – 10cm 
worst imaginable pain); 
6. Stable treatment of diabetes for at least 3 months with no anticipated changes in 
medication regimen, and no new symptoms associated with diabetes; 
7. Lower extremity pain for at least 6 months; and 
8. If female of childbearing potential, negative pregnancy test at screening and 
using acceptable method of birth control during the study. 

 
 
 
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3.3.2. 
EXCLUSION CRITERIA 
1. Peripheral neuropathy caused by condition other than diabetes; 
2. Other pain more severe than neuropathic pain; 
3. Progressive or degenerative neurological disorder; 
4. Myopathy; 
5. Have an inflammatory disorder of the blood vessels (inflammatory angiopathy, 
such as Buerger’s disease); 
6. Active infection; 
7. Chronic inflammatory disease (e.g. Crohn’s, Rheumatoid Arthritis)  
8. Positive HIV or HTLV 
9. 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  or known 
immunosuppression or on chronic treatment with immunosuppressive drugs, 
chemotherapy or radiation therapy; 
10. Stroke or myocardial infarction within last 6 months; 
11. Ophthalmologic conditions pertinent to proliferative retinopathy or conditions 
that preclude standard ophthalmologic examination: 
 
• 
Cataract surgery within 6 months of trial;  
• 
Vascular lesions of the anterior segment of the eye (infection or ulceration 
of the cornea, rubeotic glaucoma, etc);  
• 
Vascular lesions of the posterior segment of the eye or proliferative 
retinopathy, macular edema, s/p photocoagulation for macular edema or 
proliferative retinopathy; sickle cell retinopathy, ischemic retinopathy due 
to retinal venous stasis or carotid artery disease;  
• 
Choroidal angiogenesis; and  
• 
Large elevated choroidal nevi, choroidal vascular tumors (choroidal 
hemangioma), or melanomas. 
 
12. Specific laboratory values at Screening including: Hemoglobin < 9.0, g/dL, 
WBC < 3,000 cells per microliter, platelet count <75,000/mm3, Creatinine > 2.0 
mg/dL; GFR < 50, AST and/or ALT > 2 times the upper limit of normal or any 
other clinically significant lab abnormality which in the opinion of the 
investigator should be exclusionary; 
13. Use of gamma-linolenic acid (GLA), alpha lipoic acid or any other high dose 
dietary antioxidant supplement for symptomatic relief of DPN; 
14. Uncontrolled hypertension as defined as sustained systolic blood pressure (SBP) 
> 200 mmHg or diastolic BP (DBP) > 110 mmHg at baseline/screening 
evaluation; 
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); 

 
 
 
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16. Malignant tumors or abnormal screening test suspicious for cancer, or patients in 
whom screening exams indicate possible occult malignancy unless malignancy 
has been ruled out.  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; 
17. Elevated PSA unless prostate cancer has been excluded; 
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 analgesic; 
19. Major psychiatric disorder in past 6 months; 
20. History of drug or alcohol abuse / dependence in the past 2 years; 
21. History of recent tobacco abuse (within past 5 years); 
22. BMI > 45 kg/m2; 
23. Use of an investigational drug or treatment in past 12 months; and 
24. Unable or unwilling to give informed consent. 
 
 
 
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 investigator 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 dose 
escalation, 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: 
 

 
 
 
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• 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; 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.    
Note fecal occult blood test (FOBT) is not required since colonoscopy will be 
performed to screen for colon cancer. 
• Retinal Fundoscopy – in cases where fundoscopy alone is deemed insufficient to 
rule out exclusionary conditions (see exclusion criterion # 11), fluorescein 
angiography may be conducted 
• Viral screening – HIV, Anti-Human T-Cell Lymphotropic Virus (HTLV), 
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 
• EKG 
• Michigan Neuropathy Screening Instrument 
• Visual Analog Scale (VAS) score 
 
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 
When Screening has determined that the patient is eligible for study participation, 
the site will complete a Treatment Authorization Form.  The form will include the 
patient identification number, demographic information (gender, date of birth) and 
will indicate that the patient meets all in/exclusion criteria.  The Treatment 
Authorization Form will be faxed to ViroMed or its designee.  ViroMed or its 
designee will in turn indicate if the patient can be treated and specify the treatment.  
The authorization form will be returned to site by fax, and upon receipt the patient 
will be scheduled to undergo the study injections.  Note: adherence to this process is 
important to track enrollment, and to assure assignment to the proper dose level. 
 

 
 
 
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3.4.5. 
DAY 0 – 1
ST INJECTIONS 
 
3.4.5.1. 
PRE-INJECTION (WITHIN 4 HRS PRIOR TO INJECTIONS) 
• Concomitant Medications 
• Vital Signs 
• Serum Chemistry and hematology 
• Serum HGF  
• Copies of VM202 in whole blood 
• Photograph and measurement of ulcer(s) – if present 
• Visual Analog Scale (VAS) score 
• Short Form McGill Pain Questionnaire (SF-MPQ) 
• Brief Pain Inventory for Diabetic Neuropathy (BPI-DPN) 
 
3.4.5.2. 
1
ST DOSE OF VM202 
• Intramuscular injections of VM202 in calf (unilateral, right leg only unless 
contraindicated) 
 
3.4.5.3. 
POST-INJECTION 
• Vital Signs 
• Copies of VM202 in whole blood (2 hours ± 1 hour post injection) 
• Injection site assessment 
• Adverse event assessment 
 
3.4.6. 
DAY 14 ± 1 DAYS – 2
ND INJECTIONS 
 
3.4.6.1. 
PRE-INJECTION (WITHIN 4 HOURS PRIOR TO THE INJECTIONS) 
• Concomitant Medications  
• Vital Signs 
• Serum Chemistry and hematology 
• Serum HGF  
• Copies of VM202 in whole blood 
• Visual Analog Scale (VAS) score 
• Adverse event assessment 
• Injection site assessment 
 
3.4.6.2. 
2
ND DOSE OF VM202 
• Intramuscular injections of VM202 in calf (unilateral, right leg only unless 
contraindicated) 
 
3.4.6.3. 
POST-INJECTION 
• Vital Signs 
• Copies of VM202 in whole blood (2 hours ± 1 hour post injection) 
• Injection site assessment 

 
 
 
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• Adverse event assessment 
 
3.4.7. 
DAY 21 ± 3 DAYS 
• Concomitant Medications  
• Vital Signs 
• Serum Chemistry and hematology 
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 
 
3.4.8. 
DAY 30 ± 3 DAYS 
• Concomitant Medications  
• Vital Signs 
• Serum Chemistry and hematology 
• Serum HGF 
• Copies of VM202 in whole blood 
• Photograph and measurement of ulcer(s) – if present prior to first dosage 
administration) 
• Visual Analog Scale (VAS) score 
• Short Form McGill Pain Questionnaire (SF-MPQ) 
• Brief Pain Inventory for Diabetic Neuropathy (BPI-DPN) 
• Injection site assessment 
• Adverse event assessment 
 
3.4.9. 
DAY 60 ± 7 DAYS 
• Concomitant Medications  
• Vital Signs 
• Serum Chemistry and hematology 
• Serum HGF 
• Copies of VM202 in whole blood 
• Photograph and measurement of ulcer(s) – if present prior to first dosage 
administration) 
• Visual Analog Scale (VAS) score 
• Short Form McGill Pain Questionnaire (SF-MPQ) 
• Brief Pain Inventory for Diabetic Neuropathy (BPI-DPN) 
• Injection site assessment 
• Adverse event assessment 
 
 
3.4.10. 
DAY 90 ± 7 DAYS 
• Concomitant Medications  
• Vital Signs 
• Serum Chemistry and hematology 
• Copies of VM202 in whole blood 

 
 
 
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• Photograph and measurement of ulcer – if present prior to first dosage 
administration) 
• Visual Analog Scale (VAS) score 
• Short Form McGill Pain Questionnaire (SF-MPQ) 
• Brief Pain Inventory for Diabetic Neuropathy (BPI-DPN) 
• Adverse event assessment 
 
3.4.11. 
6 MONTHS ± 1 MONTH 
• Concomitant Medications  
• Vital Signs 
• Serum Chemistry and hematology 
• Photograph and measurement of ulcer – if present prior to first dosage 
administration) 
• Visual Analog Scale (VAS) score 
• Short Form McGill Pain Questionnaire (SF-MPQ) 
• Brief Pain Inventory for Diabetic Neuropathy (BPI-DPN) 
• Adverse event assessment 
 
3.4.12. 
12 MONTHS ± 1 MONTH 
• Retinal fundoscopy 
• Concomitant Medications  
• Vital Signs 
• Serum Chemistry and hematology 
• Photograph and measurement of ulcer(s) – if present prior to first dosage 
administration) 
• Visual Analog Scale (VAS) score 
• Short Form McGill Pain Questionnaire (SF-MPQ) 
• Brief Pain Inventory for Diabetic Neuropathy (BPI-DPN) 
• Adverse event assessment 
 
 
 
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. 

 
 
 
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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 dose cohort if discontinuation occurs 
prior to the 60 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 60 
• 
Copies of VM202 in whole blood if discontinued prior to Day 90 
• 
Injection site reaction assessment if discontinued prior to Day 60 
• 
Adverse Events 
 
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. 
 
 
 
 

 
 
 
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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, HGF 728 and HGF 723.  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, the Principal 
Investigator, 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. 
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.   
 
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. 
 
3.6.3. 
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 

 
 
 
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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.  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). 
 
 
 
 
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 diabetes 
history to include all events and interventions prior to study enrollment.  Other 
potential causes of peripheral neuropathy will be excluded (e.g. alcohol 
consumption, renal failure, liver disease, hypothyroidism, collagen vascular diseases, 
vasculitis, osteoarthritis of the ankle or foot, gout, bursitis, fasciitis, and B-12 or 
folate deficiency).  
 
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. 
 

 
 
 
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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.  Note: FOBT is 
not required since colonoscopy will be performed to screen for colon cancer. 
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 7). 
 
4.1.4. 
VIRAL SCREENING 
A Contract Research Laboratory (Lab to be determined) will be responsible for 
Screening Viral Testing and assays to include: HIV-1, HIV-2, HTLV, and HBV and 
HCV 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),.  The results of the viral profile will be sent to the 
investigational site. 
 
4.1.5. 
URINALYSIS 
Specific gravity, pH, color, protein, sugar, and byproducts will be evaluated at 
baseline. 
 
4.1.6. 
MICHIGAN NEUROPATHY SCREENING INSTRUMENT 
The Michigan Neuropathy Screening Instrument (MNSI) will be conducted at 
screening in order to confirm the diagnosis of diabetic peripheral neuropathy.49-51  
The MNSI is comprised of a patient questionnaire (15 questions) and of a physical 
evaluation which includes a foot inspection, vibration sensation testing, muscle 
stretch reflexes, and monofilament testing.  The MNSI forms and instructions can be 
found in Appendix 3. 
 
4.1.7. 
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 
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4.1.8. 
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/Baseline. 
 
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. 
 
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 

 
 
 
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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.  HbA1c will be conducted at Baseline, 30 days, 90 
days, 6 months and 12 months.  Laboratory testing by visit is provided in Appendix 
9. 
 
 
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 14, on Day 
30, and Day 60.  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 
 
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 1 to 3 hours post injection), Day 14 (pre-injection, and 1-3 
hours post injection), Day 21, 30, 60, and Day 90.  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 
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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. 
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 at Day 30, Day 60, Day 90, 6 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 recorded.  
 
4.2.8. 
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, before the second treatment (injection) on Day 
14, at Day 30, Day 60, Day 90, 6 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 by measuring the distance of 
the patients mark in centimeters from the beginning of the scale (the 0 mark).  The 
VAS is illustrated in Appendix 8. 
 
4.2.9. 
SHORT FORM MCGILL PAIN QUESTIONNAIRE (SF-MPQ) 
Pain will also be characterized using the Short Form version of the McGill 
Questionnaire (SF-MPQ).52  This questionnaire reviews 15 dimensions of pain: 
descriptors 1-11 represent the sensory dimension of pain experience and 12-15 
represent the affective dimension. Each descriptor is ranked on an intensity scale of 
0 = none, 1 = mild, 2 = moderate, 3 = severe. This test will be administered pre-
injection on Day 30, Day 60, Day 90, 6 months and 12 months.  The SF-MPQ can be 
found in Appendix 5. 

 
 
 
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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). 
 
A serious adverse event (SAE) is any untoward medical occurrence which: 
 
• 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 
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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 
• 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).  

 
 
 
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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. 
 
 
 
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 MedTech Consultants, Inc., 
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 

 
 
 
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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. 
 
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).  All serious unexpected AEs will be reported 
to FDA as an IND Safety Report with 15 calendar days of the event (21 CFR 
§312.32).  Any unexpected fatal or life-threatening AEs will be reported to the 
Agency within 7 calendar days. 
 
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 primary goal of this study is to determine the maximum tolerated dose that ensures 
patient safety.  Sample size estimations were not based on formal statistical hypotheses 
testing due to the exploratory nature of this Phase I/II study.  Hypothesis testing will not be 
performed on any endpoint. 
 
6.1. 
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. 
 
 

 
 
 
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6.2. 
STUDY ENDPOINTS 
The primary study endpoint is to evaluate safety and tolerability of intramuscular 
injection in the calf of VM202 in patients with painful DPN.  Secondary endpoints 
include the assessment of the potential of VM202 to reduce the pain associated with 
DPN. 
 
6.2.1. 
SAFETY 
Any patient who receives VM202 will be included in the safety analysis population.  
Adverse events, serious adverse events, and adverse events leading to treatment 
discontinuation will be summarized using descriptive statistics.  Categorical 
variables will be summarized by the number and percentage of patients in each 
category. Continuous variables will be summarized using n, mean, SD, median, 
minimum, and maximum values.  No statistical testing will be performed. 
 
6.2.2. 
PHARMACODYNAMICS 
HGF serum levels will be determined immediately pre-treatment on Day 0, 
immediately pre-treatment on Day 14, Day 30, and Day 60.  Copies of VM202 in 
whole blood will be determined at Day 0 (pre-injection, and 2 hours post injection), 
at Day 14 (pre-injection, and 2 hours post injection), Day 21, Day 30, Day 60 and 
Day 90. 
 
6.2.3. 
EFFICACY 
This is a phase I /II study, not powered to detect differences in efficacy measures.  
However, descriptive statistics of clinically meaningful endpoints will be tabulated.  
Pain as measured by the VAS pain scale, the SF-MPQ and the BPI-DPN will be 
tracked and presented.  The status of preexisting ulcers will also be reported. 
 
 
 
 
7. 
ACCESS TO STUDY DOCUMENTS AND STUDY MONITORING 
ViroMed will designate a CRO 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 its 
designated CRO.   

 
 
 
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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 (IBC) 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 National Institutes of Health (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.  If a potential clinical site does not receive any NIH 
funding (either directly or indirectly) and does not have an institutional IBC, they can 
participate in the study if they issue a certification statement to that effect.  The 
certification statement will be submitted to the 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 

 
 
 
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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. 
 
 
 
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 

 
 
 
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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. 
 
 
 
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 

 
 
 
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• All IRB correspondence (i.e., informed consent [including any approved revisions], 
protocol, AE, advertisements, newsletters) 
• Copy of the Study Monitoring Log Sheet 
• Clinical and non-clinical supply shipment forms 
• Copies of all correspondence pertaining to the study (except budget issues) between 
ViroMed or the CRO and the site 
• Copies of all SAEs reports submitted to ViroMed or designated CRO 
• Copies of all IND Safety Reports submitted to the site by ViroMed 
• Copies of approved package labeling 
• Study personnel signature log 
 
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 
 
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Economic costs of diabetes in the U.S. In 2007. Diabetes Care 2008;31:596-615. 
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Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning 
and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc 2006;81:S12-25. 
3. 
Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of 
painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care 2006;29:1518-
22. 
4. 
Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: Mechanisms to 
management. Pharmacol Ther 2008;120:1-34. 
5. 
Candrilli SD, Davis KL, Kan HJ, Lucero MA, Rousculp MD. Prevalence and the 
associated burden of illness of symptoms of diabetic peripheral neuropathy and diabetic 
retinopathy. J Diabetes Complications 2007;21:306-14. 
6. 
Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of 
diabetic peripheral neuropathy in the US. Diabetes Care 2003;26:1790-5. 
7. 
Tolle T, Xu X, Sadosky AB. Painful diabetic neuropathy: a cross-sectional survey of 
health state impairment and treatment patterns. J Diabetes Complications 2006;20:26-33. 
8. 
Yagihashi S, Yamagishi S, Wada R. Pathology and pathogenetic mechanisms of diabetic 
neuropathy: correlation with clinical signs and symptoms. Diabetes Res Clin Pract 
2007;77 Suppl 1:S184-9. 
9. 
Kles KA, Vinik AI. Pathophysiology and treatment of diabetic peripheral neuropathy: the 
case for diabetic neurovascular function as an essential component. Curr Diabetes Rev 
2006;2:131-45. 
10. 
Yokoyama H, Yokota Y, Tada J, Kanno S. Diabetic neuropathy is closely associated with 
arterial stiffening and thickness in Type 2 diabetes. Diabet Med 2007;24:1329-35. 
11. 
Coppini DV, Spruce MC, Thomas P, Masding MG. Established diabetic neuropathy 
seems irreversible despite improvements in metabolic and vascular risk markers--a 
retrospective case-control study in a hospital patient cohort. Diabet Med 2006;23:1016-
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Kasalova Z, Prazny M, Skrha J. Relationship between peripheral diabetic neuropathy and 
microvascular reactivity in patients with type 1 and type 2 diabetes mellitus -- neuropathy 
and microcirculation in diabetes. Exp Clin Endocrinol Diabetes 2006;114:52-7. 
13. 
Figueroa-Romero C, Sadidi M, Feldman EL. Mechanisms of disease: The oxidative stress 
theory of diabetic neuropathy. Rev Endocr Metab Disord 2008;9:301-14. 
14. 
Ziegler D, Sohr CG, Nourooz-Zadeh J. Oxidative stress and antioxidant defense in 
relation to the severity of diabetic polyneuropathy and cardiovascular autonomic 
neuropathy. Diabetes Care 2004;27:2178-83. 
15. 
Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: epidemiology, natural 
history, early diagnosis, and treatment options. Pain Med 2008;9:660-74. 
16. 
Genuth S. Insights from the diabetes control and complications trial/epidemiology of 
diabetes interventions and complications study on the use of intensive glycemic treatment 
to reduce the risk of complications of type 1 diabetes. Endocr Pract 2006;12 Suppl 1:34-
41. 
17. 
Martin CL, Albers J, Herman WH, et al. Neuropathy among the diabetes control and 
complications trial cohort 8 years after trial completion. Diabetes Care 2006;29:340-4. 

 
 
 
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18. 
Intensive blood-glucose control with sulphonylureas or insulin compared with 
conventional treatment and risk of complications in patients with type 2 diabetes 
(UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-53. 
19. 
Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. 
N Engl J Med 2005;352:341-50. 
20. 
Farber DC, Farber JS. Office-based screening, prevention, and management of diabetic 
foot disorders. Prim Care 2007;34:873-85, vii-viii. 
21. 
Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves 
symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 
2006;29:2365-70. 
22. 
Chaudhry V, Russell J, Belzberg A. Decompressive surgery of lower limbs for 
symmetrical diabetic peripheral neuropathy. Cochrane Database Syst Rev 
2008:CD006152. 
23. 
Bigam DL, Shapiro AJ. Pancreatic Transplantation: Beta Cell Replacement. Curr Treat 
Options Gastroenterol 2004;7:329-41. 
24. 
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. 
25. 
Nakagami H, Kaneda Y, Ogihara T, Morishita R. Hepatocyte growth factor as potential 
cardiovascular therapy. Expert Rev Cardiovasc Ther 2005;3:513-9. 
26. 
Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J 
Biochem 1996;119:591-600. 
27. 
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. 
28. 
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. 
29. 
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. 
30. 
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. 
31. 
Hashimoto N, Yamanaka H, Fukuoka T, et al. Expression of HGF and cMet in the 
peripheral nervous system of adult rats following sciatic nerve injury. Neuroreport 
2001;12:1403-7. 
32. 
Giacobini P, Messina A, Wray S, et al. Hepatocyte growth factor acts as a motogen and 
guidance signal for gonadotropin hormone-releasing hormone-1 neuronal migration. J 
Neurosci 2007;27:431-45. 
33. 
Kato N, Nemoto K, Nakanishi K, et al. Nonviral gene transfer of human hepatocyte 
growth factor improves streptozotocin-induced diabetic neuropathy in rats. Diabetes 
2005;54:846-54. 
34. 
Koike H, Morishita R, Iguchi S, et al. Enhanced angiogenesis and improvement of 
neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin 
synthase gene. FASEB J 2003;17:779-81. 

 
 
 
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35. 
Tsuchihara T, Ogata S, Nemoto K, et al. Nonviral Retrograde Gene Transfer of Human 
Hepatocyte Growth Factor Improves Neuropathic Pain-related Phenomena in Rats. Mol 
Ther 2008. 
36. 
Camera A, Hopps E, Caimi G. Diabetic microangiopathy: physiopathological, clinical 
and therapeutic aspects. Minerva Endocrinol 2007;32:209-29. 
37. 
Murakami T, Arai M, Sunada Y, Nakamura A. VEGF 164 gene transfer by 
electroporation improves diabetic sensory neuropathy in mice. J Gene Med 2006;8:773-
81. 
38. 
Quattrini C, Jeziorska M, Boulton AJ, Malik RA. Reduced vascular endothelial growth 
factor expression and intra-epidermal nerve fiber loss in human diabetic neuropathy. 
Diabetes Care 2008;31:140-5. 
39. 
Tremolada G, Lattanzio R, Mazzolari G, Zerbini G. The therapeutic potential of VEGF 
inhibition in diabetic microvascular complications. Am J Cardiovasc Drugs 2007;7:393-
8. 
40. 
Krishnan ST, Quattrini C, Jeziorska M, Malik RA, Rayman G. Neurovascular factors in 
wound healing in the foot skin of type 2 diabetic subjects. Diabetes Care 2007;30:3058-
62. 
41. 
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. 
42. 
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. 
43. 
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. 
44. 
Wolff JA, Budker V. The mechanism of naked DNA uptake and expression. Adv Genet 
2005;54:3-20. 
45. 
Malecki M, Kolsut P, Proczka R. Angiogenic and antiangiogenic gene therapy. Gene 
Ther 2005;12 Suppl 1:S159-69. 
46. 
Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events. In: 
CBER, ed. Rockville; 2006. 
47. 
Considerations for Plasmid DNA Vaccines for Infectious Disease Indications. In: CBER, 
ed. Rockville; 2007. 
48. 
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. 
49. 
Moghtaderi A, Bakhshipour A, Rashidi H. Validation of Michigan neuropathy screening 
instrument for diabetic peripheral neuropathy. Clin Neurol Neurosurg 2006;108:477-81. 
50. 
Perkins BA, Olaleye D, Zinman B, Bril V. Simple screening tests for peripheral 
neuropathy in the diabetes clinic. Diabetes Care 2001;24:250-6. 
51. 
Feldman EL, Stevens MJ. Clinical testing in diabetic peripheral neuropathy. Can J Neurol 
Sci 1994;21:S3-7. 
52. 
Melzack R. The short-form McGill Pain Questionnaire. Pain 1987;30:191-7. 
53. 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann 
Acad Med Singapore 1994;23:129-38. 

 
 
 
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APPENDICES 
 
 

 
 
 
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TABLE OF APPENDICES 
 
 
Appendix 1. 
Schedule of Evaluations and Visits................................................................. 56 
Appendix 2. 
Sample Informed Consent............................................................................... 58 
Appendix 3. 
Michigan Neuropathy Screening Instrument .................................................. 73 
Appendix 4. 
Test Article Administration ............................................................................ 78 
Appendix 5. 
Short Form McGill Pain Questionnaire .......................................................... 80 
Appendix 6. 
Brief Pain Inventory for Patients with Diabetic Peripheral Neuropathy (BPI-
DPN) ............................................................................................................... 82 
Appendix 7. 
Guidelines for the Early Detection of Cancer ................................................. 86 
Appendix 8. 
Visual Analog Scale ........................................................................................ 90 
Appendix 9. 
Laboratory Tests by Visit ................................................................................ 92 
 

 
 
 
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Appendix 1. 
Schedule of Evaluations and Visits 
 
 
 

 
 
 
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Appendix 2. 
Sample Informed Consent 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
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Page 60 of 93 
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 type I or II 
diabetes with current treatment control and, you are experiencing painful diabetic peripheral 
neuropathy (DPN) in both lower extremities.   
 
The specific events that result in painful diabetic peripheral neuropathy are not well understood, 
but high blood sugar, reduced blood flow in the limbs, and changes in the blood vessels are 
thought to result in damage to the nerves in the affected areas.  Stimulating the growth of new 
blood vessels may stimulate growth or regeneration of nerves and may reduce pain. Researchers 
have discovered that a protein called hepatocyte growth factor 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 diabetic neuropathy.  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 reduce pain related to 
diabetic neuropathy.  This study is intended to help determine: 
• The safety and tolerability of three different doses of VM202. 
• If there are any effects of VM202 on your symptoms of painful diabetic neuropathy. 
 
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 
addition to specialized laboratories to manage some parts of the detailed requirements of the 
study.   
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
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How many people will take part in this research study? 
A total of 12 to 14 patients will take part in this study at up to 3 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 an open label, dose-escalation clinical study.  This means that both you and your 
doctor will know what dose of VM202 you will receive.  Four to six subjects will be enrolled 
into each dosage group starting with the lowest dose group and ending with the highest dose 
group.  Each patient is treated with VM202 twice, with 14 days between treatments.  Each 
injection contains 0.5 ml of fluid with 0.25mg VM202 and will be placed into your right calf 
unless the study doctor determines that there are reasons to inject your left calf: 
 
Low Dose – 8 injections at each treatment.   
 
Middle Dose - 16 injections at each treatment.  
 
High Dose - 32 injections at each treatment.   
 
What tests, procedures, and diagnostic studies will be done during this study?  
There are 9 visits which span 12 months total time from visit #2 to visit #9.  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. 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
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Medication Review – Discussion with your doctor of what medications and dietary supplements 
you have taken or are currently taking.   
 
Assessment of neuropathy – 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. 
 
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 EKG – An electrocardiogram (EKG) 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 EKG machine.  This test 
typically takes approximately 15 to 20 minutes. 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
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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).  
 
Below is a list of each visit and the specific tests that will be done 
 
Visit # 1: Screening/Baseline Evaluations 
Screening is a process of evaluating your initial health status and assessing the status of your 
pain related to diabetic neuropathy.  Screening is usually completed within two months 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, vital signs, medication review, 
questionnaire, assessment of neuropathy, cancer screening, retinal fundoscopy; urine and tests 
including a viral screen; photograph and measurement of ulcer, pregnancy test (if you are a 
female), and 12 lead EKG. 
 
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 
to the first available VM202 dose group.  You will then be scheduled for the first injection 
procedure which will be done at your next visit (Visit #2).   
 
Visit # 2 – First Injection Procedure (injection of VM202 into the calf muscle) 
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  
medication review, questionnaires, vital signs, photograph and measurement of ulcer 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 at sites evenly distributed over your calf muscle.  
The number of injections depends on which dosage group you are enrolled in; you will receive 8, 
16 or 32 injections 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
Protocol VMDN-001/G 
CONFIDENTIAL 
ViroMed, Ltd. 
 
 
Page 64 of 93 
 
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, 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/Final 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, 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 at 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.  The number of injections depends on which 
dosage group you are enrolled in; you will receive 8, 16 or 32 injections. 
 
Each injection will take 20 – 30 seconds.  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, blood tests including HGF and VM202, injection site reaction assessment, and 
assessment of side effects. 
 
Before you go home you will receive detailed discharge instructions.  

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
Protocol VMDN-001/G 
CONFIDENTIAL 
ViroMed, Ltd. 
 
 
Page 65 of 93 
 
Visit # 4 – 21 Days after the First Injection Procedure 
At this visit, the following tests or evaluations will be done:  medication review, vital signs, 
blood tests including HGF and VM202, injection site reaction assessment, and assessment of 
side effects. 
 
Visit # 5 –  30 Days after the First Injection Procedure 
At this visit, the following tests or evaluations will be done:  medication review, questionnaires, 
vital signs, blood tests including HGF and VM202, photograph and measurement of any ulcers 
which were present before the first injection, injection site reaction assessment, and assessment 
of side effects. 
 
Visit # 6 – 60 Days after the First Injection Procedure 
At this visit, the following tests or evaluations will be done:  medication review, questionnaires, 
vital signs, blood tests including HGF and VM202, photograph and measurement of any ulcers 
which were present before the first injection, injection site reaction assessment, and assessment 
of side effects. 
 
Visit # 7 – 90 Days after the First Injection Procedure 
At this visit, the following tests or evaluations will be done:  medication review, questionnaires, 
vital signs, blood tests including VM202, photograph and measurement of any ulcers which were 
present before the first injection, and assessment of side effects. 
 
Visit # 8 – 6 Months after the First Injection Procedure 
At this visit, the following tests or evaluations will be done:  medication review, questionnaires, 
vital signs, blood tests, photograph and measurement of any ulcers which were present before the 
first injection, and assessment of side effects. 
 
Visit # 9 – 12 Months after the First Injection Procedure 
At this visit, the following tests or evaluations will be done:  retinal fundoscopy, medication 
review, questionnaires, vital signs, blood tests, retinal fundoscopy, photograph and measurement 
of any ulcers which were present before the first injection, 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.   

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
Protocol VMDN-001/G 
CONFIDENTIAL 
ViroMed, Ltd. 
 
 
Page 66 of 93 
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? 
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 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
Protocol VMDN-001/G 
CONFIDENTIAL 
ViroMed, Ltd. 
 
 
Page 67 of 93 
(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 
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; 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 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
Protocol VMDN-001/G 
CONFIDENTIAL 
ViroMed, Ltd. 
 
 
Page 68 of 93 
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 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 EKG  
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 diabetic neuropathy will improve.  .   
 
Knowledge from this study may help us better understand how to treat people with painful 
diabetic neuropathy.     
 
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 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
Protocol VMDN-001/G 
CONFIDENTIAL 
ViroMed, Ltd. 
 
 
Page 69 of 93 
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.   
 
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 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
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CONFIDENTIAL 
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Page 70 of 93 
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 
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 MedTech Consultants, Inc., 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?   
Currently, there are no approved drugs or treatment strategies known to stop or reverse the 
progression of diabetic peripheral neuropathy.  Treatments goals are to reduce pain, improve 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
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CONFIDENTIAL 
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Page 71 of 93 
physical function, reduce psychological distress, and improve quality of life.  Good glycemic 
control is the only factor shown to slow the progress of neuropathy symptoms.  Lowering your 
triglyceride level, losing weight (if you are overweight), stopping smoking (smokers only) and 
reducing blood pressure have also shown to reduce diabetic neuropathy symptoms. 
 
If you choose not to take part in this study, other commonly prescribed medicines may be 
available for treatment of your diabetic neuropathy.  You do not have to take part in this study to 
receive treatment for your condition.  
 
Your doctor may suggest that you use a topical over the counter medication for pain relief (such 
as lidocaine or capsaicin) and may suggest taking nutritional supplements such as α-lipoic acid 
(a chemical found naturally in various plants such as spinach and broccoli). 
 
There are only two drugs approved by FDA specifically for the treatment of the (nerve) pain 
associated with DPN: Cymbalta – (duloxetine),; and Lyrica - (pregabalin). 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE I/II OPEN LABEL, DOSE-ESCALATION STUDY TO ASSESS THE SAFETY AND TOLERABILITY 
OF VM202 IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY 
(PROTOCOL VMDN-001) 
 
 
Protocol VMDN-001/G 
CONFIDENTIAL 
ViroMed, Ltd. 
 
 
Page 72 of 93 
 
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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Appendix 3. 
Michigan Neuropathy Screening Instrument 
 
 

 
 
 
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How to Use the Michigan Neuropathy Screening Instrument 
 
 
History.  The history questionnaire is self-administered by the patient.  Responses are added to 
obtain the total score.  Responses of “yes” to items 1-3, 5-6, 8-9, 11-12, 14-15 are each counted 
as one point.  A “no” response on items 7 and 13 counts as 1 point.  Item #4 is a measure of 
impaired circulation and item #10 is a measure of general aesthenia and are not included in 
scoring.  To decrease the potential for bias, all scoring information has been eliminated from the 
patient version.    
 
 
Physical Assessment.  For all assessments, the foot should be warm (>30°C).   
 
Foot Inspection:  The feet are inspected for evidence of excessively dry skin, callous formation, 
fissures, frank ulceration or deformities.  Deformities include flat feet, hammer toes, overlapping 
toes, halux valgus, joint subluxation, prominent metatarsal heads, medial convexity (Charcot 
foot) and amputation.    
 
Vibration Sensation:  Vibration sensation should be performed with the great toe unsupported.  
Vibration sensation will be tested bilaterally using a 128 Hz tuning fork placed over the dorsum 
of the great toe on the boney prominence of the DIP joint.  Patients, whose eyes are closed, will 
be asked to indicate when they can no longer sense the vibration from the vibrating tuning fork.    
In general, the examiner should be able to feel vibration from the hand-held tuning fork for 5 
seconds longer on his distal forefinger than a normal patient can at the great toe (e.g. examiner’s 
DIP joint of the first finger versus patient’s toe).  If the examiner feels vibration for 10 or more 
seconds on his or her finger, then vibration is considered decreased.  A trial should be given 
when the tuning fork is not vibrating to be certain that the patient is responding to vibration and 
not pressure or some other clue.  Vibration is scored as 1) present if the examiner senses the 
vibration on his or her finger for < 10 seconds, 2) reduced if sensed for ≥ 10 or 3) absent (no 
vibration detection.)   
 
Muscle Stretch Reflexes: The ankle reflexes will be examined using an appropriate reflex 
hammer (e.g. Trommer or Queen square).  The ankle reflexes should be elicited in the sitting 
position with the foot dependent and the patient relaxed.  For the reflex, the foot should be 
passively positioned and the foot dorsiflexed slightly to obtain optimal stretch of the muscle.  
The Achilles tendon should be percussed directly.  If the reflex is obtained, it is graded as 
present.  If the reflex is absent, the patient is asked to perform the Jendrassic maneuver (i.e., 
hooking the fingers together and pulling).  Reflexes elicited with the Jendrassic maneuver alone 
are designated “present with reinforcement.”  If there flex is absent, even in the face of the 
Jendrassic maneuver, the reflex is considered absent. 
 
Monofilament Testing:  For this examination, it is important that the patient’s foot be supported 
(i.e., allow the sole of the foot to rest on a flat, warm surface).  The filament should initially be 
prestressed (4-6 perpendicular applications to the dorsum of the examiner’s first finger).  The 

 
 
 
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filament is then applied to the dorsum of the great toe midway between the nail fold and the DIP 
joint.  Do not hold the toe directly.  The filament is applied perpendicularly and briefly, (<1 
second) with an even pressure.  When the filament bends, the force of 10 grams has been 
applied.  The patient, whose eyes are closed, is asked to respond yes if he/she feels the filament.   
Eight correct responses out of 10 applications is considered normal: one to seven correct 
responses indicates reduced sensation and no correct answers translates into absent sensation.   
 

 
 
 
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Appendix 4. 
Test Article Administration 

 
 
 
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Appendix 5. 
Short Form McGill Pain Questionnaire 
 
 

 
 
 
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Appendix 6. 
Brief Pain Inventory for Patients with Diabetic Peripheral Neuropathy (BPI-DPN) 

 
 
 
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Appendix 7. 
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  

 
 
 
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 
a strong family history of colorectal cancer or polyps (cancer or polyps in a first-degree relative 
[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 

 
 
 
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Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 
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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Appendix 8. 
Visual Analog Scale 

 
 
 
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Completion of the VAS is based on pain that the subject is experiencing in the right leg (pain 
below the knee which may include the calf, foot, or both).  If the right leg is medically 
contraindicated, the left leg will be assessed.  A score of > 4 cm (40 mm) is required in order to 
be eligible for the study.   
 
The VAS will be completed by the subject.  The subject should be asked: “How do you currently 
rate your pain in your leg (below the knee – this includes pain in your foot) that will 
undergo/underwent study injections?  Please place one tick mark on the line below.” 
 
                          |----------|----------|----------|----------|----------|----------|----------|----------|----------|----------| 
                          0         10          20         30         40         50         60         70         80         90       100 
                    No pain                                                                                                   Pain as bad  
                     at all                                                                                                        as it can be 
 
The subject should be instructed to indicate his or her current level of pain in the affected leg 
associated with diabetic neuropathy by placing a single vertical line perpendicular to the 
horizontal line of the scale ensuring that the two lines intersect.  Additionally, the subject 
should be instructed to not use a check mark, “x” or circle that would intersect the horizontal line 
of the scale multiple times.  Ensure the subject understands that the mark must be only one line 
that is perpendicular to and intersects the scale line.  The subject should complete the VAS with 
a fine or medium point pen; felt tip pens and pencils should not be used.  
 
The VAS should be checked for accuracy and completeness immediately after it is completed by 
the subject.  If the subject’s mark does not intersect the line or intersects the line more than once, 
reinstruct the subject to modify his or her mark so it meets the appropriate criteria.  Any 
corrections should be accompanied by the subject’s initial and date.  For Days 0 and 14, all 
corrections MUST be completed prior to injections; do NOT have the subject correct the scale 
after injections.  Instead, use the data collected prior to dosing. 
 
The VAS score (0 to 100mm) will be calculated by measuring the distance from the left end of 
the line (“No Pain”) along the scale to the mark made by the subject.  If the mark made by the 
subject intersects the horizontal line of the scale multiple times and was not corrected, measure 
to the middle point between the two marks.  If the mark made by the subject does not intersect 
the line of the scale and was not corrected, project the location of the mark vertically to a point 
on the line of the scale for the measurement.  
 
 

 
 
 
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Appendix 9. 
Laboratory Tests by Visit