Clinical trial NCT02563522
Conditions: Foot Ulcer, Diabetic
Keywords: non healing ulcers VM202 Diabetic ulcers foot ulcers Engensis
Sponsor: Helixmith Co., Ltd.
Start date: 2017-06-27; Completion date: 2019-09-24
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the safety and efficacy of using gene therapy via intramuscular injections of the calf for patients with chronic non-healing foot ulcers.

Detailed description:
A phase III, randomized, double-blind, placebo-controlled, multicenter, 7-month study designed to assess the safety and efficacy of intramuscular (IM) injections in the calf of Engensis (VM202) in patients with chronic nonhealing foot ulcers. Three hundred patients will be randomized in a 2:1 ratio of VM202 or placebo injections:

* Active -Engensis (VM202) + standard of care - 200 patients
* Control - Placebo (VM202 Vehicle) + standard of care - 100 patients

Arms: arm 1: Engensis (VM202) + standard of care arm 2: Placebo (VM202 Vehicle) + standard of care
Interventions: intervention 1: Engensis (VM202) intervention 2: Placebo
Intervention descriptions: intervention 1: gene therapy intervention 2: Standard of care plus placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
Protocol VMNHU-003 
 
 
 
Protocol Title: 
A Phase III, Double-Blind, Randomized, Placebo-Controlled, 
Multicenter Study to Assess the Safety and Efficacy of VM202 to 
Treat Chronic Nonhealing Foot Ulcers in Diabetic Patients with 
Concomitant Peripheral Arterial Disease (PAD) 
 
Protocol Number: 
VMNHU-003; Version I 
NCT Number: 
NCT02563522 
Document Date: 
04 February 2020 
 






I 
 
Protocol VMNHU-003/I 
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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, Helixmith 
Co., Ltd., except to the extent necessary to conduct this study and obtain approval from the 
Institutional Review Board 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, except where 
necessary to prevent any immediate danger to the subject.   
• 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 members 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 
Helixmith Co., Ltd., with or without cause, or by me or my institution if it becomes 
necessary to protect the best interest of the study subjects.   
 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
Title 
 
 
 
Address 
 
 
 
Signature / Date 
 


 
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STUDY SYNOPSIS 
 
PROTOCOL  
TITLE 
A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter 
Study to Assess the Safety and Efficacy of VM202 to Treat Chronic 
Nonhealing Foot Ulcers in Diabetic Patients with Concomitant Peripheral 
Arterial Disease (PAD) 
STUDY PHASE 
III 
INVESTIGATIONAL 
AGENT 
VM202 
DOSE 
16 mg of VM202 administered as a divided Dose of 4 mg each at Day 0, 
Day 14, Day 28, and Day 42.  
POPULATION 
Diabetic patients with confirmed concomitant PAD aged ≥ 18 years to 
≤ 80 years diagnosed with nonhealing foot ulcers. 
STUDY DESIGN 
A phase III, randomized, double-blind, placebo-controlled, multicenter, 
7-month study designed to assess the safety and efficacy of intramuscular 
(IM) injections in the calf of VM202 in patients with chronic nonhealing 
foot ulcers.  Three hundred patients will be randomized in a 2:1 ratio of 
VM202 or placebo injections:  
 
• Active –VM202 + standard of care – 200 patients 
• Control – Placebo (VM202 Vehicle) + standard of care – 100 patients 
Up to thirty (30) sites will participate in the study.  Safety will be 
monitored throughout the study by a Data Safety Monitoring Board 
(DSMB). 
STUDY OBJECTIVES 
1. To evaluate the efficacy of VM202 in promoting ulcer healing in 
nonhealing foot ulcers  
2. To evaluate the safety of IM administration of VM202 in subjects 
with nonhealing foot ulcers 
 
INCLUSION CRITERIA 
1. Male or female, between 18 and 80 years of age; 
2. Documented symptomatic peripheral arterial disease (PAD), with 
one or more of the following criteria satisfied: 
• Ankle Brachial Index (ABI) > 0.40 and ≤ 0.90 or > 1.4 (i.e., mild 
to severe PAD without critical limb ischemia) in target limb; 
• Toe Brachial Index (TBI) ≤ 0.7 in the target limb; 
• Toe pressure of < 55 mm Hg in the target limb; 
• A history of lower extremity PAD with previous related 
intervention in a leg; 


 
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3. Documented history of Type I or II diabetes with current treatment 
control (glycosylated hemoglobin A1c [HbA1c] of ≤ 12.0% at 
Screening) and currently on oral medication, injectable medication 
and / or insulin; 
4. No significant changes anticipated in diabetes medication regimen; 
5. At Screening, subject has one ulcer on the target foot that fulfills all 
of the following criteria: 
 
• Present for ≥ 2 weeks and ≤ 1 year 
• Full-thickness and not involving bone, tendon, or capsule 
(probing to tendon or capsule) 
• No sign of infection or osteomyelitis 
• Ulcer must be 0.5 cm2 – 15 cm2 as measured at Screening Visit 
prior to debridement 
 
If more than one ulcer is present on the foot, the largest ulcer that 
fulfills inclusion and exclusion criteria will be considered the target 
(index) ulcer for the study.  Subjects will undergo protocol-defined 
standardized wound care during screening (for two weeks or longer).  
Subjects will be considered screen failures and will not receive study 
injections on Day 0 (baseline) if the target ulcer does not meet all 
entry criteria (see above) as well as being confirmed as non-healing.   
 
6. Be capable of understanding and complying with the protocol and 
signing the informed consent document prior to being subjected to 
any study-related procedures; 
7. If female of childbearing potential, negative urine pregnancy test at 
screening and using acceptable method of birth control during the 
study. 
 
EXCLUSION CRITERIA 1. 
Will require revascularization in the target leg within 3 months of 
randomization; 
2. 
In the investigator’s assessment, will require an amputation in the 
target leg within 3 months of randomization; 
3. 
Subjects with target foot ulcer with an etiology of vasculitis, 
pyoderma gangrenosum, necrobiosis lipoidica, hydrostatic 
pressure/venous insufficiency, any neoplasms (basalioma, Kaposi’s 
sarcoma, squamous cell carcinoma, etc.), or due to a burn; 
4. 
The study ulcer increased or decreased by 50% or more at baseline 
from screening (as assessed by comparison of post-debridement 
photos taken at screening and Day 0);  
5. 
Evidence of active infection (e.g., cellulitis, osteomyelitis) or deep 
ulceration exposing bone or tendon in the foot planned for treatment; 
6. 
Any gangrene; 
7. 
Current fracture in the target foot; 
8. 
Target ulcer located on an active (hot) Charcot foot; 


 
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9. 
Heart Failure with a NYHA classification of III or IV;  
10. Body mass index (BMI) > 45 kg/m2 at Screening; 
11. Stroke or myocardial infarction within last 3 months; 
12. Unstable angina; 
13. Uncontrolled hypertension defined as sustained systolic blood 
pressure (SBP) > 200 mmHg or diastolic BP (DBP) > 110 mmHg at 
baseline/screening evaluation; 
14. Ophthalmologic conditions pertinent to proliferative retinopathy or 
conditions that preclude standard ophthalmologic examination; 
15. Inflammatory disorder of the blood vessels (inflammatory 
angiopathy, such as Buerger’s disease); 
16. Subjects with advanced liver disease including decompensated 
cirrhosis, jaundice, ascites or bleeding varices; 
17. Subjects currently receiving immunosuppressive medications 
chemotherapy, or radiation therapy; 
18. Positive HIV or HTLV at Screening; 
19. Active Hepatitis B or C infection as determined by Hepatitis B 
surface antibody (HBsAb), Hepatitis B core antibody (IgG and IgM; 
HBcAb), Hepatitis B surface antigen (HBsAg) and Hepatitis C 
antibodies (Anti-HCV), at Screening; 
20. Clinically significant specific laboratory values at screening (e.g., 
Hemoglobin < 8.0 g/dL, WBC < 3,000 cells per microliter, platelet 
count <75,000/mm3,  AST and/or ALT > 3 times the upper limit of 
normal, or any other clinically significant lab abnormality which in 
the opinion of the investigator should be exclusionary); 
21. Glomerular filtration rate (GFR) < 30 mL/min/1.73 m2 
22. Subjects 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 for at least 1 year); subjects with medical history and/or 
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; 
23. Subjects with any comorbid conditions likely to interfere with 
assessment of safety or efficacy or with an estimated life expectancy 
of less than 1 year; 
24. Subjects requiring > 81 mg daily of acetylsalicylic acid. If > 81 mg 
are taken at screening, subjects may be enrolled if willing/able to 
switch to another medication for the duration of the study; 
25. Subjects requiring regular (daily) COX-2 inhibitor drug(s) or 
steroids (except inhaled steroids or ocular steroids); subjects may be 
enrolled if willing/able to undergo medication wash-out prior to the 
first dosing and to refrain from taking these drugs during the study; 
26. Major psychiatric disorder in past 6 months; 
27. History of drug or alcohol abuse / dependence in the past 2 years; 




 
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VM202 will be delivered in a solution of 0.5 mg VM202 / mL.  All 
subjects will receive sixteen (16) 0.5-mL injections of VM202 or placebo 
at each injection visit as follows: 
Subjects in the VM202 Treatment Arm will receive the following IM 
injections in the calf of the leg with the target ulcer: 
• Day 0 – 16 injections of 0.5 mL of VM202 (4 mg of VM202) 
• Day 14 – 16 injections of 0.5 mL of VM202 (4 mg of VM202) 
• Day 28 – 16 injections of 0.5 mL of VM202 (4 mg of VM202 
• Day 42 – 16 injections of 0.5 mL of VM202 (4 mg of VM202) 
Subjects in the Placebo Group will receive 16 injections of 0.5 mL 
VM202 vehicle in the ipsilateral calf of the affected foot with the target 
ulcer at each injection visit. 
Note: Visually, placebo is indistinguishable from reconstituted VM202.  
The subject and clinician will not be able to distinguish placebo from 
VM202 injections. 
 
Subjects will continue to come to the clinic once a week for dressing 
changes and wound assessment until the ulcer has healed or study exit, 
whichever comes first. 
HGF serum levels will be determined immediately pre-treatment on 
Day 0, immediately pre-treatment on Day 28, and on Day 60 and Day 90. 
The number of copies of VM202 in whole blood will be determined at 
Day 0 (pre-injection, and 2 hours [± 1 hour] post injection), at Day 14 
(pre-injection, and 2 hours [± 1 hour] post injection), at Day 28 (pre-
injection, and 2 hours [± 1 hour] post injection), at Day 42 (pre-injection, 
and 2 hours [± 1 hour] post injection) at Day 60 and at Day 90.   
Measurement of target ulcer will be performed at each follow-up visit 
until complete wound closure is achieved or until study exit.  ABI, TBI, 
and the Cardiff Wound Impact Questionnaire (CWIQ) will be conducted 
on Day 0, Day 120, and Day 210 Visits.  TcPO2 will be assessed as a sub-
study at 3 -10 sites on Day 0, Day 120, and Day 210 Visits.  Adverse 
events will be recorded after first study drug administration and 
throughout the 7-month follow-up period. 
 
SCHEDULE OF 
EXAMINATIONS 
Screening (Day -45 to Day -7) 
Day 0 
Day 14 ± 3 days 
Day 28 ± 3 days 


 
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Day 42 ± 3 days 
Day 60 ± 3 days 
Day 74 ± 3 days 
Day 90 ± 7 days 
Day 120 ± 7 days 
Day 210 ± 14 days 
STUDY ENDPOINTS 
The primary study endpoint is the proportion of subjects with a target 
wound closure by the 4-month follow-up.  Complete wound closure is 
defined as skin re-epithelization without drainage or dressing (primary 
endpoint), confirmed at a second scheduled or unscheduled visit two 
weeks (14 ± 5 days) later (secondary endpoint).  Active and placebo arms 
will be compared to determine treatment effect. 
Other endpoints will include: 
• Time to complete healing of foot ulceration in each group   
• Percent change in wound size 
• Formation of new ulcers on the target foot 
• Change in CWIQ 
• Major amputations 
• Minor amputations 
• Change in ABI  
• Change in TBI 
• Change in TcPO2 at select sites only 


 
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TABLE OF CONTENTS 
 
INVESTIGATOR’S AGREEMENT ......................................................................................................... 3 
STUDY SYNOPSIS ............................................................................................................................. 4 
TABLE OF CONTENTS ..................................................................................................................... 10 
ABBREVIATIONS ............................................................................................................................ 14 
PERSONNEL AND FACILITIES .......................................................................................................... 16 
1. 
BACKGROUND .......................................................................................................................20 
1.1. 
Nonhealing Foot Ulcers .........................................................................................20 
1.1.1. 
PAD and Diabetes – Two Roads to a Chronic Wound ............................21 
1.2. 
Wound Healing ......................................................................................................21 
1.3. 
Current Treatment Options ....................................................................................22 
1.4. 
Unmet Medical Need .............................................................................................22 
1.5. 
Hepatocyte Growth Factor (HGF) and Wound Healing ........................................23 
1.6. 
VM202 for the Treatment of Chronic Foot Ulcers ................................................24 
1.6.1. 
Safety of VM202 ......................................................................................24 
1.6.2. 
VM202 Wound Healing Data - Rationale ................................................25 
1.6.3. 
Phase I Study of VM202 in Patients with Critical Limb Ischemia ..........25 
1.6.4. 
Phase II Study of VM202 in Patients with Critical Limb Ischemia .........26 
1.6.5. 
Clinical Experience Conclusions ..............................................................28 
1.7. 
Study and Dose Rationale ......................................................................................28 
2. 
GOOD CLINICAL PRACTICES (GCP) STATEMENT ...................................................................29 
3. 
INVESTIGATIONAL PLAN ........................................................................................................29 
3.1. 
Study Objectives ....................................................................................................29 
3.2. 
Study Design ..........................................................................................................29 
3.3. 
Subject Population .................................................................................................32 
3.3.1. 
Inclusion Criteria ......................................................................................32 
3.3.2. 
Exclusion Criteria .....................................................................................33 
3.4. 
Study Procedures ...................................................................................................35 
3.4.1. 
Informed Consent .....................................................................................35 
3.4.2. 
Subject Identification ...............................................................................35 
3.4.3. 
Screening (Day -45 to Day -7)__________________________________
 ..................................................................................................................35 
3.4.4. 
Standard of Care .......................................................................................36 
3.4.4.1. 
Wound Assessment and Dressing Changes during Screening .36 
3.4.5. 
Prohibited Concomitant Medications/Treatments ....................................37 
3.4.5.1. 
Medication that may interfere with VM202 bioactivity ..........37 
3.4.5.2. 
Medications/Treatment that may interfere with assessment of 
VM202 Effect on Ulcer Healing ..............................................37 
3.4.5.3. 
Screen Failures .........................................................................37 
3.4.5.4. 
Re-Screening ............................................................................37 
3.4.6. 
Treatment Authorization ..........................................................................38 
3.4.7. 
Randomization and Blinding ....................................................................38 


 
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3.4.8. 
Day 0 – 1st Injections ................................................................................39 
3.4.8.1. 
Pre-Injection (within 4 hrs prior to injections) ........................39 
3.4.8.2. 
1st Dose of VM202 or Placebo .................................................39 
3.4.8.3. 
Post-Injection (2 hours ± 1 hour post injection) ......................40 
3.4.9. 
Wound Assessment and Dressing Changes after Day 0 ...........................40 
3.4.10. Day 14 ± 3 Days – 2nd Injections .............................................................40 
3.4.10.1. Pre-Injection (within 4 hours prior to the injections)...............40 
3.4.10.2. 2nd Dose of VM202 or Placebo ................................................40 
3.4.10.3. Post-Injection (2 hours ± 1 hour post injection) ......................40 
3.4.11. Day 28 ± 3 Days – 3rd Injections ..............................................................41 
3.4.11.1. Pre-Injection (within 4 hours prior to the injections)...............41 
3.4.11.2. 3rd Dose of VM202 or Placebo ................................................41 
3.4.11.3. Post-Injection (2 hours ± 1 hour post injection) ......................41 
3.4.12. Day 42 ± 3 Days – 4th Injections ..............................................................41 
3.4.12.1. Pre-Injection (within 4 hours prior to the injections)...............41 
3.4.12.2. 4th Dose of VM202 or Placebo ................................................41 
3.4.12.3. Post-Injection (2 hours ± 1 hour post injection) ......................42 
3.4.13. Day 60 ± 3 Days .......................................................................................42 
3.4.14. Day 74 ± 3 Days .......................................................................................42 
3.4.15. Day 90 ± 7 Days .......................................................................................42 
3.4.16. Day 120 ± 7 Days .....................................................................................43 
3.4.17. Day 210 ± 14 Days ...................................................................................43 
3.4.18. Confirmation of Ulcer Healing .................................................................43 
3.5. 
Study Completion ..................................................................................................44 
3.5.1. 
Completed Subjects ..................................................................................44 
3.5.2. 
Discontinued Subjects ..............................................................................44 
3.5.3. 
Premature Study Termination ..................................................................45 
3.6. 
Investigational Drug Product and Accountability..................................................45 
3.6.1. 
Investigational Drug Product ....................................................................45 
3.6.2. 
Placebo .....................................................................................................45 
3.6.3. 
Product Accountability .............................................................................46 
3.6.4. 
Dose and Administration ..........................................................................46 
3.7. 
Prior and Concomitant Medication ........................................................................47 
4. 
EXAMINATIONS AND EVALUATIONS ......................................................................................47 
4.1. 
Evaluations Conducted at Baseline Only ...............................................................47 
4.1.1. 
Medical History ........................................................................................47 
4.1.2. 
Physical Exam ..........................................................................................47 
4.1.3. 
Cancer Screening ......................................................................................47 
4.1.4. 
Viral Screening .........................................................................................48 
4.1.5. 
Foot X-ray ................................................................................................48 
4.1.6. 
12-Lead EKG ...........................................................................................49 
4.1.7. 
Pregnancy Test (women of childbearing potential only) .........................49 
4.2. 
Evaluations Conducted Throughout the Study ......................................................49 
4.2.1. 
Documentation of Target Ulcer ................................................................49 
4.2.2. 
Retinal Fundoscopy ..................................................................................49 
4.2.3. 
Concomitant Medications .........................................................................49 


 
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4.2.4. 
Vital Signs ................................................................................................50 
4.2.5. 
Serum Chemistry, Hematology and HbA1c .............................................50 
4.2.6. 
Serum HGF ...............................................................................................50 
4.2.7. 
Copies of VM202 in Whole Blood ...........................................................51 
4.2.8. 
Ankle Brachial Index (ABI), Toe Brachial Index (TBI) and Toe Pressure 
in the Target Limb ....................................................................................51 
4.2.9. 
Transcutaneous Oxygen Pressure (TcPO2,) .............................................51 
4.2.10. Cardiff Wound Impact Questionnaire (CWIQ) ........................................52 
4.2.11. Injection Site Reaction Assessment .........................................................52 
5. 
EVALUATION OF ADVERSE EVENTS .......................................................................................53 
5.1. 
Definitions..............................................................................................................53 
5.2. 
Assessment of Adverse Events (AEs)....................................................................54 
5.2.1. 
AE Causality .............................................................................................55 
5.2.2. 
AE Intensity ..............................................................................................56 
5.3. 
Reporting/Recording of AEs..................................................................................56 
5.4. 
Reporting / Recording of SAEs .............................................................................56 
5.4.1. 
Investigator’s Responsibility ....................................................................56 
5.4.2. 
Sponsor’s Responsibility ..........................................................................57 
6. 
STATISTICAL METHODS .........................................................................................................58 
6.1. 
Sample Size Calculation ........................................................................................58 
6.2. 
Analysis Population ...............................................................................................58 
6.2.1. 
Intent-to-Treat Population (ITT) ..............................................................58 
6.2.2. 
Safety Population .....................................................................................59 
6.2.3. 
Modified ITT (mITT) Population .............................................................59 
6.2.4. 
Per Protocol (PP) Population ....................................................................59 
6.3. 
Study Endpoints .....................................................................................................60 
6.3.1. 
Primary Endpoint .....................................................................................60 
6.3.2. 
Other Endpoints ........................................................................................60 
6.3.3. 
Safety ........................................................................................................61 
6.3.4. 
Pharmacokinetics ......................................................................................61 
6.3.5. 
Data Safety Monitoring Board (DSMB) and Interim Analysis ................61 
6.4. 
Subject Categorization ...........................................................................................61 
7. 
ACCESS TO STUDY DOCUMENTS AND STUDY MONITORING...................................................62 
8. 
QUALITY CONTROL AND ASSURANCE....................................................................................62 
9. 
INSTITUTIONAL REVIEW BOARD ............................................................................................63 
10. 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) .....................................................................64 
11. 
INFORMED CONSENT PROCESS ...............................................................................................64 
12. 
CONFIDENTIALITY .................................................................................................................64 
13. 
PROTOCOL AMENDMENTS .....................................................................................................65 
14. 
DATA MANAGEMENT .............................................................................................................65 
15. 
RECORD KEEPING AND RETENTION .......................................................................................66 
16. 
INVESTIGATOR FINAL REPORT ...............................................................................................67 


 
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17. 
STUDY REPORT AND PUBLICATION ........................................................................................67 
18. 
REFERENCES ..........................................................................................................................69 
REMOVABLE FOOTWEAR OFFLOADING OPTIONS ......................................................................... 101 
 
 
FIGURES &TABLES 
 
Figure 1. 
The overlapping relationship of risk factors associated with developing 
nonhealing ulcers in the United States ............................................................ 20 
Figure 2. 
VM202 construct ............................................................................................ 24 
 
Table 1. 
Phase I CLI Study Results: progression / healing of ulcers ............................ 26 
Table 2. 
Ulcer distribution by treatment group on Day 0 (baseline) ............................ 27 
Table 3. 
Progression of ulcers present and documented at baseline by treatment group
......................................................................................................................... 28 
Table 4. 
Treatment: Days 0, 14, 28 and 42 ................................................................... 31 
Table 5. 
Components of VM202 Vehicle ..................................................................... 46 
Table 6. 
Injection Reaction Assessment ....................................................................... 52 
Table 7. 
Statistical power by estimated responder rates for Treatment (pt) and Control 
(pc) arms .......................................................................................................... 58 
Table 8. 
Removable footwear options for off-loading by ulcer location .................... 101 
Table 9. 
Single dose preparation and delivery for Day 0, Day 14, Day 28 and Day 42 
Visits ............................................................................................................. 112 
 
 
TABLE OF APPENDICES 
 
Appendix 1. 
Schedule of Evaluations and Visits & Laboratory Tests by Visit .................. 75 
Appendix 2. 
Sample Informed Consent............................................................................... 79 
Appendix 3. 
Medications/Therapies Excluded from Use During the Study ....................... 96 
Appendix 4. 
Standardized Wound Care .............................................................................. 99 
Appendix 5. 
Target Ulcer Documentation......................................................................... 104 
Appendix 6. 
ABI, TBI and Toe Pressure ........................................................................... 107 
Appendix 7. 
Test Article Administration .......................................................................... 111 
Appendix 8. 
The Cardiff Wound Impact Questionnaire (CWIQ) ..................................... 113 
 
 


 
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ABBREVIATIONS 
 
AE 
Adverse Event 
ABI 
Ankle Brachial Index 
ALT 
Alanine Transaminase (SGPT) 
Anti-HCV 
Hepatitis C antibodies 
AST 
Aspartate Transaminase (SGOT) 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN  
 
Blood Urea Nitrogen 
cDNA 
Complementary Deoxyribonucleic Acid 
CBC 
Complete Blood Count 
CDRC 
Clinical Data Review Committee 
CFR 
Code of Federal Regulation 
CLI 
Critical Limb Ischemia 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CS 
Clinically Significant 
CWIQ 
Cardiff Wound Impact Questionnaire 
DBP 
Diastolic Blood Pressure 
DNA 
Deoxyribonucleic Acid 
DP 
Dorsal-Plantar / Dorsalis Pedis 
DPN 
Diabetic Peripheral Neuropathy 
DSMB 
Data Safety Monitoring Board 
ECM  
Extracellular Matrix 
EDC 
Electronic Data Capturing 
EKG 
Electrocardiogram 
EPC 
Endothelial Progenitor Cells  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices  
GFR 
Glomerular filtration rate 
HBV 
Hepatitis B Virus 
HBcAb 
Hepatitis B core antibody  
HBsAb 
Hepatitis B surface antibody  
HBsAg 
Hepatitis B surface antigen 
HCT 
Hematocrit 
HCV 
Hepatitis C Virus 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
Hgb 
Hemoglobin 
HGF 
Hepatocyte Growth Factor 
HIV 
Human Immunodeficiency Virus 
HTLV 
Anti-Human T-Cell Lymphotropic Virus 
IBC 
Institutional Biosafety Committee 
IRB 
Institutional Review Board 
IM 
Intramuscular 
IND 
Investigational New Drug 


 
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ITT 
Intent-to-Treat 
mITT 
Modified Intent-to-Treat 
MMP 
Matrix Metalloproteinases 
MSC 
Mesenchymal Stem Cells 
NCS 
Not Clinically Significant 
NIH 
National Institutes of Health 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs  
OBA 
Office of Biotechnology Activities 
OSP 
Office of Science Policy 
PAD 
Peripheral Arterial Disease 
PP 
Per Protocol 
PPG 
Photoplethysmography 
PT 
Posterior Tibial 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 
ROS 
Reactive Oxygen Species 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAWC 
Symposium on Advanced Wound Care 
SBP 
Systolic Blood Pressure 
SGOT 
Serum Glutamic Oxaloacetic Transaminase (same as AST) 
SGPT 
Serum Glutamic Pyruvic Transaminase (same as ALT) 
SOP  
Standard Operating Procedure 
TAR 
Treatment Authorization Request 
TBI 
Toe Brachial Index 
TcPO2 
Transcutaneous oxygen pressure 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cells 
WFI 
Water for Injection 
 
 
 










 
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1. 
BACKGROUND 
 
1.1. 
NONHEALING FOOT ULCERS 
Over 6.5 million people in the United States have chronic, nonhealing foot ulcers.1,2  
The ulcers initially occur due to trauma, pressure loading, and / or neuropathy.  
Ulcers fail to heal and become chronic when the energy demands of wound repair 
cannot be met because of infection and / or when underlying disease inhibits the 
normal pathways for energy production.   
 
Chronic wounds are unresponsive to standard therapies and persist despite 
appropriate care.3,4  The majority (approximately 90%) occur in patients with 
diabetes, but this attribution can be misleading, as 10% - 50% of these patients have 
concomitant peripheral arterial disease (PAD).5-11  Most patients have some form of 
peripheral neuropathy.12  A small percentage occurs in patients whose primary 
condition is ischemic, and in whom revascularization / reperfusion has not resulted 
in wound healing.9   
 
The lifetime risk of developing nonhealing foot ulcers for individuals with diabetes 
is 15 - 25% with a 50% - 70% recurrence rate within 5 years after the index 
occurrence.1,2,9,13,14  The chance of developing an ulcer doubles in patients with 
concomitant PAD.6,7,9,14  Figure 1 below depicts the chronic foot ulcer population 
and the degree to which ischemia and diabetes overlap.  The area circled by the thick 
black line characterizes patients with foot ulcers which suffer from both ischemia 
and diabetes. 
 
 
 
Figure 1. The overlapping relationship of risk factors associated with developing 
nonhealing ulcers in the United States1,9,11,13,15-17 
 
Nonhealing ulcers can significantly affect a patient’s quality of life, with patients 
reporting social isolation, unemployment, depression, and feelings of stigma.18-21  


 
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Current treatment strategies result in healing approximately 50% of ulcers, 
regardless of underlying comorbidity(ies), but most ulcers recur.2,22  Twenty-five 
percent (25%) of open wounds progress to gangrene or enlarge to such an extent that 
they require amputation.  The five-year mortality rate associated with an index 
occurrence of a nonhealing ulcer is comparable to or greater than that of many 
cancers.10  This significant and growing public health concern costs the US 
healthcare system over $25 billion annually without accounting for productivity loss.   
 
1.1.1. 
PAD AND DIABETES – TWO ROADS TO A CHRONIC WOUND 
Diabetes and PAD are often intertwined conditions.5,7,12,21,23  PAD is a progressive, 
atherosclerotic disease that obstructs the blood supply to the lower limbs.  It 
frequently coexists with coronary and / or cerebrovascular disease, likely due to a 
similar underlying pathology and shared risk factors (e.g., smoking, hyperlipidemia, 
hypertension, age, and obesity).   
 
The likelihood of developing PAD increases with diabetes.7,15  Diabetes is a 
metabolic disorder characterized by chronic hyperglycemia with disturbances of 
carbohydrate, fat and protein metabolism.  The metabolic dysfunction arises from 
defects in insulin secretion (type 1), insulin action (type 2), or a combination of 
both.24  Hyperglycemia accelerates atherosclerosis and worsens platelet aggregation, 
significantly increasing the chances of thrombosis, stroke, peripheral ischemia, and 
microvasculature and peripheral nerve damage.  Independently, either disease 
process can result in compromised mobility and susceptibility to peripheral tissue 
damage which can then progress to nonhealing foot ulcers.  When PAD and diabetes 
are present together, morbidity and mortality are greater. 
 
Both conditions can impair the ability of the underlying microvasculature and 
surrounding tissues to support wound healing.  Mitochondrial dysfunction, 
particularly in endothelial cells, plays a key role in the pathogenesis, because 
mitochondria provide the energy necessary to sustain wound healing.  When they 
function suboptimally, they do not produce enough energy, and wound healing 
cannot proceed normally.   
 
 
 
1.2. 
WOUND HEALING 
Normal wound repair is a relatively linear process (albeit with significant complexity 
and overlap) which progresses through three general phases: 
 
Inflammatory: including platelet aggregation, release of proinflammatory cytokines 
and recruitment of neutrophils and macrophages;  
Proliferative: including fibroblast proliferation, angiogenesis, formation of 
granulation tissue and keratinocyte proliferation, and re-epithelialization; and  
Remodeling: longest phase; includes myofibroblast transformation and restructure of 
healed wound to increase strength. 
 


 
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The three phases rely heavily on the microvasculature surrounding the wound area to 
facilitate nutrient and growth factor transport, oxygen exchange and to provide a 
conduit for the movement of immune and reparatory cells.  In patients suffering from 
ischemia and/or metabolic derangement, compromised endothelial cells can arrest 
and even hinder each stage of the repair process.  Reactive oxygen species (ROS) 
generated by mitochondria in response to intracellular hypoxia and / or 
hyperglycemia worsen and prolong inflammation.25-28  Endothelial permeability 
increases, leaving the endothelium and underlying tissues more susceptible to 
damage by the increased influx of glucose and free radicals.  And, although cellular 
immunity is activated, hypoxic conditions impair the abilities of neutrophils and 
macrophages to phagocytize bacteria and dying cells.  This increases the likelihood 
of the wounds to become chronically infected.   
 
The proliferative phase can also protract in these patients due to local hypoxic 
conditions caused either by compromised circulation, reduced erythrocyte function 
(due to nonenzymatic glycosylation), or both.  Reduced oxygen delivery to the 
wound site hinders angiogenesis and collagen synthesis.  In addition, the heightened 
energy demands (need for additional ATP) required for coordinating new blood 
vessel formation and tissue regeneration, particularly within granulation tissue, 
cannot be met by the metabolically compromised mitochondria.  
 
Finally, the remodeling phase is compromised due to local ischemic conditions and 
because pro-inflammatory cytokines remain persistently high.  This causes a 
sustained overexpression of matrix metalloproteinases (MMPs).  In normal wound 
healing, MMPs orchestrate the turnover of extracellular matrix (ECM) to form a 
more mature tissue with appropriate tensile strength.  Under pathological conditions, 
however, the overproduction of MMPs causes tissue breakdown making wound 
enlargement or re-injury more likely.   
 
 
1.3. 
CURRENT TREATMENT OPTIONS 
The standard of care for chronic foot ulcers includes debridement of the wound, 
management of any infection, revascularization procedures when indicated, 
mechanical offloading of the ulcer, management of blood glucose, and foot care 
education.  Other adjunctive therapies, such as hyperbaric oxygen, use of advanced 
wound care products, and negative-pressure wound therapy have shown some 
benefit, but reports of efficacy are mixed, and their cost-effectiveness has not been 
demonstrated.14,29   
 
 
1.4. 
UNMET MEDICAL NEED 
Chronic foot ulcers are associated with significant morbidity and mortality and 
present a growing public health concern.  At best, even advanced therapies such as 
human-derived products regulated under 21 CFR 1271 (e.g., AlloDerm, AlloPatch, 
Cumetra, etc.) and FDA-approved products such as Regranex (BLA 103691, 1997), 
Apligraf (P950032, 2000), and Dermagraft (P000036, 2001) only result in complete 


 
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wound healing in 20% - 50% of patients treated.  Clearly, it would be desirable to 
develop other therapeutic options to treat chronic ulcers. 
 
 
1.5. 
HEPATOCYTE GROWTH FACTOR (HGF) AND WOUND HEALING 
Most foot ulcers are caused by a combination of neuropathy, pressure loading, 
and/or trauma.  Ischemia and / or hyperglycemia are not the initiating factors.  
However, whether present together or singularly, these comorbidities impair 
mitochondrial function, reduce the cellular energy supply available for repair, and 
worsen local inflammatory conditions.   
 
HGF, a multi-functional cytokine with potent neovascularization effects, including 
vasculogenesis, angiogenesis and arteriogenesis, may be uniquely suited to improve 
outcomes for chronic wounds.  HGF has been described as a ‘master trigger’ because 
of its ability to interact with the c-met receptor and modulate the expression of Ets-1, 
a highly conserved transcription factor which initiates transcription of numerous 
genes encoding angiogenic modulators such as vascular endothelial growth factor 
(VEGF).30-34 More salient for wound repair, HGF can positively affect energy 
metabolism by minimizing mitochondrial caspase signaling and preventing 
apoptosis.35-40  It also triggers antioxidant genes through modulation of intracellular 
levels of glutathione, a major determinant of cellular redox potential, and of 
cytoprotective enzymes such as catalase, which further protect against damage from 
elevated levels of intracellular oxidative stress.41  Recent research also suggests that 
HGF has a role in maintaining nerve function and growth and in preserving nerve 
cell integrity in the face of metabolic derangements.37,42-46  For diabetics, 
preservation of sensation may assist with foot care and wound awareness. 
 
During normal wound healing, HGF signaling by damaged cells stimulates the 
growth of endothelial cells and migration of vascular smooth muscle cells.47,48  It 
also mobilizes circulating endothelial progenitor cells (EPCs) and mesenchymal 
stem cells (MSCs) to the damaged area.47-53 These cells, in turn, secrete additional 
growth factors and antioxidants which facilitate fibroblast proliferation, 
angiogenesis, formation of granulation tissue and keratinocyte proliferation, and re-
epithelialization (see Section 1.2).  In the remodeling phase of wound healing,  HGF 
promotes epithelial repair,54 improves tissue fibrosis, and limits collagen 
metabolism, thereby decreasing scar formation.55  In chronic wounds, however, the 
endogenous signal is insufficient to overcome the onslaught of oxidative stress and 
the ongoing metabolic dysfunction associated with the underlying pathology(ies).   
 
The challenge associated with delivering a targeted sustained dose of exogenous 
HGF is 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.56,57  
 
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 




 
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circulation and appears to remain active only at the injection site.  This is supported 
by the fact that circulating HGF levels remained fairly constant, relative to baseline 
(data not yet available for ALS study).   
 
1.6.2. 
VM202 WOUND HEALING DATA - RATIONALE 
Data from the phase I and phase II studies of VM202 in patients with critical limb 
ischemia (BB IND 13,158) suggest that VM202 promotes wound healing.  Results 
from the phase II study, in particular, showed a statistically significant improvement 
in wound healing over placebo (see Section 1.6.4).  In both studies, however, over 
half of the patients presenting with ulcers had concomitant diabetes.  As was 
discussed in the previous sections, peripheral ischemia and diabetes often coexist 
and accelerate pathology.  Both conditions create mitochondrial dysfunction, which, 
in turn damages the endothelial lining of the microvasculature.  As HGF is known to 
be a potent angiogenic and neuroprotective factor capable of upregulating 
antioxidant mechanisms and interfering with the molecular machinery of 
mitochondrial apoptotic signaling, it may be uniquely suited to treating nonhealing 
wounds.  In addition, data from the phase I and phase II studies of VM202 in 
patients with diabetic peripheral neuropathy (DPN, BB IND 13,938) suggest that 
VM202 may improve nerve health in diabetics.  In the phase I study, patients 
experienced significant improvements in pain over baseline out to 9 months.  In the 
phase II study, a prospective, randomized, placebo-controlled study of two different 
doses of VM202, subjects receiving 8 mg of VM202 per leg experienced statistically 
significant pain reduction at 3 months when compared to placebo.  Improvement in 
nerve function could be an important contributing factor in preventing ulcer 
recurrences.   
 
Considering VM202’s excellent safety profile to date, and the early evidence of its 
wound healing capabilities, this protocol involves a clinical study of VM202 in 
diabetic patients with concomitant PAD and nonhealing foot ulcers.  Sections 1.6.3 
and 1.6.4 provide a brief summary of the wound healing results from the phase I and 
phase II studies of VM202 in Critical Limb Ischemia (CLI) patients, respectively.  
 
1.6.3. 
PHASE I STUDY OF VM202 IN PATIENTS WITH CRITICAL LIMB ISCHEMIA 
The phase I study of VM202 in patients with CLI was a single-center, prospective, 
dose-escalation study designed to evaluate the safety and tolerability of 
intramuscular (IM) injections of VM202 in subjects with CLI.  The study only 
enrolled ‘no-option’ CLI patients with a Rutherford Scale score of 4 or 5.  Subjects 
received 2 mg, 4 mg, 8 mg, or 16 mg VM202.  Three subjects were treated per dose 
cohort, for a total of 12 subjects.  For each dose cohort, VM202 was administered as 
local IM injections with half of the dose administered at Day 1 of the study and the 
second half administered 2 weeks later.  Safety, tolerability, and preliminary efficacy 
(hemodynamic assessments) were evaluated at 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.  Clinical evaluations were 
conducted at Days 1 (baseline), 15, 28, 59, 91, 180, and 365.   
 




 
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followed for one year from the time of the first dose of study drug administration.  
Clinical evaluations were conducted at Day 0 (baseline), 14, 28, 42, 49, 90, 180, 270, 
and 365.   
 
52 subjects were randomized to one of the three treatment arms.  Fifty (50) subjects 
received all study injections.  If present prior to the first injection (Day 0), two 
photographs of each ulceration/gangrene area were obtained pretreatment on 
Days 14, 28 and 42, and on Day 49, Day 90, 6 months, 9 months and 12 months.   
 
Four subjects in the placebo group (4/10, 40%) had 6 ulcers at study entry.  Twelve 
subjects in the Low Dose had 25 ulcers at baseline (12/20, 60%); and seven subjects 
in the High Dose group had 14 ulcers at baseline (7/20, 35%).  All of the subjects 
with ulcers in the placebo arm had concomitant diabetes; 8/12 subjects (75%) in the 
Low Dose arm had concomitant diabetes; and, 3/7 subjects (43%) in the High Dose 
arm had concomitant diabetes.   Table 2 shows the distribution of ulcers in each 
treatment group. 
 
Table 2. 
Ulcer distribution by treatment group on Day 0 (baseline) 
Number of ulcers 
Number of subjects 
Placebo 
Low-dose 
High-dose 
1 
3/4 (75%) 
4/12 (33%) 
3/7 (43%) 
2 
0/4 (0%) 
5/12 (42%) 
1/7 (14%) 
3 
1/4 (25%) 
0/12 (0%) 
3/7 (43%) 
4 
0/4 (0%) 
3/12 (25%) 
0/7 (0%) 
Total Number of Ulcers 
6 
26 
14 
 
Ulcers were evaluated until healed, and, if not healed, to the last available study visit 
or amputation.  If an ulcer was lost due to amputation, the last recorded evaluation of 
the ulcer was carried forward.  Improvement or worsening was determined by 
changes in ulcer area.  The average area at baseline (Day 0) for ulcers in the placebo 
group was 3.7 cm2 (SD 5.6 cm2), 2.7 cm2 (SD 6.5 cm2) in the Low Dose group, and 
2.9 cm2 (SD 4.6 cm2) in the High Dose group.  The average increase in wound area 
was 4.3 cm2 (SD 12.6 cm2). 
 
Improvements were statistically significant for wound healing in both treatment 
groups.  Ulcers improved most in the High Dose group when compared to Placebo 
(p < 0.02).  Nine of the 14 ulcers in the High Dose Group (9/14, 64.3%) completely 
healed.  Of the 5 remaining ulcers, 4 improved (4/14, 28.6%) and one worsened 
(1/14, 7.1%).  Improvements were also seen in the Low Dose Group.  Fourteen of 
the 26 ulcers (14/26, 53.8%) present at baseline completely healed.  Of the 
remaining 12 ulcers, 8 improved (8/26, 30.8%), and 4 ulcers worsened (4/26, 
15.4%).  In the placebo group, only one (1) of the 6 ulcers (16.7%) completely 
healed from baseline.  The 5 other ulcers (5/6, 83.3%) increased in size.  Table 3 lists 
the progression of ulcers at the last available follow-up by treatment group. 
 




 
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2. 
GOOD CLINICAL PRACTICES (GCP) 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 GCP 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 that may affect the safety and welfare 
of study participants 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 III study is to evaluate the safety and efficacy of IM 
administration of VM202 in the treatment of chronic nonhealing foot ulcers in 
diabetic patients with concomitant PAD.   
 
 
3.2. 
STUDY DESIGN 
This is a phase III, double-blind, randomized, placebo-controlled, multicenter, 7-
month study designed to assess the safety and efficacy of VM202 to treat chronic 
nonhealing foot ulcers in diabetic patients with concomitant PAD.  Subjects with 
diabetes and a single chronic nonhealing foot ulcer on the target foot will be 
screened for study eligibility after giving informed consent.   
 
Initial Screening Activities. Prior to full screening, subjects with diabetes will 
provide informed consent and then undergo target ulcer documentation prior to 
debridement.  Only subjects whose target ulcer meets eligibility criteria (inclusion 
#5) will be allowed to proceed with the full screening procedures.  
 
Screening. Screening should occur at least 7 days and maximal 45 days prior to 
Day 0 (day of injection).  If the target ulcer criteria are met, the rest of screening will 
proceed to assess study eligibility in the following order: 
• Medical history 
• Concomitant medication review 
• Vital signs 
• Documentation of symptomatic PAD: 
o ABI > 0.40 and ≤ 0.90 or > 1.4 (i.e., mild to severe PAD without critical 
limb ischemia) in target limb 
o TBI ≤ 0.7 in the target limb 
o Toe pressure of < 55 mm Hg in the target limb 
o A history of lower extremity PAD with previous related intervention in a 
leg 
• Physical exam 
• Urine pregnancy testing (women of childbearing potential only)  


 
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• Chemistry, hematology, and HbA1c  
• Viral screening 
• 12-lead EKG  
• Foot x-ray  
• Fundoscopy  
• Cancer screening tests 
 
At Screening, standard of care for all wounds on the target foot will be initiated that 
will continue for the duration of the study, as follows: 
 
• Surgical debridement of necrotic tissue or devitalized tissue 
• Use of appropriate off-loading when ambulating 
• Maintenance of a clean and moist wound environment 
 
The target ulcer will be documented at screening visit before and after debridement.  
This includes photograph and surface area measurement, depth perimeter and 
volume.  Subjects will come in once a week for dressing changes and for wound 
evaluation during screening.  At these visits, vital signs, concomitant medications, 
target ulcer documentation. Any change in the subject’s medical condition should be 
documented in the medical history. 
 
If applicable, the subject will be washed out of prohibited medications prior to Day 0 
injections (see Appendix 3).  During washout, screening procedures may be 
performed.  At Day 0, the target ulcer will be documented by photograph, surface 
area measurement, depth, perimeter and volume before and after debridement.  
Subjects must have a non-healing ulcer on Day 0 that meets study inclusion criterion 
# 5 and exclusion criterion #6 to be eligible for study participation.   
 
Randomization.  Subjects who meet the eligibility criteria will be randomly assigned 
in a 2:1 fashion to one of the two treatment arms: VM202 (16 mg VM202 total 
dose), or placebo, respectively.  Assignment to a treatment arm will be centralized, 
using an independent predetermined randomization scheme in a double-blinded 
fashion (please refer to IWRS manual).  Blinding will be achieved by having the 
study medication (VM202 and placebo [VM202 vehicle]) prepared by the study 
pharmacist or designee.  Reconstituted VM202 is indistinguishable from the VM202 
vehicle. 
 
First Treatment.  Prior to the first injection, vital signs, concomitant medications, 
ABI, and TBI will be conducted.  TcPO2 will only be assessed as a sub-study at 3 -
10 sites. The target ulcer will be documented by photograph, surface area 
measurement, perimeter, depth and volume.  The Cardiff Wound Impact 
Questionnaire (CWIQ) will be completed.  Study entry criteria should be verified 
again.  In addition, blood will be drawn for determination of serum chemistry and 
hematology, HbA1c, serum HGF, and copies of VM202.   
 




 
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(photograph, surface area, depth, perimeter and volume measurements), and the 
occurrence of injection site reactions (if the visit occurs within 60 days) and AEs 
will be assessed. 
 
All subjects will be assessed at Day 60, Day 74, Day 90, Day 120 and Day 210; at 
all these visits, vital signs, concomitant medications, assessment of AEs and, if 
applicable, target ulcer documentation (photograph, surface area, depth, perimeter 
and volume measurements) will be conducted.     
 
The occurrence of injection site reactions will be assessed on Day 60. 
 
Blood will be drawn for determination of serum HGF, and copies of VM202 on 
Days 60 and 90.  Blood will be drawn for determination of serum chemistry and 
hematology on Days 90, 120 and 210.  Blood will be drawn for determination 
HbA1c on Days 120 and 210.  
 
ABI, TBI, and CWIQ will be determined on Day 120, and 210.  TcPO2 will be 
assessed as a sub-study at 3 -10 sites at these visits. 
 
Note, if the ulcer has healed, the subject needs to return to the clinic in 14 days (± 
5 days) in order to confirm complete wound closure at two consecutive study visits 
two weeks apart.  If target foot ulcer healing is first documented on Day 210, the subject 
will return for one additional visit 14 ± 5 days after Day 210 for a confirmation of ulcer 
healing visit. This confirmation visit may coincide with a pre-specified visit or may 
require an unscheduled visit.  
  
A summary of the schedule of evaluations and visits can be found in Appendix 1. 
 
 
3.3. 
SUBJECT POPULATION 
A total of 300 evaluable subjects with diabetes mellitus (DM) and concomitant PAD 
meeting the following study entry criteria will be enrolled.  
 
3.3.1. 
INCLUSION CRITERIA 
Subjects must satisfy all of the following criteria to be included in the study: 
 
1. 
Male or female, between 18 and 80 years of age; 
2. 
Documented history of symptomatic PAD, with one or more of the following 
criteria satisfied: 
 
• 
ABI > 0.40 and ≤ 0.90 or > 1.4 (i.e., mild to severe PAD without critical 
limb ischemia) in target limb; 
• 
TBI ≤ 0.7 in the target limb; 
• 
Toe pressure of < 55 mm Hg in the target limb; 
• 
A history of lower extremity PAD with previous related intervention in a 
leg; 


 
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3. 
Documented history of Type I or II diabetes with current treatment control 
(HbA1c of ≤ 12.0% at Screening) and currently on oral medication, injectable 
medication and / or insulin; 
4. 
No significant changes anticipated in diabetes medication regimen; 
5. 
At Screening, subject has one ulcer on the target foot that fulfills all of the 
following criteria: 
 
• 
Present for ≥ 2 weeks and ≤1 year 
• 
Full- thickness and not involving bone, tendon, or capsule (probing to 
tendon or capsule) 
• 
No sign of infection or osteomyelitis 
• 
Ulcer must be 0.5 cm2 – 15 cm2 as measured at Screening Visit prior to 
debridement 
 
If more than one ulcer is present on the foot, the largest ulcer that fulfills 
inclusion and exclusion criteria will be considered the target (index) ulcer for 
the study.  Subjects will undergo protocol-defined standardized wound care 
during screening (for two weeks or longer).  Subjects will be considered screen 
failures and will not receive study injections on Day 0 (baseline) if the target 
ulcer does not meet all entry criteria (see above) as well as being confirmed as 
non-healing.   
 
6. 
Be capable of understanding and complying with the protocol and signing the 
informed consent document prior to being subjected to any study related 
procedures; 
7. 
If female of childbearing potential, negative urine pregnancy test at screening 
and using acceptable method of birth control during the study. 
 
3.3.2. 
EXCLUSION CRITERIA 
Subjects will not be eligible for the study if any of the following criteria are present: 
 
1. 
Will require revascularization in the target leg within 3 months of 
randomization; 
2. 
In the investigator’s assessment, will require an amputation in the target leg 
within 3 months of randomization; 
3. 
Subjects with target foot ulcer with an etiology of vasculitis, pyoderma 
gangrenosum, necrobiosis lipoidica, hydrostatic pressure/venous insufficiency, 
any neoplasms (basalioma, Kaposi’s sarcoma, squamous cell carcinoma, etc.), 
or due to a burn; 
4. 
The study ulcer increased or decreased by 50% or more at baseline from 
screening (as assessed by comparison of post-debridement photos taken at 
screening and Day 0);  
5. 
Evidence of active infection (e.g., cellulitis, osteomyelitis) or deep ulceration 
exposing bone or tendon in the foot planned for treatment; 
6. 
Any gangrene; 


 
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7. 
Current fracture in the target foot; 
8. 
Target ulcer located on an active (hot) Charcot foot; 
9. 
Heart Failure with a NYHA classification of III or IV;  
10. Body mass index (BMI) > 45 kg/m2 at Screening; 
11. Stroke or myocardial infarction within last 3 months; 
12. Unstable angina; 
13. Uncontrolled hypertension defined as sustained systolic blood pressure (SBP) 
> 200 mmHg or diastolic BP (DBP) > 110 mmHg at baseline/screening 
evaluation; 
14. Ophthalmologic conditions pertinent to proliferative retinopathy or conditions 
that preclude standard ophthalmologic examination; 
15. Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as 
Buerger’s disease); 
16. Subjects with advanced liver disease including decompensated cirrhosis, 
jaundice, ascites or bleeding varices; 
17. Subjects currently receiving immunosuppressive medications chemotherapy, or 
radiation therapy; 
18. Positive HIV or HTLV at Screening; 
19. Active Hepatitis B or C infection as determined by Hepatitis B surface antibody 
(HBsAb), Hepatitis B core antibody (IgG and IgM; HBcAb), Hepatitis B 
surface antigen (HBsAg) and Hepatitis C antibodies (Anti-HCV), at Screening; 
20. Clinically significant specific laboratory values at screening (e.g.,  Hemoglobin 
< 8.0 g/dL, WBC < 3,000 cells per microliter, platelet count < 75,000/mm3, 
AST and/or ALT > 3 times the upper limit of normal, or any other clinically 
significant lab abnormality which in the opinion of the investigator should be 
exclusionary); 
21. Glomerular filtration rate (GFR) < 30 mL/min/1.73 m2 
22. Subjects 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 for at least 1 year); subjects 
with medical history and/or 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; 
23. Subjects with any comorbid conditions likely to interfere with assessment of 
safety or efficacy or with an estimated life expectancy of less than 1 year; 
24. Subjects requiring > 81 mg daily of acetylsalicylic acid. If > 81 mg are taken at 
screening, subjects may be enrolled if willing/able to switch to another 
medication for the duration of the study; 
25. Subjects requiring regular (daily) COX-2 inhibitor drug(s) or steroids (except 
inhaled steroids or ocular steroids); subjects may be enrolled if willing/able to 
undergo medication wash-out prior to the first dosing and to refrain from taking 
these drugs during the study; 
26. Major psychiatric disorder in past 6 months; 
27. History of drug or alcohol abuse / dependence in the past 2 years; 


 
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28. Use of an investigational drug in the past 3 months; use of an investigational 
biologic in the past 12 months; concurrent participation in investigational 
protocol or unapproved therapeutics; and 
29. Unable or unwilling to give informed consent. 
 
3.4. 
STUDY PROCEDURES 
Prior to recruitment of any subjects into the study, written approval of the protocol 
and informed consent must be obtained from the IRB and IBC (if applicable). 
 
3.4.1. 
INFORMED CONSENT 
The investigator or designee with appropriate delegation will explain the study 
purpose, procedures, and subject’s responsibilities to the potential participant.  The 
subject's willingness and ability to meet the follow-up requirements will be 
determined and written informed consent will be obtained (Appendix 2).  The 
subject will sign and date the informed consent form.  The investigator or designee 
will also sign and date the consent form.  The original informed consent form will be 
retained with the subject records; a copy will be provided to the subject.   
 
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. 
SUBJECT IDENTIFICATION 
To maintain confidentiality, the subject’s name should not be recorded on any study 
document other than the informed consent form.  All subjects that give informed 
consent (sign the informed consent form) will be assigned a unique identifier in the 
following format: XX-YY-ZZZ.  XX is the 2-digit assigned site number, YY is the 
sequential subject ID number, and ZZZ are the subject initials (initials of first 
name/middle name (if applicable)/last name).  For example, the first subject named 
John Simon Doe at site 11 will be assigned 11-01-JSD.  Subject ID numbers will not 
be reused (e.g., if the subject is determined to be a screen failure).    
 
3.4.3. 
SCREENING (DAY -45 TO DAY -7) 
 
Prior to full screening, subjects with diabetes and PAD will provide informed 
consent and then undergo target ulcer documentation (photograph, surface area, 
depth, perimeter and volume measurements) prior to debridement.  Only subjects 
whose target ulcer meets eligibility criteria (inclusion #5) will be allowed to proceed 
with the full screening procedures.  
 
Full screening procedures involve, in the following order: 
• Evaluation of eligibility criteria 
• Medical history 
• Concomitant medication review 
o Start of prohibited concomitant medication washout (if applicable)   
• Vital signs 


 
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• Documentation of symptomatic PAD: 
o ABI > 0.40 and ≤ 0.90 or > 1.4 (i.e., mild to severe PAD without critical 
limb ischemia) in target limb; 
o TBI ≤ 0.7 in the target limb 
o Toe pressure of < 55 mm Hg in the target limb 
o A history of lower extremity PAD with previous related intervention in a 
leg; 
• Physical exam, including height 
• Urine pregnancy testing (women of childbearing potential only)  
• Serum chemistry (including eGFR), hematology, and HbA1c  
• Viral screening– HIV, Anti-Human T-Cell Lymphotropic Virus (HTLV), 
Hepatitis B core antibody (IgG and IgM; HBcAb), antibody to Hepatitis B 
antigen (HBsAb), Hepatitis B surface antigen (HBsAg) and Hepatitis C 
antibodies (Anti-HCV). 
• 12-lead EKG  
• Foot x-ray  
• Fundoscopy  
• Cancer screening should be conducted per the current American Cancer Society 
Guidelines for the Early Detection of Cancer.  Testing is described in 
Section 4.1.3 
 
 
3.4.4. 
STANDARD OF CARE 
At screening, standard of care for all wounds on the target foot will be initiated that 
will continue for the duration of the study/until the ulcer has completely healed: 
 
• Surgical debridement of necrotic tissue or devitalized tissue 
• Use of appropriate off-loading when ambulating 
• Maintenance of a clean and moist wound environment 
 
Detailed instructions can be found in Appendix 4. 
 
3.4.4.1. 
WOUND ASSESSMENT AND DRESSING CHANGES DURING SCREENING 
During the Screening period, subjects will come in once a week for dressing changes 
and wound evaluation.  If a study visit is already scheduled for that week, the 
dressing change and wound evaluation will occur as part of the study visit. At these 
visits, the following assessments will be performed: 
 
• Documentation of target ulcer (photograph and measurements of surface area, 
depth, perimeter and volume) before and after debridement 
• Vital signs (except for weight) 
• Concomitant medications 
• Assessment of pre-treatment AEs 
 


 
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3.4.5. 
PROHIBITED CONCOMITANT MEDICATIONS/TREATMENTS 
 
3.4.5.1. 
MEDICATION THAT MAY INTERFERE WITH VM202 BIOACTIVITY 
COX-1 and COX-2 inhibiting drugs, steroids (except inhaled steroids or ocular 
steroids), and anti-Vascular Endothelial Growth Factor (VEGF) agents may interfere 
with the bioactivity of VM202 and are therefore prohibited from use during the 
study.  Other than the maximal 81 mg daily dose of aspirin (acetylsalicylic acid), 
subjects must agree to not take any of these drugs for the duration of the study.  The 
subject needs to be advised that common over the counter medications excluded 
include: acetylsalicylic acid (> 81mg), Excedrin, Aleve, Advil (Motrin, ibuprofen).  
A full list of the excluded medications, including the washout period, can be found 
in Appendix 3. 
 
3.4.5.2. 
MEDICATIONS/TREATMENT THAT MAY INTERFERE WITH ASSESSMENT OF 
VM202 EFFECT ON ULCER HEALING 
Subjects must refrain from using the following medications/ undergoing the 
following therapies for the duration of the study (Appendix 3): 
 
• Gels or creams with growth factors, e.g., Regranex® gel (becaplermin) 
• Larval debridement 
• Skin substitutes, e.g., Dermagraft®, Apligraf®  
• Hyperbaric oxygen therapy 
• Hydrotherapy 
• Negative pressure wound therapy 
• Electrical stimulation therapy 
 
3.4.5.3. 
SCREEN FAILURES 
Subjects not meeting all study entry criteria will be designated as screen failures.  
End of study procedures will not be performed for these subjects, but their reason for 
discontinuation will be recorded in EDC.   
 
3.4.5.4. 
RE-SCREENING 
Subjects whose target foot ulcer was initially not eligible (e.g., ulcer surface area 
was too large or too small; ulcer was infected) may be re-screened if the target ulcer 
remains open 2 weeks after screen failure and now meets inclusion and exclusion 
criteria.  Any subject who has been screen failed may only undergo one re-screening. 
 
Subjects who failed to meet any other inclusion or exclusion criteria may not be re-
screened without sponsor permission. 
 
The following screening assessments, if completed during the first screening and 
found to meet eligibility criteria, may not need to be repeated when the subject 
returns for re-screening:  
• Viral screening (Hepatitis B and C, HIV, HTLV) if performed within 6 months 
of signing the new informed consent; 


 
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• Cancer screening assessments if performed within the timeframe stipulated in 
protocol Section 4.1.3 before signing the new informed consent; for fecal occult 
blood test, a negative result within 12 months of signing the new informed 
consent will not need to be repeated; 
• Ophthalmological examination if performed within 3 months of signing the new 
informed consent; 
• Target foot x-ray if performed within 6 months of signing the new informed 
consent and the subject has not sustained any new trauma to the foot 
 
All other screening assessments will need to be repeated. 
 
3.4.6. 
TREATMENT AUTHORIZATION 
After providing written informed consent, potential study participants will undergo 
screening assessments.  If the subject meets all inclusion criteria and none of the 
exclusion criteria, the subject will be assigned to study treatment using the IWRS.  
Refer to the IWRS manual for instructions. 
3.4.7. 
RANDOMIZATION AND BLINDING 
A randomization schedule with subjects allocated to VM202 (treatment) or placebo 
(control) in a 2:1 ratio will be used.   
 
The Pharmacist will review the subject’s treatment allocation and assigned kit 
number in IWRS.  All documents related to investigational product and treatment 
allocation will be kept in a secure location with access limited to Pharmacy 
personnel responsible for preparing the syringes with assigned study treatment. 
 
After study initiation, VM202 and VM202 vehicle (placebo) will be provided to the 
site’s pharmacy.  Depending on the assigned study treatment, syringes of VM202 or 
placebo will be prepared after the clinic notifies the Pharmacy that the subject has 
arrived in the clinic to undergo study treatment. 
 
This is a double-blind study. The patients, Investigators, study site staff, or Sponsor 
or any of the Sponsor’s representatives or vendors will not know the assigned 
treatment.  Blinding will be achieved by having the study medication (VM202) 
prepared by the study pharmacist or designee.  Reconstituted VM202 is 
indistinguishable from VM202 vehicle (placebo).  The site pharmacist or designee 
prepares the vials according to the instructions.  The site pharmacist or designee and 
select individuals at the CRO (but excluding blinded study monitors and the blinded 
clinical trial manager) will be unblinded to the treatment assignments.  The subject 
and study personnel, including core labs, principal investigator, co-investigators, 
study coordinators, study monitors, data managers, and the clinical trial manager will 
remain blinded until all data have been entered into the database and the database is 
locked.  
 
IN CASE OF EMERGENCY ONLY, i.e., SERIOUS ADVERSE EVENT (SAE) 
AND ONLY WHEN THIS INFORMATION INFLUENCES THE SUBJECT'S 


 
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MANAGEMENT AND WHEN KNOWLEDGE OF THE TREATMENT 
ASSIGNMENT IS ESSENTIAL TO THE WELFARE OF THE PATIENT, the 
Investigator or designee may request unblinding of that patient. Whenever feasible, 
the Sponsor (or the Sponsor’s representative) should be consulted in advance of 
breaking the blind for any patient. In any case, the Sponsor (or the Sponsor’s 
representative) must be notified of the unblinding, and the Investigator or designee 
will document the reason(s) necessary to break the blind for any patient. Complete 
instructions on this process are detailed in the Study Reference Manual 
(VMNHU-003 Subject Emergency Unblinding Communication Plan). 
 
3.4.8. 
DAY 0 – 1ST INJECTIONS 
 
3.4.8.1. 
PRE-INJECTION (WITHIN 4 HRS PRIOR TO INJECTIONS) 
The first assessment will entail: 
 
• Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) 
o If eligibility is confirmed, the blinded study coordinator will randomize 
the subject using IWRS and notify the pharmacist or his/her 
representative to prepare the randomly assigned study medication. 
o If the subject is no longer eligible, the subject will exit the study and will 
be designated a screen failure. 
o If a subject withdraws from the study after being randomized but prior to 
being dosed, the subject will be designated early terminated in IWRS.  
However, because the subject has not received any study drug, no Early 
Termination Visit will be conducted. 
 
If the subject is confirmed to be eligible per inclusion criterion #5 and exclusion 
criterion #4, the following procedures will be performed prior to injection: 
 
• Vital signs 
• Concomitant medications 
• Serum chemistry and hematology 
• HbA1c 
• Serum HGF  
• Copies of VM202 in whole blood 
• ABI 
• TBI 
• TcPO2 (as a sub-study at 3 -10 sites) 
• Completion of CWIQ 
 
3.4.8.2. 
1ST DOSE OF VM202 OR PLACEBO 
Sixteen (16) IM injections of randomly assigned study medication in the ipsilateral 
calf of the affected foot with the target ulcer will be administered. 
 


 
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3.4.8.3. 
POST-INJECTION (2 HOURS ± 1 HOUR POST INJECTION) 
The following procedures will be performed 1-3 hours post injection: 
 
• Vital signs 
• Copies of VM202 in whole blood 
• Injection site assessment  
• Adverse event assessment 
 
3.4.9. 
WOUND ASSESSMENT AND DRESSING CHANGES AFTER DAY 0 
Following Day 0, subjects will come in once a week for dressing change and wound 
evaluation.  If a study visit is already scheduled for that week, the dressing change 
and wound evaluation will occur as part of the study visit.  
At these visits, the following assessments will be performed: 
 
• Documentation of target ulcer (photograph and measurements of surface area, 
depth, perimeter and volume) before and after debridement. 
• Vital signs (except for weight) 
• Concomitant medications 
• Injection site assessment (visits prior to Day 60) 
• Adverse event assessment 
 
3.4.10. DAY 14 ± 3 DAYS – 2ND INJECTIONS 
 
3.4.10.1. PRE-INJECTION (WITHIN 4 HOURS PRIOR TO THE INJECTIONS) 
The following procedures will be performed prior to injection: 
 
• Vital signs 
• Concomitant medications 
• Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) before and after debridement. 
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 
 
3.4.10.2. 2ND DOSE OF VM202 OR PLACEBO 
Sixteen (16) IM injections of randomly assigned study medication in the ipsilateral 
calf of the affected foot with the target ulcer will be administered. 
 
3.4.10.3. POST-INJECTION (2 HOURS ± 1 HOUR POST INJECTION) 
The following procedures will be performed 1-3 hours post injection: 
 
• Vital signs 
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 


 
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3.4.11. DAY 28 ± 3 DAYS – 3RD INJECTIONS 
 
3.4.11.1. PRE-INJECTION (WITHIN 4 HOURS PRIOR TO THE INJECTIONS) 
The following procedures will be performed prior to injection: 
• Vital signs 
• Concomitant medications 
• Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) before and after debridement. 
• Serum HGF  
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 
 
3.4.11.2. 3RD DOSE OF VM202 OR PLACEBO 
Sixteen (16) IM injections of randomly assigned study medication in the ipsilateral 
calf of the affected foot with the target ulcer will be administered. 
 
3.4.11.3. POST-INJECTION (2 HOURS ± 1 HOUR POST INJECTION) 
The following procedures will be performed 1-3 hours post injection: 
• Vital signs 
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 
 
3.4.12. DAY 42 ± 3 DAYS – 4TH INJECTIONS 
 
3.4.12.1. PRE-INJECTION (WITHIN 4 HOURS PRIOR TO THE INJECTIONS) 
The following procedures will be performed prior to injection: 
 
• Vital signs 
• Concomitant medications 
• Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) before and after debridement. 
• Serum chemistry and hematology 
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 
 
3.4.12.2. 4TH DOSE OF VM202 OR PLACEBO 
Sixteen (16) IM injections of randomly assigned study medication in the ipsilateral 
calf of the affected foot with the target ulcer will be administered. 
 


 
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3.4.12.3. POST-INJECTION (2 HOURS ± 1 HOUR POST INJECTION) 
The following procedures will be performed 1-3 hours post injection: 
 
• Vital signs 
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 
 
3.4.13. DAY 60 ± 3 DAYS 
 The following procedures will be performed: 
 
• Vital signs 
• Concomitant medications 
• Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) before and after debridement. 
• Copies of VM202 in whole blood  
• Serum HGF 
• Injection site assessment 
• Adverse event assessment 
 
3.4.14. DAY 74 ± 3 DAYS 
The following procedures will be performed: 
 
• Vital signs 
• Concomitant medications 
• Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) before and after debridement. 
• Adverse event assessment 
 
3.4.15. DAY 90 ± 7 DAYS 
The following procedures will be performed: 
 
• Vital signs 
• Concomitant medications 
• Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) before and after debridement. 
• Serum chemistry and hematology 
• Copies of VM202 in whole blood  
• Serum HGF 
• Adverse event assessment 
 


 
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3.4.16. DAY 120 ± 7 DAYS 
The following procedures will be performed: 
 
• Vital signs 
• Concomitant medications 
• Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) before and after debridement. 
• Serum chemistry and hematology 
• HbA1c 
• ABI 
• TBI 
• TcPO2 (as a sub-study at 3 -10 sites) 
• CWIQ 
• Adverse event assessment 
 
3.4.17. DAY 210 ± 14 DAYS 
The following procedures will be performed: 
 
• Retinal fundoscopy 
• Vital signs 
• Concomitant medications 
• Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) before and after debridement. 
• Serum chemistry and hematology 
• HbA1c 
• ABI 
• TBI 
• TcPO2 (as a sub-study at 3 -10 sites) 
• CWIQ 
• Adverse event assessment 
 
3.4.18. CONFIRMATION OF ULCER HEALING 
If the ulcer heals, healing must be confirmed 14 days (± 5 days) after healing was 
first reported.  This visit may coincide with a pre-specified visit or may require an 
unscheduled visit: 
 
• Concomitant medications  
• Vital signs (except for weight) 
• Documentation of the healed ulcer (photograph) 
• Injection site assessment (if visit occurs prior to Day 60) 
• Adverse event assessment 
 
 
 


 
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3.5. 
STUDY COMPLETION 
 
3.5.1. 
COMPLETED SUBJECTS 
Each subject in the study will be considered completed when all assessments through 
7 months have been performed in accordance with the study protocol. 
 
3.5.2. 
DISCONTINUED SUBJECTS 
Any subject may voluntarily discontinue the study at any time without prejudice.  
The investigator may discontinue a subject from the study at any time if (s)he 
considers that remaining in the study compromises the subject’s health or the subject 
is not sufficiently cooperative.  In either event, reason(s) for discontinuation should 
be recorded on the study worksheets. 
 
Possible reasons for study discontinuation include the following: 
 
• Adverse events necessitating discontinuation from the study. 
• The subject is lost to follow-up. 
• Subject decision (specify). 
• Investigator decision (specify). 
• Other reason (specify). 
 
The reasons for any subject discontinuation will be recorded on the study completion 
form of the study worksheets. 
 
Additional subjects may be enrolled if subjects discontinue prior to the 4 Month visit 
in order to achieve a 300-subject dataset with 4-month data. 
 
Subjects discontinued for AE(s) will be followed-up after subject’s discontinuation 
until the event is resolved or considered medically stable by the investigator.   
 
Subjects that withdraw after receiving any treatment injections but prior to study 
completion will undergo the following, if possible: 
 
• 
Vital signs 
• 
Concomitant medications 
• 
Documentation of the target ulcer (photograph and measurements of surface 
area, depth, perimeter and volume) before and after debridement. 
• 
Serum chemistry and hematology 
• 
Serum HGF if discontinued prior to Day 90 
• 
Copies of VM202 in whole blood if discontinued prior to Day 90  
• 
Injection site reaction assessment if discontinued prior to Day 60 
• 
Adverse event assessment 
 
In case of a subject lost-to-follow-up, the investigator/designee must do his/her best 
to contact the subject (by phone or letter) at least twice.  If no response is obtained 
from the subject, the investigator is encouraged to contact one of the subject’s 






 
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3.7. 
PRIOR AND CONCOMITANT MEDICATION 
All concomitant medications (taken within 60 days of the first injection) will be 
recorded 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 at study exit). 
 
 
 
4. 
EXAMINATIONS AND EVALUATIONS 
 
4.1. 
EVALUATIONS CONDUCTED AT BASELINE ONLY 
 
4.1.1. 
MEDICAL HISTORY 
A relevant medical history will be obtained at Baseline.  All positive and negative 
findings will be carefully documented on the study worksheets.  A new finding 
discovered during the Screening/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 and 
PAD history to include all events and interventions prior to study enrollment.  Care 
should be taken to exclude ulcers due vasculitis, pyoderma gangrenosum, 
necrobiosis lipoidica, hydrostatic pressure/venous insufficiency, any neoplasms 
(basalioma, Kaposi’s sarcoma, squamous cell carcinoma etc.), or a burn.  
 
4.1.2. 
PHYSICAL EXAM 
A physical exam will be performed at Screening.  The exam will include the 
following: head, eyes, ears, nose, and throat (HEENT), heart, lungs, abdomen, 
extremities, lymph nodes, musculoskeletal, neurological, and gastrointestinal 
systems.  Any abnormalities should be categorized as clinically significant (CS) or 
not clinically significant (NCS), and the abnormalities should be recorded in the 
subject’s study worksheets.  Actual height will be measured. 
 
4.1.3. 
CANCER SCREENING 
All subjects participating in this trial must undergo routine cancer screening.  The 
history and diagnosis of potential or apparent malignant and non-malignant diseases 
and neoplasms will be assessed through several diagnostic tests and procedures.  
Some diagnostic tests and procedures performed prior to study consent and 
documented in the subject’s medical history may be acceptable where noted.  
Routine cancer screening includes the following: 
 


 
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1. Cervical Cancer Screening - Papanicolaou (PAP) smear  
• Women < 21 years – no screening required 
• Women that have undergone a complete hysterectomy – no screening required 
• Women between the ages of 21 and 65 (inclusive), testing within the last 3 
years 
• Women > 65 years old with regular screening within the last 10 years with 
normal results – no screening required.  Any abnormal finding in the past 10 
years requires screening at study entry. 
 
2. Breast Cancer Screening (women only) - mammogram 
• Women between the ages of 45 and 54 (inclusive) – normal findings within 
one year 
• Women ≥ 55 – normal findings within 2 years 
 
3. Lung Cancer Screening - For subjects ≥ 55 years and ≤ 74 years: low dose chest 
CT scan (LDCT w/o contrast) conducted within 3 months prior to signing the 
informed consent form IF the subject has a ≥ 30 pack year smoking history AND 
is still smoking or quit within the last 15 years.  If results are not available, 
screening needs to be performed.   
 
A pack year is number of cigarette packs smoked per day multiplied by the 
number of years the subject has smoked (e.g., someone who smoked a pack of 
cigarettes per day for 30 years has a 30 pack-year smoking history, as does 
someone who smoked 2 packs a day for 15 years).     
 
4. Colon Cancer - For subjects ≥ 50 years: fecal occult blood test.  A positive fecal 
occult blood test requires follow-up testing which is beyond the scope of this 
study.  If follow-up testing rules out cancer, the subject will be able to participate 
in the study if the subject is still interested. 
 
Subjects with a medical history or family history of colon cancer in any first-
degree relative must have documentation of a negative colonoscopy performed 
within the past 12 months. 
 
4.1.4. 
VIRAL SCREENING 
The local laboratory will be responsible for Screening viral testing and assays to 
include: HIV-1, HIV-2, HTLV, Hepatitis B surface antibody (HBsAb), Hepatitis B 
core antibody (IgG and IgM; HBcAb), Hepatitis B surface antigen (HBsAg) and 
Hepatitis C antibodies (Anti-HCV). 
 
4.1.5. 
FOOT X-RAY 
X-rays of the target foot will be taken in two projections: dorsal-plantar (DP) and 
oblique. These can be done under weight bearing or non-weight bearing conditions, 
at the investigator’s discretion. 
 


 
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4.1.6. 
12-LEAD EKG 
A 12-lead electrocardiogram (EKG) will be conducted at Screening.  The EKG 
recording will be printed out, and a copy will be placed with subject records.  Any 
(clinically significant) abnormalities will be reported.  
 
4.1.7. 
PREGNANCY TEST (WOMEN OF CHILDBEARING POTENTIAL ONLY) 
For women of childbearing potential, a urine beta human chorionic gonadotropin (β-
HCG) test will be performed at Screening.  Results of the test must be negative and 
effective contraception documented.  Acceptable methods of contraception include: 
 
• Barrier type devices (e.g., female condom, diaphragm and contraceptive sponge) 
used only in combination with a spermicide; 
• Intrauterine device; 
• Oral contraceptive agents; 
• Depo-provera (medroxyprogesterone acetate); 
• Levonorgestrel implants; 
 
Abstention, the rhythm method, or contraception by a partner are not considered 
acceptable methods of contraception. 
 
 
4.2. 
EVALUATIONS CONDUCTED THROUGHOUT THE STUDY 
 
4.2.1. 
DOCUMENTATION OF TARGET ULCER 
At each visit at which the target ulcer is present, a photograph of the ulcer will be 
taken before and after debridement.  Measurements of the surface area, depth, 
perimeter and volume of the target ulcer will be performed.  Instructions can be 
found in Appendix 5. 
 
4.2.2. 
RETINAL FUNDOSCOPY 
Proliferative retinopathy, 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 for eligibility and repeated at Day 210.  Retinal fundoscopy must be 
performed by an ophthalmologist within 3 months of Screening.   
 
In cases where fundoscopy alone is deemed insufficient to determine eligibility, 
fluorescein angiography may be conducted at Screening. 
 
4.2.3. 
CONCOMITANT MEDICATIONS 
Concomitant medications will be recorded at each visit using the trade name or 
generic name as described in Section 3.7. 
 










 
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A serious adverse event (SAE) is any untoward medical occurrence which: 
• Results in death; 
• Is life-threatening; 
• Requires inpatient hospitalization (admission to hospital with a stay > 24 hours) 
or prolongation of hospitalization which is not specifically required by the 
protocol or is elective.  Hospitalization for elective treatment of a pre-existing 
condition that has not worsened is not considered to be an AE.  Hospital 
admissions or surgery planned before any study drug is administered are not to 
be considered AEs unless there is unexpected deterioration of the subject’s 
condition after study drug treatment (e.g., surgery must be performed earlier than 
planned). 
• 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 subject 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 subject 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 subjects’ ability to carry 
out normal life functions.   
 
An unexpected AE is an AE, the nature or severity of which is not consistent with 
the applicable product information (e.g., Investigator Brochure for an unapproved 
product).  Expected means that the event has been previously observed with the test 
article and is identified and/or described in the applicable product information.  It 
does not mean that the event is expected with the underlying disease(s) or 
concomitant medications.  It is expected that certain disease states will have 
reoccurring adverse events some of which may be considered expected over time. 
 
5.2. 
ASSESSMENT OF ADVERSE EVENTS (AES) 
All AEs, regardless of severity, occurring following the first study drug 
administration and the 7-month follow-up visit of the study by a subject must be 
recorded in the AE form of the EDC.  Any events occurring before the injections 
will be added to the medical history.  This will include the following information: 


 
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• Description of the AE 
Every effort must be made to report the underlying condition or unifying 
diagnosis for the event.  In order to avoid vague, ambiguous or colloquial 
expressions, the AE should be recorded in standard medical terminology rather 
than the subject’s own words when possible.  Signs and symptoms that are 
considered unrelated to an encountered syndrome or disease should be recorded 
as individual AEs (e.g., if congestive heart failure and severe headache are 
observed at the same time, each event should be recorded as an individual AE.  
In addition, AEs occurring secondary to other events (e.g., sequelae) should 
be identified by the primary cause (i.e., a "primary" AE, if clearly identifiable, 
generally represents the most accurate clinical term to record; events occurring 
secondary to the primary event should be described in the narrative description 
of the case [e.g., orthostatic hypotension → fainting and fall to floor → head 
trauma → neck pain; the primary AE is orthostatic hypotension]). 
• 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.  The Sponsor 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 (IM 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.   
 




 
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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 (including the 
Investigator’s opinion of the relationship of the SAE to the study medication) 
concerning each SAE to the CRO and Sponsor within 5 working days of first 
learning of the event.  The investigator or designee will provide copies of related 
source documentation such as results/reports, hospitalization records, and other 
relevant information involving the SAE. 
 
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 the Sponsor or their designee.  In 
any event, the Investigator will provide a narrative summary of circumstances/events 
related to the death, and cause of death, if known.   
 
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), and Institutional Biosafety Committee (IBC) if applicable.  
Upon receipt from the Sponsor of an initial or follow-up IND Safety Report or other 
safety information, the Investigator must promptly notify his or her IRB, and IBC (if 
applicable). 
 
5.4.2. 
SPONSOR’S RESPONSIBILITY 
All AEs and SAEs will be reported on an annual basis to FDA in accordance with 
the IND regulation (21 CFR Part 312).  Per the 2010 FDA Guidance Document for 
Industry and Investigators “Safety Reporting Requirements for INDs and BA/BE 
Studies,” events categorized as ‘possibly’ or ‘probably’ related will be treated as 
‘suspected adverse reactions.’  Events categorized as ‘definitely’ related will be 
treated as an ‘adverse reaction.’ 
 
All serious, unexpected adverse reactions and suspected adverse reactions will be 
reported to FDA and to all participating investigators as an IND Safety Report 
within 15 calendar days of the event after the Sponsor determines that the suspected 
adverse reaction qualifies for reporting (21 CFR §312.32).  Any unexpected fatal or 
life-threatening AEs will be reported to the Agency within 7 calendar days after the 
Sponsor’s initial receipt of the information. 
 
The Sponsor 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. 
 
 




 
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original treatment assignment, regardless of actual treatment received.  The primary 
analyses of the primary efficacy endpoint will be based on this ITT population. 
 
6.2.2. 
SAFETY POPULATION 
The safety analysis population will contain all subjects who are randomized and 
receive at least one study injection. Subjects will be grouped according to their 
actual treatment received, not according to their randomization assignment (as 
randomized).  Subjects treated with any VM202 dose will be grouped in the VM202 
group; subjects treated without any VM202 will be grouped in the placebo group. 
 
6.2.3. 
MODIFIED ITT (MITT) POPULATION 
The mITT population includes all subjects randomized who meet the following: 
 
• 
Received any study drug injections 
• 
Had at least one post-baseline wound assessment 
• 
Have no safety or efficacy parameter results prior to dosing on Day 0 that 
would have made the subject ineligible for participation if the results had been 
known or disclosed at Screening. This determination will be made in a blinded 
fashion by the Clinical Data Review Committee (CDRC, members to be 
determined) prior to analyses. 
 
Subjects will be grouped based on the randomly assigned treatments, not the actual 
treatment received.  The mITT population will be used in the sensitivity analyses for 
the primary endpoint. 
 
6.2.4. 
PER PROTOCOL (PP) POPULATIONS 
 
6.2.4.1. 
PP1 
The first Per Protocol (PP1) population is a subset of mITT.  It includes all mITT 
subjects who meet the following criterion: 
 
• 
Have not used the protocol-specified prohibited concomitant medications or 
treatments such as COX-2 inhibitor drug(s) or non-specific COX-1/COX-2-
inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs), anti-VEGF agents 
(e.g., Lucentis®, Avastin®, Eylea®), steroids (except inhaled steroids or ocular 
steroids), Regranex® gel (becaplermin), larval debridement, skin substitutes 
(e.g., Dermagraft®, Apligraf®), hyperbaric oxygen therapy, hydrotherapy, 
negative pressure wound therapy, or electrical stimulation therapy which may 
affect the wound healing.  The use and effect of protocol-specified prohibited 
concomitant medications will be determined by the CDRC in a blinded 
fashion prior to analyses. 
 


 
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6.2.4.2. 
PP2 
The second Per Protocol population is a further subset of the mITT.  It includes all 
subjects in the first PP population who also meet all of the following criteria: 
 
• 
Meets major protocol eligibility criteria determined by the CDRC in a blinded 
fashion prior to analyses 
• 
Received all injections based on the randomized treatment. 
• 
Maintained standard of care for their wounds for the duration of the study, as 
follows: 
o Surgical debridement of necrotic tissue or devitalized tissue 
o Use of appropriate off-loading when ambulating 
o Maintenance of moist wound environment 
• 
Additional criteria, if any, established by the CDRC before unblinding of the 
randomization code. 
 
The PP populations will be used in the sensitivity analyses for the primary efficacy 
endpoint. 
 
 
6.3. 
STUDY ENDPOINTS 
 
6.3.1. 
PRIMARY ENDPOINT 
The primary study endpoint is the proportion of subjects with a target wound closure 
by the 4-month follow-up.  Complete wound closure is defined as skin re-
epithelialization without drainage or dressing (primary endpoint), confirmed at a 
second scheduled or unscheduled visit two weeks (14 ± 5 days) later (secondary 
endpoint).  Active and placebo arms will be compared to determine treatment effect. 
 
6.3.2. 
OTHER ENDPOINTS 
Other exploratory endpoints will include: 
 
• Time to complete wound closure of foot ulcer 
• Proportion of subjects with a target wound closure prior to or at 7 months 
• Percent change in wound volume at 2 months, 2.5 months, 3 months, 4 months, 
and 7 months 
• Percent change in wound perimeter, area and wound depth at 2 months, 
2.5 months, 3 months, 4 months, and 7 months 
• Proportion of subjects with formation of new ulcers on the target foot at 
2 months, 2.5 months, 3 months, 4 months, and 7 months 
• Time to the major amputations 
• Time to the minor amputation 
• Change in ABI at 4 months, and 7 months 
• Change in TBI at 4 months, and 7 months 
• Change in TcPO2 at 4 months, and 7 months 


 
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• Change in each domain score (quality of life, social life, well-being, physical 
symptoms and daily living) of CWIQ from Day 0 at 4 months and 7 months 
 
 
6.3.3. 
SAFETY 
Safety analyses in this study will evaluate the safety profile of VM202, as compared 
with control.  No formal statistical testing will be conducted for the safety analyses.  
All subjects in the safety subset will be included in these analyses.  Subjects will be 
grouped by treatment received.  All summaries will be derived based on available 
data.  No imputation will be performed for missing values. 
 
6.3.4. 
PHARMACOKINETICS 
HGF serum levels will be determined immediately pre-treatment on Day 0, 
immediately pre-treatment on Day 28, on Day 60 and Day 90.  
 
The number of copies of VM202 in whole blood will be determined at Day 0 (pre-
injection, and 2 hours [± 1 hour] post injection), at Day 14 (pre-injection, and 
2 hours [± 1 hour] post injection), Day 28 (pre-injection, and 2 hours [± 1 hour] post 
injection), at Day 42 (pre-injection, and 2 hours [± 1 hour] post injection), Day 60 
and Day 90.   
 
6.3.5. 
DATA SAFETY MONITORING BOARD (DSMB) AND INTERIM ANALYSIS 
An independent data safety monitoring board (DSMB) will periodically review a 
limited set of un-blinded tables and/or listings, including all reported AEs.  The 
objectives of the DSMB meetings are to review the safety outcomes of the study and 
provide guidance to study Sponsor regarding the safety of the VM202.  The data 
analyses for the DSMB meetings will be directly provided to the DSMB members 
and no data will be released to the study Sponsor and blinded designees.  There will 
be no adjustment for multiple testing due to the DSMB data review.  Further details 
of DSMB responsibilities are included in the DSMB Charter. 
 
An interim futility analysis will be performed by an independent statistician when 
50% of subjects who receive study drug injections reach the 4-month follow-up visit.  
The analysis will concern only the primary endpoint data and will present the 
percentages of subjects with complete wound closure by the 4-month follow-up by 
treatment group and the conditional power for success at the final analysis.  The 
study will not be stopped due to the possible finding of VM202 efficacy superiority 
based on the interim analysis, so the significance level for the final analysis remains 
at 0.05.  Details of the interim analysis are provided in the Statistical Analysis Plan. 
 
 
 
6.4. 
SUBJECT CATEGORIZATION 
Screen Failure - Any subject who was consented and entered into the Screening 
process appropriately, but subsequently did not meet the entry criteria in order to be 
treated.  Subjects who fail screening will not be followed for safety or efficacy 


 
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assessment, and no other study procedures will be performed.  Screen failures will 
be replaced. 
 
Evaluable Subject - Any subject who received the study drug. 
 
Lost to follow-up - A subject deemed to be lost to follow-up is any subject who 
received treatment, but who does not complete scheduled study visits.  This includes 
those subjects who withdraw consent and refuse further study participation and all 
attempts to contact the subject are deemed unsuccessful. 
 
Detailed statistical methods are described in the Statistical Analysis Plan (SAP). 
 
 
 
7. 
ACCESS TO STUDY DOCUMENTS AND STUDY MONITORING 
The Sponsor will utilize a designated CRO to monitor the progress of this study.  The 
clinical monitor, as a representative of the Sponsor, has the obligation to follow this study 
closely.   
 
The Sponsor or its designee may meet with investigators prior to the initiation of the study 
in order to review the adequacy of the subject population, facilities, and equipment with 
respect to the needs of the study, and to familiarize the investigator with the study protocol.   
 
The Sponsor or its designee may meet with the investigator(s) at the time study subjects 
begin to be enrolled in order to ensure that subjects are being properly selected and that 
study data are being correctly recorded.   
 
During the study, 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 source 
documents and worksheets to verify the accuracy and completeness of the information 
provided on the case report forms (CRFs).  Study worksheets and source documents must 
contain all data provided on the CRFs.  All data generated during this study and the study 
worksheets/source documents from which they originated are subject to inspection by the 
Sponsor or its representatives, the FDA and other regulatory agencies. 
 
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 
The Sponsor employees and/or their contracted representatives utilize Standard Operating 
Procedures (SOPs) designed to ensure that research procedures and documentation are 


 
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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 the Sponsor 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 study worksheets, 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 the Sponsor 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 the Sponsor or its designee prior to release of study 
supplies. 
 
FDA/relevant health authority regulations require that all advertisements for subject 
recruitment be approved by an IRB prior to implementation.  The complete text and format 
must be submitted to the Sponsor 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 the CRO.   
 
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 the Sponsor within 2 months 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. 
 
 


 
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10. INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) 
The sites at which this trial is being conducted will ensure that an Institutional Biosafety 
Committee (IBC) is in place.  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 subject in the study.  The Investigator will also be required to obtain and 
follow all biohazard safety guidelines promulgated by the IBC, and to report all findings as 
required to the IBC and to NIH/OBA.  
 
 
 
 
11. INFORMED CONSENT PROCESS 
It is the responsibility of the investigator or his/her qualified designee to inform each 
subject, 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 subject’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 
the Sponsor or its designee, prior to submission to an IRB.  After approval by the Sponsor 
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 subject must read, 
sign and date the informed consent form.  The person executing the consent must also sign 
and date the final consent form page.  One original informed consent form is to be retained 
by the study site and a copy is to be given to the subject.  The informed consent process 
must be documented in the subject’s medical record. 
 
The informed consent must be written in a language in which the subject is fluent.  If a 
foreign language translation is required, a statement of certification of the translation must 
be issued.  Regulations require that foreign language informed consent forms be submitted 
to the IRB for approval.  The investigator must forward a copy of the consent form, the 
certified foreign language translation and an IRB approval letter to the Sponsor or its 
designee. 
 
 
12. CONFIDENTIALITY 
In accordance with GCP and with the national data protection laws, all information 
concerning the subjects 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 
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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 subject 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 subjects, a change may be made preferably after 
discussion with the Sponsor or its designee.  In these instances, the IRB and FDA will be 
notified as soon as possible.  
 
 
14. DATA MANAGEMENT 
Electronic data capture (EDC) will be utilized for this study.  Study worksheets will be 
provided by the Sponsor or its designee to the site before data collection.  In order to 
facilitate data entry, the worksheets coincide with the data entry pages in the EDC system.  
The design of the data entry screens will follow the same flow as the provided worksheets 
in order to insure minimal issues during data entry.  The use of worksheets is optional; sites 
may elect to use other source documents that contain data recorded on the CRF.  Note, 
study worksheets and/or source documents must contain all data provided on the CRFs.  If 
used, appropriate worksheets will be completed and initialed or signed where indicated at 
each examination.  All worksheets will be completed in a legible manner in black/blue ink.   
Any corrections to the worksheets will be made by drawing a single line through the 
incorrect entry, recording the correct information, and initialing and dating the change.   
 
Once the data is ready to be entered into the EDC System, then the site will begin entering 
the data into the system.  Afterwards, the monitor will review the data against the source 
documents and/or worksheets and either approve the data records or create queries to the 
site for further review.  If the data records are deemed “clean” with the approval of the 
monitor, then the investigator can e-sign the records.  Finally, when the data records are 
ready to be locked, the data manager will perform the interim lock in the system.  However, 
the data manager also has the right to unlock the data record if any updates to the data are 
necessary.  
 
Data are protected by preventing unauthorized users from accessing the system with the 
use of username and password combination.  In addition, each individual user will be 
assigned a specific role in the EDC System which will grant that user the right to view, edit 
and/or delete the data.  Furthermore, any changes to the data are captured in the EDC 
System’s audit trail where a reason for change is required.   
 
All clinical data generated in the study will be submitted to the Sponsor or designated CRO 
for quality assurance review and statistical analysis.  All worksheets and data entered into 
the EDC system will be reviewed for completeness and evident recording errors will be 


 
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rectified by contact with the appropriate clinical site.  Computerized data checks will be 
used to identify unusual data entries for verification prior to statistical analysis. 
To minimize the amount of missing data, investigators will be trained on the deleterious 
effect that missing data have on trial integrity and credibility and that missing data could 
diminish the scientific value of all subjects' altruistic contributions.  
 
 
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, the Sponsor and its representatives and 
FDA/relevant health authorities/regulatory agencies.  All reports and communications 
relating to study subjects will identify subjects only by initials and subject identification 
number.  Complete subject 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 the Sponsor or its designee 
immediately.  The investigator will also grant Sponsor representatives the same privileges 
offered to FDA/relevant health authority or regulatory agents/officers/employees. 
 
The Investigator must provide the Sponsor 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 the Sponsor or its designee for submission to the FDA. 
• 
Current signed curriculum vitae (within 2 years prior to study initiation) and current 
medical licenses 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). 
• 
A copy of the original approval for conducting the study by the IBC, if applicable.  
Renewals, with continuance of the study, must be submitted at yearly intervals or as 
required by IBC policy. 
• 
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. 
• 
The signature page of the Investigator Brochure signed and dated by the Principal 
Investigator. 


 
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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. 
• Copy of delegation of authority log. 
• All original informed consent forms with required signatures. 
• All IRB correspondence (i.e., informed consent [including any approved revisions], 
protocol, AE, advertisements, newsletters). 
• All IBC correspondence. 
• Copy of the Study Monitoring Log 
• Clinical and non-clinical supply shipment forms 
• Copies of all pertinent correspondence pertaining to the study (except budget issues) 
between the Sponsor or the CRO and the site 
• Copies of all SAEs reports submitted to the Sponsor or its designee 
• Copies of all IND Safety Reports submitted to the site by the Sponsor its designee 
• Copies of approved package labeling 
 
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.  
The Sponsor will notify the principal investigator when records are no longer needed.  The 
investigator will not discard any records without notifying the Sponsor.  If the principal 
investigator moves from the current investigational site, the Sponsor 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 the Sponsor 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 the Sponsor with an accurate final report within 
2 months after completion, termination or discontinuation of the study.  The final report 
may not precede final data submission which has not been monitored. 
 
 
17. STUDY REPORT AND PUBLICATION 
The data resulting from this study will be the proprietary information of the Sponsor 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 the 


 
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Sponsor.  At the end of the study, a clinical study report will be written by the Sponsor or 
its designee.   
 
 


 
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18. REFERENCES 
1. 
Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. 
JAMA : the journal of the American Medical Association 2005;293:217-28. 
2. 
Sen CK, Gordillo GM, Roy S, et al. Human skin wounds: a major and snowballing threat 
to public health and the economy. Wound repair and regeneration : official publication of 
the Wound Healing Society [and] the European Tissue Repair Society 2009;17:763-71. 
3. 
Lazarus GS, Cooper DM, Knighton DR, Percoraro RE, Rodeheaver G, Robson MC. 
Definitions and guidelines for assessment of wounds and evaluation of healing. Wound 
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4. 
Chronic cutaneous ulcer and burn wounds - developing products for treament. In: FDA, 
ed. FDA Guidance Document; 2006:22. 
5. 
Peripheral arterial disease in people with diabetes. Diabetes care 2003;26:3333-41. 
6. 
Prompers L, Schaper N, Apelqvist J, et al. Prediction of outcome in individuals with 
diabetic foot ulcers: focus on the differences between individuals with and without 
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7. 
Althouse AD, Abbott JD, Forker AD, et al. Risk Factors for Incident Peripheral Arterial 
Disease in Type 2 Diabetes: Results From the Bypass Angioplasty Revascularization 
Investigation in Type 2 Diabetes (BARI 2D) Trial. Diabetes care 2014;37:1346-52. 
8. 
Madanchi N, Tabatabaei-Malazy O, Pajouhi M, Heshmat R, Larijani B, Mohajeri-
Tehrani MR. Who are diabetic foot patients? A descriptive study on 873 patients. Journal 
of diabetes and metabolic disorders 2013;12:36. 
9. 
Brechow A, Slesaczeck T, Munch D, et al. Improving major amputation rates in the 
multicomplex diabetic foot patient: focus on the severity of peripheral arterial disease. 
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Morbach S, Furchert H, Groblinghoff U, et al. Long-term prognosis of diabetic foot 
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11. 
Hinchliffe RJ, Andros G, Apelqvist J, et al. A systematic review of the effectiveness of 
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Alavi A, Sibbald RG, Mayer D, et al. Diabetic foot ulcers: Part I. Pathophysiology and 
prevention. Journal of the American Academy of Dermatology 2014;70:1 e-18; quiz 9-
20. 
13. 
Reiber GE, Raugi GJ. Preventing foot ulcers and amputations in diabetes. Lancet 
2005;366:1676-7. 
14. 
Greer N, Foman NA, MacDonald R, et al. Advanced wound care therapies for nonhealing 
diabetic, venous, and arterial ulcers: a systematic review. Annals of internal medicine 
2013;159:532-42. 
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Lower extremity disease among persons aged > or =40 years with and without diabetes--
United States, 1999-2002. MMWR Morbidity and mortality weekly report 2005;54:1158-
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Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Inter-Society 
Consensus for the Management of Peripheral Arterial Disease (TASC II). Journal of 
vascular surgery 2007;45 Suppl S:S5-67. 


 
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17. 
Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic 
population. The international journal of lower extremity wounds 2011;10:152-66. 
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Goodridge D, Trepman E, Sloan J, et al. Quality of life of adults with unhealed and 
healed diabetic foot ulcers. Foot & ankle international / American Orthopaedic Foot and 
Ankle Society [and] Swiss Foot and Ankle Society 2006;27:274-80. 
19. 
Snyder RJ, Hanft JR. Diabetic foot ulcers--effects on QOL, costs, and mortality and the 
role of standard wound care and advanced-care therapies. Ostomy/wound management 
2009;55:28-38. 
20. 
Winkley K, Sallis H, Kariyawasam D, et al. Five-year follow-up of a cohort of people 
with their first diabetic foot ulcer: the persistent effect of depression on mortality. 
Diabetologia 2012;55:303-10. 
21. 
Lozano FS, Gonzalez-Porras JR, March JR, Lobos JM, Carrasco E, Ros E. Diabetes 
mellitus and intermittent claudication: a cross-sectional study of 920 claudicants. 
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22. 
Sargen MR, Hoffstad O, Margolis DJ. Geographic variation in Medicare spending and 
mortality for diabetic patients with foot ulcers and amputations. Journal of diabetes and 
its complications 2013;27:128-33. 
23. 
Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. 
Diabetic medicine : a journal of the British Diabetic Association 2010;27:4-14. 
24. 
Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: 
perspectives on the past, present, and future. Lancet 2014;383:1068-83. 
25. 
Pedersen BL, Baekgaard N, Quistorff B. Muscle mitochondrial function in patients with 
type 2 diabetes mellitus and peripheral arterial disease: implications in vascular surgery. 
European journal of vascular and endovascular surgery : the official journal of the 
European Society for Vascular Surgery 2009;38:356-64. 
26. 
Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a 
mitochondrial love-hate triangle. American journal of physiology Cell physiology 
2004;287:C817-33. 
27. 
Aldakkak M, Stowe DF, Heisner JS, Spence M, Camara AK. Enhanced Na+/H+ 
exchange during ischemia and reperfusion impairs mitochondrial bioenergetics and 
myocardial function. Journal of cardiovascular pharmacology 2008;52:236-44. 
28. 
Di Marco E, Gray SP, Chew P, et al. Pharmacological inhibition of NOX reduces 
atherosclerotic lesions, vascular ROS and immune-inflammatory responses in diabetic 
Apoe(-/-) mice. Diabetologia 2014;57:633-42. 
29. 
Alexiadou K, Doupis J. Management of diabetic foot ulcers. Diabetes therapy : research, 
treatment and education of diabetes and related disorders 2012;3:4. 
30. 
Paumelle R, Tulasne D, Kherrouche Z, et al. Hepatocyte growth factor/scatter factor 
activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. 
Oncogene 2002;21:2309-19. 
31. 
Hashiya N, Jo N, Aoki M, et al. In vivo evidence of angiogenesis induced by 
transcription factor Ets-1: Ets-1 is located upstream of angiogenesis cascade. Circulation 
2004;109:3035-41. 
32. 
Cooper CD, Newman JA, Gileadi O. Recent advances in the structural molecular biology 
of Ets transcription factors: interactions, interfaces and inhibition. Biochemical Society 
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33. 
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. 
34. 
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. 
35. 
Nakagami H, Morishita R, Yamamoto K, et al. Hepatocyte growth factor prevents 
endothelial cell death through inhibition of bax translocation from cytosol to 
mitochondrial membrane. Diabetes 2002;51:2604-11. 
36. 
Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in 
development, organ regeneration and cancer. Nature reviews Molecular cell biology 
2010;11:834-48. 
37. 
Ishihara N, Takagi N, Niimura M, et al. Inhibition of apoptosis-inducing factor 
translocation is involved in protective effects of hepatocyte growth factor against 
excitotoxic cell death in cultured hippocampal neurons. Journal of neurochemistry 
2005;95:1277-86. 
38. 
Ishigaki A, Aoki M, Nagai M, et al. Intrathecal delivery of hepatocyte growth factor from 
amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic 
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39. 
Jin M, Yaung J, Kannan R, He S, Ryan SJ, Hinton DR. Hepatocyte growth factor protects 
RPE cells from apoptosis induced by glutathione depletion. Investigative ophthalmology 
& visual science 2005;46:4311-9. 
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Tulasne D, Foveau B. The shadow of death on the MET tyrosine kinase receptor. Cell 
death and differentiation 2008;15:427-34. 
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Kannan R, Jin M, Gamulescu MA, Hinton DR. Ceramide-induced apoptosis: role of 
catalase and hepatocyte growth factor. Free radical biology & medicine 2004;37:166-75. 
42. 
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. 
43. 
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. 
44. 
Kadoyama K, Funakoshi H, Ohya W, Nakamura T. Hepatocyte growth factor (HGF) 
attenuates gliosis and motoneuronal degeneration in the brainstem motor nuclei of a 
transgenic mouse model of ALS. Neuroscience research 2007;59:446-56. 
45. 
Li M, Ona VO, Guegan C, et al. Functional role of caspase-1 and caspase-3 in an ALS 
transgenic mouse model. Science 2000;288:335-9. 
46. 
Niimura M, Takagi N, Takagi K, et al. Prevention of apoptosis-inducing factor 
translocation is a possible mechanism for protective effects of hepatocyte growth factor 
against neuronal cell death in the hippocampus after transient forebrain ischemia. Journal 
of cerebral blood flow and metabolism : official journal of the International Society of 
Cerebral Blood Flow and Metabolism 2006;26:1354-65. 
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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 
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48. 
Nakagami H, Kaneda Y, Ogihara T, Morishita R. Hepatocyte growth factor as potential 
cardiovascular therapy. Expert Rev Cardiovasc Ther 2005;3:513-9. 
49. 
Gao YF, Ha XQ, Lu TD, Han JP. Effects of hepatocyte growth factor-mediated activation 
of Dll4-Notch-Hey2 signaling pathway. Chinese medical journal 2011;124:127-31. 
50. 
Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J 
Biochem 1996;119:591-600. 
51. 
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. 
52. 
van de Kamp J, Jahnen-Dechent W, Rath B, Knuechel R, Neuss S. Hepatocyte growth 
factor-loaded biomaterials for mesenchymal stem cell recruitment. Stem cells 
international 2013;2013:892065. 
53. 
Le Goff A, Ji Z, Leclercq B, et al. Anti-apoptotic role of caspase-cleaved GAB1 adaptor 
protein in hepatocyte growth factor/scatter factor-MET receptor protein signaling. The 
Journal of biological chemistry 2012;287:35382-96. 
54. 
D'Angelo F, Bernasconi E, Schafer M, et al. Macrophages promote epithelial repair 
through hepatocyte growth factor secretion. Clinical and experimental immunology 
2013;174:60-72. 
55. 
Xiao Z, Xi C. Hepatocyte growth factor reduces hypertrophy of skin scar: in vivo study. 
Advances in skin & wound care 2013;26:266-70. 
56. 
Kawaida K, Matsumoto K, Shimazu H, Nakamura T. Hepatocyte growth factor prevents 
acute renal failure and accelerates renal regeneration in mice. Proceedings of the National 
Academy of Sciences of the United States of America 1994;91:4357-61. 
57. 
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. 
58. 
Snyder RJ, Kirsner RS, Warriner RA, 3rd, Lavery LA, Hanft JR, Sheehan P. Consensus 
recommendations on advancing the standard of care for treating neuropathic foot ulcers 
in patients with diabetes. Ostomy/wound management 2010;56:S1-24. 
 
 
 


 
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APPENDICES 
 
 
 
 


 
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TABLE OF APPENDICES 
 
 
Appendix 1. Schedule of Evaluations and Visits & Laboratory Tests by Visit ......................... 75 
Appendix 2. Sample Informed Consent ..................................................................................... 79 
Appendix 3. Medications/Therapies Excluded from Use During the Study ............................. 96 
Appendix 4. Standardized Wound Care..................................................................................... 99 
Appendix 5. Target Ulcer Documentation ............................................................................... 104 
Appendix 6. ABI, TBI and Toe Pressure ................................................................................. 107 
Appendix 7. Test Article Administration................................................................................. 111 
Appendix 8. The Cardiff Wound Impact Questionnaire (CWIQ) ........................................... 113 
 
 
 


 
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Appendix 1. 
Schedule of Evaluations and Visits & Laboratory Tests by Visit 
 
 
 








 
 
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Appendix 2. 
Sample Informed Consent 
 




 
 
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Do I have to take part? 
Taking part in this study is entirely voluntary, and you may refuse to participate or withdraw 
from the study at any time without influencing your regular medical treatment and without 
giving a reason.  A decision to withdraw at any time, or a decision not to take part, will not affect 
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, peripheral arterial disease [narrowing of blood vessels 
that reduce the blood flow to your limbs], and, you have a chronic, nonhealing ulcer on one of 
your feet.   
 
Ulcers initially occur due to trauma, pressure loading [force applied to the skin], and / or 
neuropathy [problems with the nerves in your feet].  Ulcers don’t heal because of infection and / 
or when your diabetes and poor circulation interfere with normal healing.   
 
Researchers have discovered that a protein called hepatocyte growth factor (HGF) that your body 
naturally produces in small amounts may cause the growth of new blood vessels, protect nerves, 
and stimulate wound healing.  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 leg.  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 
helps ulcer healing.  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 two studies (a small feasibility study and a larger study) in the United 
States in subjects with critical limb ischemia [decreased blood flow to the legs]; in a study in 
Korea in subjects with coronary artery disease and in two other studies in the United States in 
subjects with painful diabetic neuropathy.  VM202 is currently tested in the United States in 
subjects with Lou Gehrig’s disease.  VM202 has also been tested in people undergoing coronary 
bypass surgery.  It is hoped that VM202 injected into your calf muscle will help heal your ulcer 
on your foot.   
 
This study is intended to help determine the safety and efficacy of VM202 in subjects with a 
chronic, nonhealing ulcer.  VM202 will be injected into your calf muscles in one leg (the leg 
with the ulcer on your foot), using a syringe with a fine needle.     
 
Who is in charge of this study? 
The Principal Investigator is [INSERT PRINCIPAL INVESTIGATOR NAME].  This study is 
sponsored and funded by Helixmith Co., Ltd.  [INSERT PRINCIPAL INVESTIGATOR NAME] 
is being paid by Helixmith Co., Ltd. to conduct this study.  Together with your doctor, Helixmith 


 
 
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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.   
 
How many people will take part in this research study? 
A total of 300 patients will take part in this study at up to 30 research centers 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.  If you do not meet all of the study 
entry criteria, you will not be able to participate in the study and your study doctor will discuss 
with you other options that you may have for treatment of your medical condition.  The study 
doctor will tell you whether you are able to participate in this study after the initial test results are 
received and reviewed.   
 
This study is a double-blind, placebo-controlled, randomized clinical study.  If you agree and are 
eligible to participate you will be “randomly” assigned [like flipping a coin] to one of two groups 
as listed below.  “Double-blind” means that you and your doctor will not know the treatment you 
are getting during the study.  However, your doctor can find out if needed for safety reasons.  
“Placebo controlled” means that not all participants will be assigned to a treatment group that 
will receive the study drug.  Some participants may only receive saline injections.  What group 
you are assigned to is done by a computer and is not known by you and your doctor until the 
study is completed.   
 
You will be randomly assigned to one of two possible study groups.  In each study group, you 
will receive 16 injections in one calf at the Day 0, Day 14, Day 28 and Day 42 visits.  The 
contents of the injections depend on your study group:  
 
• VM202 Treatment Group – if you are selected for this group, you will receive 16 mg of 
VM202 over the course of the four injection visits (4 mg of VM202 at the Day 0 visit, 4 mg 
of VM202 at the Day 14 visit, 4 mg of VM202 at the Day 28 visit, and 4 mg of VM202 at the 
Day 42 visit).  At all 4 injection visits, you will receive 16 injections of 0.5 mL of VM202 in 
one calf.  The total volume of all of the injections is about 2 teaspoons of fluid.  
Approximately sixty-five percent (65%) of patients will be assigned to this group.   
 
• Placebo Control Group – if you are selected for this group, you will not receive VM202.  
You will only receive injections of saline.  At all 4 injection visits, you will receive 16 
injections of 0.5 mL of saline in one calf.   The total volume of all of the injections is about 
2 teaspoons of fluid.  Approximately thirty-five percent (35%) of patients will be assigned to 
this group.   
 
What tests, procedures, and diagnostic studies will be done during this study?  
There are 10 visits which span 7 months total time from visit #2 to visit #10.  Depending on the 
visit, different tests will be done.  Visit #1 may actually take more than one visit to accomplish 
depending on how many tests can be scheduled on that first day, but is usually completed within 


 
 
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1 to 2 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.   
 
You will also need to come in once a week for dressing changes and assessment of your ulcer, 
unless that visit coincides with a pre-specified visit described above.  The study doctor will 
provide you with dressings and instructions to clean the wound at home between visits if 
necessary.  
 
Please note: after your ulcer heals, you will need to come in 2 weeks later to confirm that your 
ulcer is truly healed. This confirmation visit may coincide with a pre-specified visit or may 
require an additional visit.  Even after the ulcer heals, you will still be asked to attend all visits 
described below. 
 
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, heart rate and weight (vital signs).   
 
Medication review – Discussion with your doctor of what medications and dietary supplements 
you have taken and are currently taking.  Please note, some medications/treatments may not be 
taken during the study since they may interfere with the potential effect of the study medication 
or ability to assess the response to the study medication.  The doctor will talk to you about these 
medications/treatments; if you are currently taken any of these medications, you will be asked to 
stop taking these medications for the duration of the study.      
 
Assessment of the ulcer – A photograph of the ulcer will be taken, and the size of the ulcer will 
be determined.  Please note, the photograph is a close-up of your ulcer; no one will be able to 
identify you in the photo.   
 
Foot X-ray – Two X-rays will be taken of your foot with the ulcer. 
 
Injection site reaction assessment – Assessment by your doctor of any pain or other reaction at 
the locations where VM202 or placebo 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 complete a short questionnaire the effects of your ulcer on 
your life. 
 
Measurement of blood pressure in your leg (ABI, TBI and toe pressure) – The ankle-
brachial index (ABI) and the toe-brachial (TBI) index is the ratio of the blood pressure in the 


 
 
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lower legs to the blood pressure in the arms. Compared to the arm, lower blood pressure in the 
leg is a symptom of blocked arteries.  Blood pressure measurements are taken at the arms and 
ankles and toes. You may experience some minor discomfort associated with compressing the 
artery with the cuff.  It will last only a few seconds. 
 
Transcutaneous oxygen pressure (TcPO2), at Select sites Only – Omit section if not 
applicable – Transcutaneous oxygen pressure (TcPO2) is a measurement of how much oxygen 
reaches your skin.  It requires that a small device be placed on the skin for 15 – 20 minutes.  
There is no pain or risk associated with this procedure. 
 
Cancer screening – Cancer screening may include pap smear and mammogram depending on 
your age and screening status (females only); and a CT scan of the chest depending on your 
current smoking status and tobacco use history (all subjects).  Please ask your study doctor, 
which tests you may need. 
 
If you are 50 years of age or older, fecal occult blood test [stool samples will be tested for the 
presence of blood] - if you have a personal or family history of colon cancer in any first degree 
relative, you must have undergone a colonoscopy in the past 12 month with negative findings. 
 
Retinal fundoscopy (specific eye exam) – An ophthalmologist (eye doctor) will 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 7 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 
to confirm that you are not pregnant.  You cannot participate if you are pregnant, plan to become 
pregnant, or are breastfeeding 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. 
 
Blood tests – Routine 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).  


 
 
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Below is a list of each visit and the specific tests that will be done: 
 
Visit # 1: Screening Evaluations 
Screening is a process of evaluating your initial health status and assessing your ulcer.  Screening 
is usually completed within 1 week 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, ulcer assessment, foot x-rays, measurement of blood 
pressures in your leg, cancer screening, retinal fundoscopy, blood tests including a viral screen, 
urine pregnancy test (if you are a female of childbearing age), and a 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.   
 
Please note: Starting at this visit, you will receive standard of care treatment for your ulcer which 
includes removal of dead or damaged tissue, the use of an appropriate off-loading device (boot or 
sandal that will be keep the pressure off your ulcer), and the ulcer will be kept clean and moist 
using a special dressing.     
 
It takes approximately 2 to 4 weeks to get all of the screening test results.  After your doctor has 
reviewed the results of these tests, he/she will determine whether you are eligible for 
participation in the study.  If you are eligible for the study and you do wish to continue, you will 
be assigned by chance (randomly) to receive VM202 or placebo.  You will then be scheduled for 
the first set of injections which will be done at your next visit (Visit #2).    
 
Visit # 2 – First Injection Procedure (injections of VM202 or placebo into your calf 
muscles) 
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done: ulcer 
assessment, photograph of your ulcer, medication review, completion of questionnaire, vital 
signs, measuring blood pressures in your leg, measurement of how much oxygen reaches your 
skin (select sites), and blood tests including HGF and 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 or saline solution at sites evenly distributed over your 
calf muscles.  You will receive 16 injections in one calf.  Each injection will take 3 - 5 seconds.  
Each site will be marked with an indelible marker.  The entire injection procedure is expected to 
take 15-30 minutes. 
 
After Injection Procedure:  


 
 
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After the injection procedure is performed, the following tests and/or evaluations will be done: 
vital signs, injection site reaction assessment, blood tests for VM202, and assessment of side 
effects. 
 
Before you go home discharge instructions about what you need to do to take care of yourself, 
what medications you should take, and who to call if you have a problem after you leave the 
clinic, will be reviewed with you by the nurse and/or doctor.  Research personnel will be on call 
anytime to answer any questions that you may have and respond to reports you may have of any 
symptoms.   
 
Visit # 3 – Second Injection Procedure (injections of VM202 or placebo into your calf 
muscles; 14 Days after the First Injection Procedure) 
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done: ulcer 
assessment, photograph of your ulcer, medication review, vital signs, injection site reaction 
assessment and assessment of side effects, and blood test for 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 or saline solution at sites evenly distributed over your 
calf muscles.  You will receive 16 injections in one calf.  Each injection will take 3 - 5 seconds.  
Each site will be marked with an indelible marker.  The entire injection procedure is expected to 
take 15-30 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 test for VM202, and assessment of side 
effects. 
 
Before you go home 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 # 4 – Third Injection Procedure (injections of VM202 or placebo into your calf 
muscles; 14 Days after the Second Injection Procedure) 
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done: ulcer 
assessment, medication review, vital signs, injection site reaction assessment and assessment of 
side effects, and blood tests for HGF and VM202. 
 
Injection Procedure:   


 
 
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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 or saline solution at sites evenly distributed over your 
calf muscles.  You will receive 16 injections in one calf.  Each injection will take 3 - 5 seconds.  
Each site will be marked with an indelible marker.  The entire injection procedure is expected to 
take 15-30 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 test for VM202, and assessment of side 
effects. 
 
Before you go home 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 # 5 – Fourth (Last) Injection Procedure (injections of VM202 or placebo into your calf 
muscles; 14 Days after the Third Injection Procedure) 
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done: ulcer 
assessment, medication review, vital signs, injection site reaction assessment and assessment of 
side effects, and blood tests including 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 or saline solution at sites evenly distributed over your 
calf muscles.  You will receive 16 injections in one calf.  Each injection will take 3 - 5 seconds.  
The entire injection procedure is expected to take 15-30 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 test for VM202, and assessment of side 
effects. 
 
Before you go home 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 # 6 – 60 Days after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: ulcer assessment and photograph, 
medication review, vital signs, blood tests for HGF and VM202, injection site reaction 
assessment and assessment of side effects. 


 
 
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Visit # 7 – 74 Days after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: ulcer assessment, medication 
review, vital signs, and assessment of side effects. 
 
Visit # 8 – 90 Days (3 Months) after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: ulcer assessment, medication 
review, vital signs, blood tests including HGF and VM202, and assessment of side effects. 
 
Visit # 9 – 4 Months after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: ulcer assessment, medication 
review, vital signs, completion of questionnaire, measuring blood pressures in your leg, 
measurement of how much oxygen reaches your skin (select sites), blood tests, and assessment 
of side effects. 
 
Visit # 10 – 7 Months after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: retinal fundoscopy, ulcer 
assessment, medication review, vital signs, completion of questionnaire, measuring blood 
pressures in your leg, measurement of how much oxygen reaches your skin (select sites), blood 
tests, and assessment of side effects. 
 
After you have completed your 7-month follow-up visit, you do not have to return for any more 
visits.   
 
Medication Use during the Study 
The study doctor will review your current medications/therapies with you.  The following 
therapies are not allowed during the study: 
• Gels or creams with growth factors, e.g., Regranex® gel (becaplermin) 
• Larval debridement 
• Skin substitutes, e.g., Dermagraft®, Apligraf®  
• Hyperbaric oxygen therapy 
• Hydrotherapy 
• Negative pressure wound therapy 
• Electrical stimulation therapy 
Your doctor will review these medications and treatments with you to make sure that you 
understand what is prohibited during the study. 
 
You are not allowed to use COX-2 inhibitor drug(s), non-specific COX-1/COX-2 inhibiting 
drugs, steroids, (except inhaled steroids or ocular steroids), anti-Vascular Endothelial Growth Factor 
(VEGF) agents, and more than 81 mg/day of aspirin during the study because these medications 
may interfere with VM202.  For example, this includes medications such as Bayer aspirin 
(> 81 mg), Motrin, ibuprofen (Advil), Aleve, and Excedrin. Your doctor will review these 
medications with you to make sure you understand which medications are prohibited during the 
study. 
 


 
 
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If the study doctor or you feel that you cannot adhere to these directions, please do not sign up 
for study participation. 
 
How long will I be in this research study? 
Your last follow up visit will be approximately 7 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.  Please note, some medications (prescription and non- 
prescription medications) may not be taken during the study since they may interfere with the 
potential effect of the study medication or ability to assess the response to the study medication.   
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 any time 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 or placebo 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 


 
 
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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 (if you receive VM202) has the potential 
to create new blood vessels (angiogenesis), there may be risk of promoting tumor growth 
(cancer).   
 
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 you are sexually active and with 
childbearing potential, you must agree to use an acceptable method of birth control during 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 14 times over 
approximately 11 months.  Each time your blood is drawn roughly 1 to 2 tablespoons of blood 
will be taken.   
 
Risks from foot X-ray 
A foot X-ray is a safe and painless test that uses a small amount of radiation.  The average dose 
of two foot X-rays is 0.2 mrem.  In comparison, most people receive 300 mrem every year from 
natural background sources of radiation.   
 


 
 
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Risks from cancer screening 
Cancer screening may include pap smear and mammogram if not performed within past 12 
months (females only) and CT scan of the chest.  All subjects 50 years of age or older will 
undergo a fecal occult blood test. If you have a personal or family history of colon cancer in any 
first degree relative, you must have undergone a colonoscopy in the past 12 months with 
negative findings. 
 
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).  Some discomfort 
can be associated with a Pap smear and mammography (if you are female).  Risks from 
colonoscopy include bowel perforation (a hole or tear in the wall of the colon) requiring a repair 
operation (fewer than 1 out of 1,000 tests), heavy or persistent bleeding from biopsy or polyp-
removal sites (1 out of 1,000 tests), adverse reaction to sedative medication causing breathing 
problems or low blood 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, the drops 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 at Screening).  
Side effects associated with injection of fluorescein dye into a vein in the arm include nausea 
and/or vomiting (approximately 5% of subjects) hives and itching (approximately 0.5% of 
subjects) 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 
your ulcer may heal faster.    
 


 
 
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Knowledge from this study may help us better understand how to treat people with chronic 
nonhealing ulcers.     
 
What if new information becomes available? 
If additional data regarding potential safety risks become available during the study, your 
research doctor will tell you about it and discuss with you whether you want to continue in the 
study.  If you decide to withdraw from the study, your research doctor will make arrangements 
for your care to continue.  If you decide to continue in the study, you may be asked to sign an 
updated consent form which will explain the new information clearly.   
 
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/placebo injections.  Helixmith 
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 will 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 
subject identifier code number and your initials.  Except when required by law, you will not be 


 
 
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identified by name, social security number, address, telephone number, or any other direct 
personal identifier in study records.   
 
Your records may be reviewed in order to meet Federal Food and Drug Administration (US 
FDA) regulations, or other national and/or local health regulatory authorities.  Your records may 
be copied by, or for these groups.  If your research record is reviewed by any of these groups, 
they may also need to review your entire medical record.  Copies of the study records that do not 
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 (Helixmith Co., Ltd.), or its representatives 
such as members of the Data Safety Monitoring Committee, the Contract Research Organization, 
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 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, and an IRB (research ethics committee). 
 
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.   
 


 
 
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What alternatives are there to participation in this study?   
The standard of care for chronic foot ulcers includes debridement of the wound, management of 
any infection, revascularization procedures when indicated, mechanical offloading of the ulcer, 
management of blood glucose, and foot care education.   
 
Other adjunctive therapies, such as hyperbaric oxygen, use of advanced wound care products, 
and negative-pressure wound therapy have shown some benefit, but reports of efficacy are 
mixed, and their cost-effectiveness has not been demonstrated. 
 
Note: You do not have to take part in this study to receive treatment for your condition.   
 
 


 
 
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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, Helixmith 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 understand that a description of this clinical trial will be 
available on http://www.ClinicalTrials.gov, as required by U.S. Law.  This Website will not 
include information that can identify me.  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 site file; 1 copy for subject.   
 


 
 
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Appendix 3. 
Medications/Therapies Excluded from Use During the Study 
 




 
 
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OTHER PROHIBITED MEDICATIONS/THERAPIES DURING STUDY PARTICIPATION 
 
Subjects must refrain from using the following medications/ undergoing the following therapies 
for the duration of the study: 
• Gels or creams with growth factors, e.g., Regranex® gel (becaplermin) 
• Larval debridement 
• Skin substitutes, e.g., Dermagraft®, Apligraf®  
• Hyperbaric oxygen therapy 
• Hydrotherapy 
• Negative pressure wound therapy 
• Electrical stimulation therapy 
 
Subject must agree to remain off of these medications/treatments until completion of the 7-
month follow-up visit. 
 
 
 
 


 
 
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Appendix 4. 
Standardized Wound Care 
 
 
 
 
 


 
 
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Starting at screening, wound care will be standardized as follows for the duration of the 
study/until the ulcer has completely healed: 
 
Surgical debridement of necrotic tissue or devitalized tissue 
The extent of debridement is based on the wound and will be determined by the Principal 
Investigator or his/her representative based on his/her standard of care. 
 
Maintenance of a clean and moist wound environment 
• A wound cleanser will be used to maintain a clean environment; specifically, Puracyn® Plus 
(Innovacyn, Inc, Rialto, CA) will be provided to the sites for use in study subjects in order to 
increase compliance and standardization 
• A non-medicated, absorbent hydrocellular foam dressing will be used. Specifically, 
ALLEVYN Gentle (Smith & Nephew, London, UK) with a soft gel adhesive which 
minimizes trauma to the wound at dressing change will be provided to the sites for use in 
study subjects in order to increase compliance and standardization. 
Note: in subjects with multiple ulcers on the target foot, all ulcers will be cleansed with Puracyn® 
Plus and dressed with ALLEVYN Gentle in order to maintain standardized care for the entire 
target foot. 
 
Use of appropriate off-loading when ambulating 
Removable footwear will be used for ulcer offloading.  Choice of footwear will depend on the 
location of the ulcer.  A boot should be considered for plantar ulcers; an off-loading 
postoperative shoe should be considered for all ulcers located elsewhere below the malleolus. 
Examples adapted from: Consensus Recommendations on Advancing the Standard of Care for 
treating Neuropathic Foot Ulcers in Patients with Diabetes, Snyder, RJ (2010)58 are provided in 
Table 8.  
 






 
 
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Instructions for the Subject 
Subjects will be provided with the following instructions: 
Home care instructions for maintaining your wound 
The ulcer will be cared for by maintaining an optimal wound environment. 
1. 
Wash your hands thoroughly and apply gloves.  
2. 
Remove the old dressing and gently cleanse the wound with saline water.  
3. 
Gently pat the ulcer and surrounding skin from the center of the wound outward with dry 
gauze. 
4. 
Try to avoid disrupting the tissue or causing bleeding of the wound. 
5. 
Be sure to completely dry the area around the wound after cleansing the wound or washing 
the foot. Note: No antimicrobial soap or products should be used to cleanse the wound or 
the foot.  Do not use any lotions, gels, or ointments on the wound. 
6. 
Apply the assigned primary and secondary dressings to the wound.  
7. 
Apply your sock and the appropriate offloading device.  
 
 
 


 
 
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Appendix 5. 
Target Ulcer Documentation 
 
 
 


 
 
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SilhouetteStar + SilhouetteConnect system (ARANZ Medical, Christchurch, New Zealand) will 
be used to capture photographs, and measure the target ulcer. 
 
• 
The SilhouetteStar is a 3D camera that connects to a Windows computer using a USB 
cable.  
• 
SilhouetteConnect is software installed on a Windows computer that controls the 
SilhouetteStar camera. 
 
Silhouette contains a 3-megapixel camera that is always in focus, with its own lighting system 
that provides consistent ambient background lighting, and a single button (for image 
capture). Users are able to repeatedly obtain high quality and consistent images from visit to 
visit using a device that may be the easiest-to-use digital camera available. 
 
 
Silhouette is a family of products for imaging, measuring and documenting wounds. Silhouette 
is designed to improve workflow in wound assessment, allowing a user to quickly image 
and accurately analyze a wound using a portable, non-contact device, with all measurements 
saved directly into an electronic database designed specifically for wounds and other external 
surface features. All measurements are made without touching the patient, eliminating patient 
discomfort and reducing risk of infection. 
 
Key features of SilhouetteStar + SilhouetteConnect include: 
 
• 
Multiple tools in one – wound imaging, measurement and documentation 
• 
Repeatable and accurate measurements 
• 
Accurate measurement of surface area, length, width, perimeter, maximum depth, average 
depth, and volume 
• 
Non-contact measurements 
• 
The ability to track wound healing over time 
• 
Quick and easy to use 
 
The third component in the Silhouette Product Suite is SilhouetteCentral.™ 
 


 
 
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SilhouetteCentral enables central storage for the collection of high-quality data of each target 
ulcer (including images and measurements) for all clinical sites through transmission of data 
through the internet. Furthermore, SilhouetteCentral: 
• Enables review by personnel from remote location 
• Facilitates export of data for analyses 
• Capable of automatic report generation and report distribution 
 
Measurements – Accuracy and Repeatability 
Studies have shown that the inter- and intra-rater repeatability of measurements of wound 
surface area made using Silhouette are superior to those made using acetate tracings, the 
current clinical standard for such measurements.a  
A study of SilhouetteStar + SilhouetteConnectb shown that the inter-rater and intra-rater 
variability were less than 1% for both area and perimeter, and less than 2% for average depth 
and volume on wound models.  This indicates that repeated measurements over time, even by 
different users, will detect small differences as a wound changes in size. 
 
Studies on large skin featuresc (for example areas of erythema) have also shown that 
Silhouette can accurately measure surface area of lesions ranging from 150 cm2 to 900 cm2. 
In this study both the repeatability associated with the three raters and intra-rater variability 
for each of the three raters were less than 2%. 
 
Training 
Each site will be trained in the use of the SilhouetteStar + SilhouetteConnect system prior to 
enrollment of any subjects into the study. 
 
 
 
 
 
a Nixon MA, Davey BLK, Fright WR, McCallum BC, Kieser D, Comparison Between Two Methods of 
Wound Measurement on Wound Models: Acetate Tracing and a Hand-Held, Electronic Wound Measurement 
Device, Symposium on Advanced Wound Care (SAWC) April 2009, Dallas, Texas, Oral Presentation. 
 
b Nixon MA, Rivett TR, Robinson BR, Assessment of Accuracy and Repeatability on Wound Models of a New 
Hand-Held, Electronic Wound Measurement Device, Symposium on Advanced Wound Care (SAWC) Spring, April 
2012, Atlanta, Georgia, Poster Presentation. 
c Nixon MA, Goodwin SR, Davey BLK, Accuracy and Repeatability of Area Measurements on Large Areas of 
Erythema using an Electronic Wound Measurement Device, Symposium on Advanced Wound Care (SAWC) 
Spring, April 2011, Dallas, Texas, Poster Presentation. 


 
 
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Appendix 6. 
ABI, TBI and Toe Pressure  
 
 
 
 


 
 
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Ankle-Brachial Index (ABI) and Toe Brachial Index (TBI) will be determined at Screening, on 
Day 0, Day 120 (4 months) and Day 210 (7 months) in the target limb.  Toe pressure will be 
determined at Screening in the target limb. 
 
Definitions 
• 
Dorsalis pedis (DP) — pulse located at approximately the mid-anterior aspect of the ankle 
joint. 
• 
Posterior tibial artery (PT) — pulse located just posterior to the medial malleolus of the 
ankle joint. 
• 
ABI — the ABI for each limb is defined as the ratio between the higher of the two pedal 
systolic blood pressure measurements (dorsalis pedis and posterior tibialis) on a leg and the 
higher of the two systolic brachial pressure measurements (right or left brachial).   
 
Right ABI = Highest pressure in right foot/highest systolic pressure in both arms  
 
Left ABI = Highest pressure in left foot/highest systolic pressure in both arms 
 
• 
TBI — The TBI is calculated as the ratio of the systolic blood pressure of the first toe on 
each side divided by the higher of the systolic blood pressures of the two arms. 
 
Right TBI = right toe systolic pressure/highest systolic pressure in both arms  
 
Left TBI = left toe systolic pressure/highest systolic pressure in both arms  
 
Equipment needed: 
• Doppler 
• Ultrasound gel 
• Blood pressure cuff  
 
Performing a Resting ABI 
1. 
Resting ABI measurements must be taken after the subject has rested for at least 10 
minutes in the supine position.  All ABI measurements must be made using a continuous 
wave 5-10 MHz Doppler probe. 
2. 
Use the appropriate cuff for the limb you are assessing—a standard cuff for the upper limbs 
and an ankle cuff for the lower limbs.  If an ankle cuff is not available, choose the 
appropriate size cuff for the upper and lower limbs.  It may be necessary to use 2 different 
cuff sizes. 
3. 
Resting ABI pressures should be obtained in a horseshoe shape starting with right arm and 
finishing with the left arm. 
4. 
Use a generous amount of gel. 
5. 
Adjust the probe, before inflating the cuff, until you find the strongest (loudest), clearest 
pulse sound. 
6. 
Keep hand and Doppler probe stabilized (i.e., on bed, subject, etc.). 


 
 
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7. 
Watch the Doppler probe while inflating the cuff; not the sphygmomanometer.  This will 
ensure that the probe is not inadvertently moved, thereby losing the pulse. 
8. 
Inflate the cuff about 20 mmHg above the last audible pulse sound. 
9. 
Turn attention to the sphygmomanometer and deflate the cuff slowly (about 2 mmHg per 
second).  Record the reading of the first sound you hear that you are confident is a pulse 
sound. 
10. Wait twenty seconds, with the cuff completely deflated.  Repeat steps 4 through 9 to obtain 
a second pressure at each vessel.  Use the average of the two measurements to define a 
single pressure for each vessel.  If individual pressures for a vessel are ≥ 10 mmHg 
different from each other, repeat the process until the difference between the pair of 
systolic pressures is < 10 mmHg. 
 
Performing a Resting TBI 
1. 
Resting TBI measurements must be taken after the subject has rested for at least 10 minutes 
in the supine position.   
2. 
Resting TBI pressures should be obtained in a horseshoe shape starting with right arm and 
finishing with the left arm (brachial pressures should be obtained even if previously 
obtained for ABI measurements). 
3. 
Use arm cuff appropriate to the size of the arm being tested. 
4. 
Position cuff so the middle of the bladder is over brachial vessel & wrap cuff tight enough 
so that no more than two fingers can be inserted between the cuff and the arm. 
5. 
Use an adequate amount of gel. 
6. 
Use Doppler (not a stethoscope). 
7. 
Search for strongest pulse, prior to inflating the cuff (do not use first sound heard). 
8. 
Keep hand and Doppler stabilized (i.e., on bed, subject, etc.). 
9. 
Watch Doppler hand while inflating cuff. 
10. Inflate approximately 20mm above last heard pulse. 
11. Deflate cuff slowly, approximately 2mm every second. 
12. Record the reading of the first sound you hear that you are relatively certain is a pulse 
sound. 
13. Deflate cuff and wait at least 20 seconds.  
14. Repeat steps 1 through 13 on the same vessel. Use the average of the two measurements to 
define a single pressure for that vessel.   
15. If the first and second readings are 10mm or more different from each other, discard both 
readings and restart the assessment of the pressure of this vessel.  
 
 
 


 
 
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Toe Pressure (using a photoplethysmography [PPG]): 
1. 
Apply double-sided clear tape over the pad of the big toe 
2. 
Use a toe cuff 
3. 
Ensure any ulcers present are protected.  Position the cuff comfortably snug around the 
base of the big toe 
4. 
Affix the PPG probe to the pad of the toe where the double-sided tape was applied 
5. 
Ensure the subject’s toes are warm to the touch prior to obtaining the pressure 
6. 
Set the PPG machine waveform motion to run at 5 mm per second and allow the readout to 
stabilize 
7. 
Ensure the printed waveform fits well within the printed readout 
8. 
Inflate the cuff approximately 20 mmHg above last viewed reading 
9. 
Watch both the waveform motion on the PPG and the sphygmomanometer while deflating 
the cuff 
10. Deflate the cuff slowly, approximately 2 mmHg every second 
11. Identify the return of the systolic pressure (first viewed waveform motion) 
12. Deflate cuff and wait at least 20 seconds before obtaining the next pressure 
13. Repeat above steps on the same vessel for a second measurement 
14. The average of the two pressures in the affected limb will be assessed against the inclusion 
criteria.  
 
Toe Pressure (using a 5-10 MHz Doppler probe):   
1. 
Use a toe cuff 
2. 
Ensure any ulcers present are protected.  Position the cuff comfortably snug around the 
base of the big toe 
3. 
Ensure the subject’s toes are warm to the touch prior to obtaining the pressure 
4. 
Search for strongest pulse, prior to inflating the cuff (do not use first sound heard) 
5. 
Keep hand and Doppler stabilized (i.e., on bed, subject etc.) 
6. 
Watch Doppler hand while inflating cuff 
7. 
Inflate the cuff approximately 20 mmHg above last heard pulse 
8. 
Deflate the cuff slowly, approximately 2 mmHg every second 
9. 
Appropriately identify the return of the systolic pulse (first sound that you hear that you are 
relatively certain is a pulse sound) 
10. Deflate cuff and wait at least 20 seconds before obtaining the next pressure 
11. Repeat above steps on the same vessel for a second measurement 
12. The average of the two pressures in the affected limb will be assessed against the inclusion 
criteria.  
 


 
 
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Appendix 7. 
Test Article Administration 




 
 
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Appendix 8. 
The Cardiff Wound Impact Questionnaire (CWIQ)  
 
 
 
 
 
Upon completion of the questionnaire, the study coordinator will check the CWIQ for 
completeness.  Note, the subject will be required to initial and date the CWIQ. 
 
 
 


 
 
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Cardiff Wound Impact Schedule 
 
 
 
 
 
 
 
 
 
 
 


 
 
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 The following questionnaire is concerned with the effects that your wound has on your daily life.  
Please answer the questions carefully by placing a tick in the box which most closely reflects how 
you feel; it should take about ten minutes to complete. 
 
If you are unsure about how to answer a question, please tick the answer which is closest to how 
you feel.  All answers are confidential. 
 
Personal Details 
 
Subject Initials 
 
 Subject Number 
 
 
Gender 
    
 (Please circle) 
 
Date of Birth 
 
 
Assessment Date 
 
 
Assessment 
 (Please circle) 
 
Next Assessment Due 
 
 
Wound status 
Healed 
   Not Healed 
 
 
Do you live on your own?      Yes 
                No 
 
 
 
How often do you see your family and friends? 
 
Once a day 
 
                Once a month 
 
 
Once a week 
 
Less than once a month 
 
M 
F 
D 
D 
M 
M 
M 
Y 
Y 
D 
D 
M 
M 
M 
Y 
Y 
5th 
1st 
2nd 
3rd 
4th 
D 
D 
M 
M 
M 
Y 
Y 


 
 
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 Well-being 
 
To what extent do you agree/disagree with the following statements? 
 
 
 
Strongly 
Disagree 
Not Sure 
Agree 
Strongly 
 
Disagree 
 
Agree 
I feel anxious about my 
wound(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I feel frustrated at the time it is 
taking for the wound(s) to heal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I am confident that the 
wound(s) I have will heal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I worry that I may get another 
wound in the future 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The appearance of the wound 
site is upsetting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I feel anxious about bumping 
the wound site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I worry about the impact of the 
wound(s) on my family/friends 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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 Physical Symptoms and Daily Living 
 
Have you experienced any of the following during the past week? 
 
 
Not at all/ 
Seldom 
Sometimes Frequently Always 
 
Not applicable 
Disturbed sleep 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Difficulty in bathing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immobility around the home 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immobility outside the home 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leakage from the wound 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain from the wound site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discomfort from the 
bandaging/dressing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unpleasant odour or smell 
from the wound 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Problems with everyday 
tasks (eg shopping) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Difficulty in finding 
appropriate footwear 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Problems with the amount 
of time needed to care for 
 
 
 
 
 
 
 
 
 
the wound site 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Financial difficulties as a 
result of the wound 
 
 
 
 
 
 
 
 
 
Physical Symptoms and Daily Living 
 
How stressful has this experience been for you? 
 
 
Not at all/ 
Slightly 
Moderately Quite 
Very 
 
Not applicable 
 
 
a bit 
Disturbed sleep 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Difficulty in bathing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immobility around the home 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immobility outside the home 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leakage from the wound 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain from the wound site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discomfort from the 
bandaging/dressing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unpleasant odour or smell 
from the wound 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Problems with everyday 
tasks (eg shopping) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Difficulty in finding 
appropriate footwear 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Problems with the amount 
of time needed to care for 
 
 
 
 
 
 
 
 
 


 
 
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the wound site 
 
 
 
 
 
 
 
 
 
 
 
Financial difficulties as a 
result of the wound 
 
 
 
 
 
 
 
 
 


 
 
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Social Life 
 
Have you experienced any of the following during the past week? 
 
 
 
Not at all/ 
Slightly 
Moderately Quite 
Very 
 
Not applicable 
 
 
a bit 
Difficulty getting out and 
about 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relying more on others 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Your family/friends being 
over protective 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unable to enjoy your usual 
social life (eg hobbies) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited contact with 
family/friends 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not going out for fear of 
bumping your wound site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wanting to withdraw from 
people 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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 Social Life 
 
How stressful has this experience been for you? 
 
 
 
Not at all/ 
Slightly 
Moderately Quite 
Very 
 
Not applicable 
 
 
a bit 
Difficulty getting out and 
about 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relying more on others 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Your family/friends being 
over protective 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unable to enjoy your usual 
social life (eg hobbies) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited contact with 
family/friends 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not going out for fear of 
bumping your wound site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wanting to withdraw from 
people 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Overall Quality of Life 
 
How would you rate your overall quality of life during the past week? 
 
Please circle a number below 
 
 
(Score = number as circled) 
 
How good is your quality of life? 
 
 
 
My quality of 
life is the 
worst possible 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
My quality of life 
is the best 
possible 
 
 
 
How satisfied are you with your overall quality of life? 
 
Not at all 
satisfied 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 Very satisfied 
 
 
 
Overall Comment(s) 
 
 
 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan 
 
 
 
Protocol Title: 
A Phase III, Double-Blind, Randomized, Placebo-Controlled, 
Multicenter Study to Assess the Safety and Efficacy of VM202 to 
Treat Chronic Nonhealing Foot Ulcers in Diabetic Patients with 
Concomitant Peripheral Arterial Disease (PAD) 
SAP Version: 
VMNHU-003 SAP; Version E 
Protocol Number: 
VMNHU-003; Version I 
NCT Number: 
NCT02563522 
Document Date: 
04 February 2020 
 


 
 
 
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Statistical Analysis Plan 
 
A Phase III, Double-blind, Randomized, Placebo-controlled, 
Multicenter Study to Assess the Safety and Efficacy of VM202 to 
Treat Chronic Nonhealing Foot Ulcers in Diabetic Patients with 
Concomitant Peripheral Arterial Disease (PAD)  
Protocol VMNHU-003/I (February 4, 2020) 
 
 
February 4, 2020 
VMNHU-003-SAP/E 
 
 
Sponsor: 
Helixmith Co., Ltd. 
 
 
 
 
 
 
 
  
 
 
Prepared by:  
Helixmith Co., Ltd. 
 
 
 
 
 
 
Revision: 
 
E 
 




 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 6 
1. 
INTRODUCTION........................................................................................................... 7 
2. 
ANALYSIS OBJECTIVES ............................................................................................ 8 
3. 
STUDY DESIGN ............................................................................................................. 8 
4. 
STUDY ENDPOINTS ................................................................................................... 13 
4.1. 
Primary Efficacy Endpoint ...................................................................................... 13 
4.2. 
Other Efficacy Endpoints ......................................................................................... 13 
4.3. 
Safety Outcomes ........................................................................................................ 13 
4.4. 
Pharmacokinetics ...................................................................................................... 14 
4.5. 
Planned Covariates ................................................................................................... 14 
5. 
DEFINITIONS .............................................................................................................. 14 
5.1. 
Basic Definitions ........................................................................................................ 14 
5.2. 
Study Points of Reference ........................................................................................ 15 
5.3. 
Study Specific Definitions ........................................................................................ 15 
5.3.1. Definitions of Safety Outcomes .............................................................................. 15 
5.3.2. Definitions of Efficacy Endpoints .......................................................................... 16 
5.4. 
Derived Variables...................................................................................................... 17 
6. 
SAMPLE SIZE CALCULATION ............................................................................... 18 


 
 
 
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7. 
ANALYSIS POPULATIONS ...................................................................................... 19 
7.1. 
Intent-to-Treat (ITT) Population ............................................................................ 19 
7.2. 
Safety Population ...................................................................................................... 19 
7.3. 
Modified Intent-to-Treat (mITT) Population ........................................................ 19 
7.4. 
Per Protocol (PP) Populations ................................................................................. 19 
7.5. 
Subgroup Analysis Subsets ...................................................................................... 20 
8. 
DATA HANDLING ...................................................................................................... 20 
8.1. 
General Principles of Data Handling ...................................................................... 20 
8.2. 
Visit Windows............................................................................................................ 21 
8.3. 
Unmasking of Randomization Codes ...................................................................... 21 
8.4. 
Multiplicity Adjustment ........................................................................................... 22 
8.5. 
Data Safety Monitoring Board ................................................................................ 22 
8.6. 
Handling of Missing and Incomplete Data ............................................................. 22 
8.6.1. Missing Values for the CWIQ ................................................................................ 22 
8.6.2. Missing / Unknown Values of Covariates .............................................................. 22 
8.6.3. Missing Dates and Times ........................................................................................ 23 
9. 
STATISTICAL METHODS ........................................................................................ 23 
9.1. 
General Principles of Data Analyses ....................................................................... 23 
9.2. 
Subject Enrollment and Disposition........................................................................ 24 
9.3. 
Demographics and Baseline Characteristics .......................................................... 24 
9.4. 
Efficacy Endpoint Analyses ..................................................................................... 25 
9.4.1. Primary Efficacy Endpoint ..................................................................................... 25 
9.4.1.1. Primary Analysis of the Primary Efficacy Endpoint ...................................... 25 
9.4.1.2. Sensitivity Analyses of the Primary Efficacy Endpoint ................................. 25 
9.4.1.2.1. Odds ratio from a logistic regression model ............................................... 25 
9.4.1.2.2. Analysis in other analysis populations ....................................................... 26 


 
 
 
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9.4.2. Subgroup Analyses of the Primary Efficacy Endpoint ........................................... 26 
9.4.3. Analysis of Covariates ............................................................................................ 26 
9.4.4. Other Efficacy Endpoints ........................................................................................ 26 
9.4.4.1. Time to complete wound closure of foot ulcer ............................................... 26 
9.4.4.2. Proportion of subjects with a wound closure by 7 months. ............................ 27 
9.4.4.3. Percent change in wound volume at 2, 2.5, 3, 4, and 7 months ...................... 27 
9.4.4.4. Percent change in wound perimeter, area and depth at 2, 2.5, 3, 4, and 7 
months ............................................................................................................. 27 
9.4.4.5. Proportion of subjects with formation of new ulcers on the target foot by 2, 
2.5, 3, 4, and 7 months .................................................................................... 28 
9.4.4.6. Time to a major amputation in the target limb ............................................... 28 
9.4.4.7. Time to a minor amputation in the target limb ............................................... 28 
9.4.4.8. Change in target limb ABI at 4 and 7 months ................................................ 28 
9.4.4.9. Change in target limb TBI at 4 and 7 months ................................................. 28 
9.4.4.10. Change in each domain score of CWIQ at 4 months and 7 months ............... 28 
9.5. 
Safety Analyses .......................................................................................................... 28 
9.5.1. Study Drug Exposure .............................................................................................. 29 
9.5.2. Injection Site Adverse Events ................................................................................. 29 
9.5.3. Adverse Events ....................................................................................................... 29 
9.5.4. Vital Signs ............................................................................................................... 30 
9.5.5. HbA1c, Serum Chemistry and Hematology ........................................................... 30 
9.5.6. Prior and Concomitant Medications ....................................................................... 30 
9.5.7. Retinal Fundoscopy ................................................................................................ 31 
9.5.8. Pharmacokinetics .................................................................................................... 31 
10. 
INTERIM ANALYSIS ............................................................................................. 31 


 
 
 
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LIST OF ABBREVIATIONS 
ABI 
Ankle Brachial Index 
AE 
Adverse Event 
BMI 
Body Mass Index 
CDRC 
Clinical Data Review Committee  
CWIQ 
Cardiff Wound Impact Questionnaire 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EKG 
Electrocardiogram 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HGF 
Hepatocyte Growth Factor 
HIV 
Human Immunodeficiency Virus 
HRQoL 
Health-Related Quality of Life 
HTLV 
Anti-Human T-Cell Lymphotropic Virus 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
PAD 
Peripheral Arterial Disease  
PP 
Per Protocol 
PPG 
Photoplethysmography 
SAE 
Serious AE 
SOC 
System Organ Class 
TBD 
To be determined 
TBI 
Toe Brachial Index 
TEAE 
Treatment-Emergent AE 
WHODDE 
World Health Organization Drug Dictionary Enhanced 


 
 
 
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1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Helixmith Co., Ltd. (formerly ViroMed Co., Ltd.) Protocol 
VMNHU-003/I [A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
to Assess the Safety and Efficacy of VM202 to Treat Chronic Nonhealing Foot Ulcers in 
Diabetic Patients with Concomitant Peripheral Arterial Disease (PAD)].  The purpose of this 
plan is to provide specific guidelines from which the analysis will proceed.  Any deviations from 
these guidelines will be documented in the clinical study report. 
Study enrollment commenced under Protocol VMNHU-003/C.  There were 7 subjects enrolled 
under protocol version C, 5 enrolled under version E, 16 enrolled under version F, and 16 
enrolled under version G; no subjects were enrolled under protocol version D, H or I.  
Protocol VMNHU-003/E introduced the following changes to exclusion criteria in VMNHU-
003/C: 
- The study ulcer decreased by 50% or more at baseline from Screening (as assessed by 
comparison of post-debridement photos taken at Screening and Day 0); previously only ulcers 
that increased by 50% or more at baseline from Screening were excluded. 
- Target ulcer located on an active (hot) Charcot foot; previously any Charcot foot was excluded. 
- Body mass index (BMI) > 45 kg/m2 at Screening; previously BMI > 35 kg/m2 was excluded. 
- All steroids except inhaled or ocular steroids; previously only high dose steroids were 
excluded. 
Since these changes to the exclusion criteria were not expected to have a meaningful influence in 
favor of VM202 on the efficacy and safety parameters, no inferential analyses to account for the 
protocol version will be conducted.  Descriptive summaries of the primary efficacy endpoint and 
overall adverse event rates will be produced for the subjects enrolled under different versions of 
the protocol. 
Protocol VMNHU-003/F submitted with SAP revision C introduced the following changes to the 
inclusion criteria:   
- the upper age limit for study participants will be raised to 80 years; 
- addition of ABI > 1.4 (indicative of non-compressible vessels at the ankle) as a qualifying 
criterion for documented PAD; 
- revision of 1 criterion for documented PAD to: history of lower extremity peripheral artery 
disease with previous related intervention in a leg. 
Protocol VMNHU-003/G introduced the following changes to the exclusion criteria:   


 
 
 
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- Removal of exclusion #2: unhealed prior amputation 
- Removal of exclusion #5: more than one (1) ulcer on target foot 
- Change to exclusion #22: removal of creatinine > 2.0 mg/dL as an exclusion 
- Change to exclusion #23: glomerular filtration rate (GFR) ≤ 30 mL/min/1.73 m2 updated to < 
30 mL/min/1.73 m2 
Protocol VMNHU-003/H had no significant changes related to the SAP. 
Protocol VMNHU-003/I being submitted with this SAP revision introduces the following 
changes: 
- The definition of the intent-to-treat (ITT) population was broadened to all subjects who were 
randomized. 
- The definition of the modified intent-to-treat (mITT) population was narrowed to include only 
those subjects who: 1) received any study drug injections, 2) had at least one post-baseline 
wound assessment, and 3) had no safety or efficacy parameter results before dosing that would 
have made the subject ineligible if the results had been known or disclosed at Screening 
- Two per protocol (PP) populations have been defined. The former mITT population is now the 
first PP population (PP1), which includes all subjects in the revised mITT population who did 
not use the protocol-specified prohibited concomitant medications or treatments. The former PP 
population is now the second PP population (PP2), which includes all subjects in PP1 who: 
1) met the major protocol eligibility criteria, 2) received all injections based on the randomized 
treatment, 3) maintained standard of care for their wounds for the duration of the study, and 
4) any other additional criteria established by the CDRC before unblinding.  
- The primary endpoint has been modified to include all subjects with a target wound closure by 
the 4-month follow-up, and no longer requires that wound closure be confirmed at two 
consecutive study visits at least two weeks apart. 
2. ANALYSIS OBJECTIVES 
• 
To evaluate the efficacy of VM202 in promoting ulcer healing in nonhealing foot ulcers 
• 
To evaluate the safety of intramuscular administration of VM202 in subjects with 
nonhealing foot ulcers 
3. STUDY DESIGN 
This is a phase III, randomized, double-blind, placebo-controlled, multicenter, 7-month study 
designed to assess the safety and efficacy of intramuscular injections of VM202 in the calf of 
diabetic patients with chronic nonhealing foot ulcers and concomitant PAD.  Subjects with 
confirmed PAD and diabetes aged ≥ 18 years to ≤ 80 years diagnosed with nonhealing foot 
ulcers will be screened for study eligibility after giving informed consent. 










 
 
 
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4. 
STUDY ENDPOINTS 
4.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with a target wound closure by the 
4-month follow-up. 
The statistical hypotheses for the primary efficacy endpoint are: 
 
H0: Pt = Pc versus Ha: Pt ≠ Pc 
 
where Pt and Pc are the proportions of subjects with a target wound closure by the 4-month 
follow-up for the VM202 and placebo groups, respectively. 
The hypothesis testing will be at a two-sided alpha of 0.05. 
4.2. 
Other Efficacy Endpoints 
• 
Time to complete wound closure of foot ulcer 
• 
Proportion of subjects with a target wound closure by 7 months 
• 
Percent change in wound volume at 2 months (Day 60), 2.5 months (Day 74), 3 months 
(Day 90), 4 months (Day 120), and 7 months (Day 210) 
• 
Percent change in wound perimeter, area and wound depth at 2 months, 2.5 months, 
3 months, 4 months, and 7 months 
• 
Proportion of subjects with formation of new ulcers on the target foot by 2 months, 
2.5 months, 3 months, 4 months, and 7 months 
• 
Time to major amputation in the target limb 
• 
Time to minor amputation in the target limb 
• 
Change in target limb ABI at 4 months and 7 months  
• 
Change in target limb TBI at 4 months and 7 months  
• 
Change in TcPO2 at 4 months and 7 months 
• 
Change in the overall quality of life and each domain score (well-being, physical 
symptoms and daily living, social life) of CWIQ from Day 0 at 4 months and 7 months 
 
4.3. 
Safety Outcomes 
• 
Adverse events 
• 
Injection site adverse events 


 
 
 
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• 
Vital signs 
o 
Blood pressure 
o 
Weight 
o 
Heart rate 
o 
Respiration Rate 
o 
Temperature 
• 
HbA1c 
• 
Serum Chemistry and Hematology 
• 
Retinal fundoscopy 
4.4. 
Pharmacokinetics 
• 
HGF serum levels 
• 
Number of copies of VM202 in whole blood 
4.5. 
Planned Covariates 
The primary efficacy endpoint will be analyzed by adjusting for each of the following 
covariates separately and all covariates simultaneously using the methods described in 
Section 9.4.3: 
• 
Wound location (medial malleolus, lateral malleolus, ankle flexure, posterior ankle, 
dorsum of foot, sole of foot, medial aspect of foot, lateral aspect of foot, big toe, 2nd 
through 5th toes [collapsed]; these locations have been re-examined and were re-
categorized based on the distribution and clinical considerations prior to database lock. 
Data will be summarized as weight bearing (plantar foot surface), and not weight-
bearing (non-plantar foot surface).  
• 
Age (≤ median and > median) 
• 
Baseline wound area (≤ median and > median) 
5. 
DEFINITIONS 
5.1. 
Basic Definitions 
Study Drug 
Study drug for this study refers to VM202 or placebo. 


 
 
 
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5.2. 
Study Points of Reference 
Study Day 0 
The date of the first study drug administration or the date of enrollment for subjects who were 
not administered any dose of study drug. 
Study Day  
For protocol defined assessments, the number of days from the day 0 visit to a date of interest, 
is calculated as: 
Visit day = date of interest – date of study day 0.  
Note that per CDISC dataset standards, the standard study day in the datasets will actually be 
calculated as: 
If the date of interest is >= first dose date: 
Study day= date of interest- date of first dose + 1 (there is no day 0) 
If the date of interest is < first dose date: 
Study day= date of interest- date of first dose + 1  
5.3. 
Study Specific Definitions 
5.3.1. Definitions of Safety Outcomes 
Adverse Event (AE) 
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 it is considered causally related to the product. 
Based on the protocol, conditions or diseases that are chronic but stable are NOT considered as 
AEs, nor are changes in a chronic condition or disease that are consistent with natural disease 
progression. 
Serious AE (SAE) 
Any untoward medical occurrence which results in death; is a life-threatening experience; 
requires hospitalization (admission to hospital with a stay > 24 hours) or prolongation of an 
existing 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. 


 
 
 
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5.3.2. Definitions of Efficacy Endpoints 
Complete Wound Closure 
Defined as skin 100% re-epithelization without drainage or dressing at any time during the 
study. Complete wound closure will be assessed by the investigator at the sites and 100% 
reconciled with the ARANZ data, when possible. The primary analysis will be based on the 
eCRF page “Photography and Measurement of Ulcer in Target Leg”.  
Wound Volume, Wound Perimeter, Wound Area, and Wound Depth 
The target wound’s volume, perimeter, area, and depth will be measured using ARANZ 
Silhouette products at baseline and every scheduled post-baseline visit until wound closure. 
Formation of New Foot Ulcer 
Defined as a newly formed non-healing or poorly healing full-thickness wound, below the ankle 
on the target foot; these will be identified solely based the AE data provided by the site. The AE 
verbatim term will be scanned for the text “ULCER” and for “LEFT” vs. “RIGHT”. The side 
will be matched with the target limb side from the eCRF and, if no information on site is 
present, it will be assumed that the new ulcer is on the target limb. 
Major amputation 
Defined as an amputation of the lower extremity above the ankle; these will be identified based 
on a blinded review of the AE data.  The affected leg identified in the verbatim term on the AE 
electronic case report form (eCRF) and target foot noted on Physical Exam eCRF will be used 
to determine if the major amputation was in the target limb. These amputations will be noted in 
the clinical study report (CSR). 
Minor amputation 
Defined as an amputation of a foot or any parts of a foot such as toes; these will be identified 
based on a blinded review of the AE data.  The affected leg identified in the verbatim term on 
the AE eCRF and target foot noted on Physical Exam eCRF will be used to determine if the 
minor amputation was in the target limb. These amputations will be noted in the CSR.  
Cardiff Wound Impact Questionnaire (CWIQ) 
The CWIQ is a patient-reported outcome measure designed to assess the impact of leg and 
diabetic foot ulcers on patient health-related quality of life (HRQoL).  There are 3 
domains/subscales: 
• 
well-being (7 items, graded on a 5-point scale [1 = strongly disagree to 5 = strongly 
agree]) 
• 
physical symptoms and daily living (24 items, graded on a 5-point scale [1 = not at all 
to 5 = always]) 


 
 
 
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• 
social life (14 items, graded on a 5-point scale [1 = not at all/not applicable to 
5 = very]) 
The first and third subscales measure both the experience of the given concerns/symptoms and 
the stress they caused the patient; this duplication was not present in the referenced 
development and validation report cited below.  In addition, there are Overall Quality of Life 
questions (2 items graded on a 11-point scale [0 = my quality of life is the worst possible or not 
at all satisfied to 10 = my quality of life is the best possible or very satisfied]). 
Individual items are scored based on the CWIQ scoring instructions and summed for each 
domain and the Overall Quality of Life items.  The tool is scored in such a way that a high score 
represents a 'good' HRQoL and a low score represent a 'poor' HRQoL. With the exception of 
one item in the well-being domain (“I am confident that the wound(s) I have will heal”), all 
items are scored 5-1 within the subscales reading from left to right on the questionnaire.  
 
Reference: 
Price P, Harding K. Cardiff Wound Impact Schedule: the development of a condition-specific 
questionnaire to assess health-related quality of life in patients with chronic wounds of the lower limb. 
Int Wound J 2004;1:10-17. 
5.4. 
Derived Variables 
Baseline Value 
The last non-missing value prior to first dose of study drug.  If a subject does not receive any 
study drug, baseline is the latest recorded measurement on or before the randomization date. 
Change from Baseline Value 
Change from baseline value is the arithmetic difference between a value of interest and a 
baseline value: Change from baseline value = (value of interest – baseline value). 
Percent Change from Baseline Value 
The ratio of the arithmetic difference between a value of interest and the baseline value to the 
baseline value multiplied by 100: (Change from Baseline / Baseline)  100. 
Time to Complete Wound Closure 
Time to complete wound closure is the time interval (in days) from Day 0 to the date of the first 
visit date within the allowed visit window where wound closure is so indicated by the 
investigator.  If a subject has not experienced complete wound closure, the subject will be 
considered censored at the subject’s end of study date.   
Time to a major amputation in the target limb 
Time to a major amputation in the target limb is the time interval (in days) from Day 0 to the 
earliest date of a reported AE of an amputation of the lower extremity above the ankle of the 
target limb. 




 
 
 
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7. 
ANALYSIS POPULATIONS 
7.1. 
Intent-to-Treat (ITT) Population 
The ITT population includes all subjects who are randomized.  Subjects in the ITT population 
will be analyzed according to the randomized assignment, regardless of the actual treatment 
received.  All baseline characteristics will be summarized based on the ITT population.  The 
primary analyses of the primary efficacy endpoint will be based on the ITT population. 
7.2. 
Safety Population 
The safety population will contain all subjects who are randomized and receive at least one 
study drug injection.  Subjects will be grouped according to their actual treatment received, not 
according to their randomization assignment.  Subjects treated with any VM202 will be grouped 
in the VM202 group; subjects never treated with any VM202 will be grouped in the placebo 
group.  All safety summaries will be based on the safety population.  
7.3. 
Modified Intent-to-Treat (mITT) Population 
The mITT population includes all subjects randomized that meet the following criteria: 
• 
Received any study drug injections 
• 
Had at least one post-baseline wound assessment 
• 
Have no safety or efficacy parameter results prior to dosing on Day 0 that would have 
made the subject ineligible for participation if the results had been known or disclosed 
at Screening. This determination will be made in a blinded fashion by the Clinical Data 
Review Committee (CDRC, members to be determined) prior to analyses. 
Subjects will be grouped based on the randomly assigned treatment, not the actual treatment 
received.  The mITT population will be used in the sensitivity analyses for the primary efficacy 
endpoint. 
7.4. 
Per Protocol (PP) Populations 
The first Per Protocol population is a subset of the mITT.  It includes all mITT subjects who 
meet the following criterion: 
• 
Have not used the protocol-specified prohibited concomitant medications such as COX-
2 inhibitor drug(s) or non-specific COX-1/COX-2 inhibiting NSAIDS, anti-VEGF 
agents (e.g., Lucentis®, Avastin®, Eylea®), steroids (except inhaled steroids or ocular 
steroids), Regranex® gel (becaplermin), larval debridement, skin substitutes (e.g., 
Dermagraft®, Apligraf®), hyperbaric oxygen therapy, hydrotherapy, negative pressure 
wound therapy, or electrical stimulation therapy which may affect the wound healing.  
The use and effect of protocol-specified prohibited concomitant medications will be 
determined by the CDRC in a blinded fashion prior to analyses. 
The second Per Protocol population is a further subset of the mITT.  It includes all subjects in 
the first PP population who also meet all of the following criteria: 


 
 
 
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• 
Meets major protocol eligibility criteria determined by the CDRC in a blinded fashion 
prior to analyses 
• 
Received all injections based on the randomized treatment 
• 
Maintained standard of care for their wounds for the duration of the study, as follows: 
o 
Surgical debridement of necrotic tissue or devitalized tissue 
o 
Use of appropriate off-loading when ambulating 
o 
Maintenance of moist wound environment 
• 
Additional criteria, if any, established by the CDRC before unblinding of the 
randomization code 
The PP populations will be used in the sensitivity analyses for the primary efficacy endpoint. 
7.5. 
Subgroup Analysis Subsets 
The primary and exploratory efficacy endpoints will be evaluated as described in Section 9.4.2 
for the following subgroup subsets; except where noted, these subsets are based on the 
categories of the covariates described in Section 4.5. 
• 
Wound location (weight-bearing [sole of the foot], and not weight-bearing [all other 
locations]) 
• 
Age (≤ median and > median) 
• 
Baseline wound area (≤ median and > median) 
These subgroups will be re-examined and may be recategorized or eliminated (if only two 
categories) due to small sample size (if there are < 10% of subjects within each subgroup) 
before unblinding for analysis.  
The treatment by subgroup interaction will be examined and tested as described in 
Section 9.4.2.  The subgroup analyses will be exploratory in nature and will be conducted in the 
ITT population. 
8. 
DATA HANDLING 
8.1. 
General Principles of Data Handling 
Data screening will be conducted in a blinded fashion periodically during the conduct of the 
study.  The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses.  Any 
questionable values or situations will be reported to the CDRC for blinded review and 
confirmation. 
Except as noted below, the data source for all safety and efficacy endpoints will be the study’s 
Electronic Data Capture database (DATATRAK).  Extracts from the Interactive Web Response 
System used for randomization will be the data source for the randomized treatment.  The actual 
treatment received will be determined from the randomized treatment with adjustments based 




 
 
 
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8.4. 
Multiplicity Adjustment 
No multiplicity adjustment will be performed since the study has one primary efficacy endpoint 
with one primary population and analysis method.  Sensitivity analyses for the primary efficacy 
endpoint are supportive and analyses for other efficacy endpoints are exploratory. 
8.5. 
Data Safety Monitoring Board 
An independent DSMB will periodically review a limited set of unblinded safety tables and/or 
listings, including all reported AEs.  The objectives of the DSMB meetings are to review the 
safety outcomes of the study and provide guidance to the study sponsor regarding the safety of 
VM202.  The data analyses for the DSMB meetings will be directly provided to the DSMB 
members and no data will be released to the study sponsor and blinded designees.  There will be 
no adjustment for multiple testing due to the DSMB data reviews.  The DSMB may be asked to 
review and provide guidance regarding protocol deviations that may affect the determination of 
the PP populations.  Further details of DSMB responsibilities are included in the DSMB 
Charter. 
8.6. 
Handling of Missing and Incomplete Data 
Subjects may have missing specific data points for a variety of reasons.  In general, data may be 
missing due to a subject’s early withdrawal from study, a missed visit, or a clinical parameter 
not measured at a particular point in time.  The general procedures outlined below describe how 
missing data are handled. 
8.6.1. Missing Values for the CWIQ 
No imputation for missing item scores within the CWIQ Overall Quality of Life will be 
performed; if a Quality of Life question (item) is unanswered at a subject’s visit then the 
Overall Quality of Life score will be missing for that visit.  Missing individual item scores 
within the three CWIQ domains may be imputed using the average score across the non-missing 
items within the domain at a subject’s visit provided that the proportion of missing items scores 
within that domain is less than 25%; otherwise the domain score at that visit is missing.  Thus, 
at least 11 of 14 items in the social life domain, 6 of 7 items in the well-being domain, and 19 of 
24 items in the physical symptoms and daily living domain must be non-missing to avoid 
having a missing corresponding domain score. 
8.6.2. Missing / Unknown Values of Covariates 
For categorical covariates, the missing / unknown values will be combined with the category 
with the most subjects if the missing / unknown rate is ≤ 2% of the pooled data and will be 
classified into a separate category if the missing / unknown rate is ≥ 2% of the pooled data.  If 
the covariate is also used as a subgrouping variable, the imputed values of the subgrouping 
variable will not be used for subgroup categorization. 




 
 
 
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The statistical analyses will be reported using summary tables, figures and listings.  Continuous 
variables will be summarized with means, standard deviations, medians, minimums, 
maximums, and number of non-missing observations for each treatment group.  Other selected 
percentiles, such as the 25th percentile and 75th percentile, may be presented for parameters that 
are not normally distributed or are suspected of exhibiting that tendency.  Categorical variables 
will be summarized by counts and the percentage of subjects in corresponding categories.  All 
data collected, including for subjects screened but not randomized, will be included in data 
listings. 
All inferential statistical analyses will be performed with a two-sided confidence level of 95% 
or a two-sided significance level of 0.05. 
All analyses and tabulations will be performed using SAS Version 9.3 or higher on a PC 
platform. 
9.2. 
Subject Enrollment and Disposition 
Subject disposition will be summarized for all the randomized subjects, including the number 
and percentage (based on the total number of subjects randomized) of subjects in each of the 
following categories: 
• 
Early Termination based on the ITT population 
• 
Safety, ITT, mITT, and PP populations 
Major protocol deviations for subjects not in the PP populations will be listed. 
9.3. 
Demographics and Baseline Characteristics 
The following outcomes will be summarized by the standard methods for continuous and 
categorical variables described in Section 9.1. 
The demographics include the following parameters: 
• 
Age at informed consent 
• 
Sex 
• 
Race  
• 
Ethnicity 
The baseline characteristics include the following: 
• 
Wound location 
• 
Baseline wound volume 
• 
Baseline ABI  
• 
Baseline TBI 
• 
Toe pressure categorized by assessment method (Doppler, PPG) 


 
 
 
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• 
TcPO2 (collected at a subset of study centers) 
• 
Baseline BMI 
• 
Baseline HbA1c 
• 
Vital signs: blood pressure, weight, BMI, heart rate, respiration rate, temperature 
• 
Medical history categorized by MedDRA system organ class (SOC) 
• 
12-lead EKG Interpretation: Normal, Abnormal NCS, Abnormal CS 
• 
Urine pregnancy test: Positive, Negative, and Not Applicable 
These parameters will be summarized by treatment group for the ITT population and included 
in data listings.  Other collected baseline characteristics will be listed only. 
9.4. 
Efficacy Endpoint Analyses 
9.4.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with a target wound closure by the 
4-month follow-up (responder).  The responder rate will be compared between the two 
treatment groups (VM202 and placebo). 
9.4.1.1. 
Primary Analysis of the Primary Efficacy Endpoint 
The primary analysis for the responder rate will be based on the ITT population. 
Fisher’s exact test will be used to compare the responder rate between the treatment groups.  
The 95% confidence interval of the responder rate of each treatment group will be derived using 
the binomial distribution and the 95% confidence interval of the responder rate difference will 
be calculated. 
Subjects whose status of wound closure cannot be assessed at 4 months (e.g., due to earlier 
discontinuation from the study), will be considered non-responders. 
9.4.1.2. 
Sensitivity Analyses of the Primary Efficacy Endpoint 
To further evaluate and demonstrate the robustness of the results for the primary efficacy 
outcome, the following supportive sensitivity analyses will be conducted. 
9.4.1.2.1. 
Odds ratio from a logistic regression model 
A logistic regression with treatment as the main effect (using placebo as the reference category) 
will be used for comparing the primary efficacy endpoint between the treatment groups.  The 
odds ratio and corresponding 2-sided 95% Wald confidence interval will be provided. 
The analyses above will be performed based on the ITT population. 


 
 
 
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9.4.1.2.2. 
Analysis in other analysis populations 
Fisher’s exact test for the primary efficacy endpoint will be performed on the mITT and PP 
populations as defined in Sections 7.3 and 7.4, respectively.  The estimated responder rates and 
the corresponding exact 95% confidence interval based on binomial distribution will be 
calculated for each treatment group.  The exact 95% confidence interval of the responder rate 
difference will also be obtained.   
9.4.2. Subgroup Analyses of the Primary Efficacy Endpoint 
For each subgrouping variable identified in Section 7.5 meeting the minimum group size 
requirement (the subgroup is included if there are ≥ 10% of subjects within that subgroup), the 
available data for primary efficacy endpoint will be summarized by treatment group for the ITT 
population.  Fisher’s exact test will be performed within each such subgroup. 
The Cochran–Mantel–Haenszel test will be performed to compare the responder rates between 
the treatment groups adjusted for the subgrouping variable.  Additionally, the possible 
treatment-by-subgroup interaction will be tested for each subgrouping variable as follows: 
• The Breslow-Day test will be performed for each subgrouping variables.  If the p-value 
of the Breslow-Day test is ≥ 0.05, the treatment-by-subgroup interaction is not 
significant. 
• If the interaction effect is statistically significant (i.e., p-value < 0.05), then the Gail and 
Simon1 test will be used to test for the qualitative interaction at a significance level of 
0.05 and provided as an aid for interpretation. 
9.4.3. Analysis of Covariates 
The logistic regression model with treatment and all covariates listed in Section 4.5 will be used 
to obtain the 2-sided 95% confidence intervals for the covariate-adjusted estimate of the 
treatment effect for the primary efficacy endpoint. 
9.4.4. Other Efficacy Endpoints 
All the exploratory efficacy analyses will be based on the available data in the ITT population. 
9.4.4.1. 
Time to complete wound closure of foot ulcer  
The log-rank test will be used to compare the distributions of the time to complete wound 
closure (event) between the treatment groups.  Kaplan-Meier estimates of the survival function 
for each treatment group will be graphically displayed.  Kaplan-Meier estimates of quartiles 
 
1  
Gail, MH, and Simon, R., Testing for qualitative interactions between treatment effects and patient 
subsets. Biometrics, 1985;41: 361-372. 
 


 
 
 
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(25th, median, and 75th percentiles) with 2-sided 95% confidence interval will be calculated if 
estimable. 
The log-rank test and Kaplan-Meier methods above will be performed for this endpoint for each 
subgroup identified in Section 7.5 meeting the minimum group size requirement.  Differences 
between the time-to-event distributions of the treatment groups will be compared adjusting for 
the subgrouping variable using the log-rank test with the subgrouping variable added as a 
stratification factor in the modeling. 
9.4.4.2. 
Proportion of subjects with a wound closure by 7 months. 
The proportion of subjects with wound closure by the 7-month follow-up will be calculated for 
each treatment group.  The 95% confidence intervals of the proportion will be provided based 
on the binomial distribution and the exact 95% confidence intervals of the proportion difference 
will also be obtained.  Fisher’s exact test will be used to compare the proportions between two 
treatment groups. 
The subgroup analyses described in Section 9.4.2 will also be performed for this exploratory 
endpoint. 
9.4.4.3. 
Percent change in wound volume at 2, 2.5, 3, 4, and 7 months 
The percent change in wound volume at 2, 2.5, 3, 4, and 7 months from baseline will be 
summarized for each treatment group and compared between the treatment groups using a linear 
mixed-effects model for repeated measures2.  The model will include treatment, visit, and 
treatment-by-visit interaction as the main fixed effects, and baseline wound volume as a 
covariate using an unstructured variance-covariance matrix.  The point estimates for the least-
squares mean of the treatment difference (VM202 – Placebo) at each visit and the 
corresponding 95% confidence interval and p-value will be summarized.  Other variance-
covariance structures may be substituted if convergence problems arise using corrected 
Akaike’s information criterion (AICC) to pick from among the following structures: compound 
symmetry (CS), autoregressive (“AR(1)”), variance components (VC), and Toeplitz (TOEP).  
The repeated measures analysis above will be performed for this endpoint for each subgroup 
identified in Section 7.5 meeting the minimum group size requirement.  Differences between 
treatment groups will be compared adjusting for the subgrouping variable using the repeated 
measures with the subgrouping variable added as a fixed effect in the modeling. 
9.4.4.4. 
Percent change in wound perimeter, area and depth at 2, 2.5, 3, 4, and 7 months 
The analyses on the percent change in wound perimeter, area and depth at 2, 2.5, 3, 4, and 
7 months from baseline will be based on statistical methods described in Section 9.4.4.3 with 
the corresponding baseline wound measurement as the covariate. 
 
2  
Vonesh, EF and Chinchilli, VM (1996), Linear and Nonlinear Models for the Analysis of Repeated 
Measurements, New York: Marcel-Dekker. 


 
 
 
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9.4.4.5. 
Proportion of subjects with formation of new ulcers on the target foot by 2, 2.5, 3, 
4, and 7 months 
The proportion of subjects with new ulcers formed by the 2-, 2.5-, 3-, 4-, and 7- month follow-
up visits will be calculated for each treatment group.  The 95% confidence intervals of the 
proportion will be provided based on the binomial distribution and the exact 95% confidence 
intervals of the proportion difference will also be obtained.  Fisher’s exact test will be used to 
compare the proportion between the treatment groups at each time point. 
The subgroup analyses described in Section 9.4.2 will be performed for these exploratory 
endpoints. 
9.4.4.6. 
Time to a major amputation in the target limb  
The log-rank test and Kaplan-Meier methods described in Section 9.4.4.1 will be used for 
comparing the time to a major amputation between the treatment groups.  Similar subgroup 
analyses will also be performed as described in Section 9.4.4.1. 
9.4.4.7. 
Time to a minor amputation in the target limb 
The log-rank test and Kaplan-Meier methods described in Section 9.4.4.1 will be used for 
comparing the time to a minor amputation between the treatment groups.  Similar subgroup 
analyses will also be performed as described in Section 9.4.4.1. 
9.4.4.8. 
Change in target limb ABI at 4 and 7 months 
Change in ABI at 4 and 7 months will be analyzed in a manner similar to the repeated 
measurement models described in Section 9.4.4.23 with the baseline ABI values as the 
covariate. 
9.4.4.9. 
Change in target limb TBI at 4 and 7 months 
Change in TBI at 4 and 7 months will be analyzed in a manner similar to the repeated 
measurement models described in Section 9.4.4.23 with the baseline TBI values as the 
covariate.  An additional fixed factor for the method of toe pressure assessment used (Doppler 
vs PPG) will be added to the models.  TBI results for a subject will be omitted from the analysis 
if the same method was not used for all his/her toe pressure assessments. 
9.4.4.10. 
Change in each domain score of CWIQ at 4 months and 7 months 
Descriptive statistics of each CWIQ domain score and overall Quality of Life scores will be 
summarized by treatment group at each visit (baseline, 4 months, and 7 months).  Change in 
each CWIQ score at 4 and 7 months will be analyzed in a manner similar to the repeated 
measurement models described in Section 9.4.4.23 with the baseline score as the covariate. 


 
 
 
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9.5. 
Safety Analyses 
No formal statistical testing will be conducted for the safety analyses.  The following sections 
summarize the descriptive analysis presented for these safety endpoints.  All subjects in the 
safety population will be included in these analyses, with subjects grouped by the actual 
treatment received.  All summaries will be derived based on available data at scheduled visits; 
safety data at unscheduled visits will only be included in data listings.  No imputation will be 
performed for missing values. 
9.5.1. Study Drug Exposure 
Study drug exposure (number of injections and total volume administered) will be summarized 
by treatment group for Day 0, Day 14, Day 28, and Day 42 using descriptive statistics for 
continuous variables. 
9.5.2. Injection Site Adverse Events 
 The number and percentage of subjects with an injection site AE, by type (injection site 
reaction, ulceration, allergic reaction/hypersensitivity) and overall, will be summarized by 
treatment group at each weekly ‘wound assessment and dressing change’ visit and for the pre- 
and post-injection assessments on scheduled injection visit days (i.e., Days 0, 14, 28, and 42).  
The denominator for these percentages will be based on the number in the risk set following a 
given injection, which is the number of subjects who received that specific injection.  The 
number and percentage of subjects for each grade within a given type of injection site AE will 
be summarized by treatment group at each assessment time point. 
9.5.3. Adverse Events 
Adverse events will be collected once subjects meet all the study eligibility criteria and are 
randomized and administered study drug.  However, all adverse event summaries will be 
restricted to Treatment-Emergent Adverse Events (TEAE), which are defined as those AEs that 
occurred after first dosing and those pre-existing conditions that worsened during the study.  If 
the start time for an AE that occurs on the first date of dosing is unknown, then the event will be 
assumed to be a TEAE.  If the start date of an AE is unknown, the event will be assumed to be a 
TEAE.   
The number of subjects experiencing a particular event, the percentage of subjects experiencing 
the event, and the total number of events will be presented.  The following summaries will be 
created: 
• Overall summary of TEAEs, which includes the subject incidence of TEAEs and total 
number of unique TEAEs from each of the following AE summaries without regard to 
MedDRA system organ class or preferred term 
• TEAE by SOC and preferred term 
• TEAE by SOC and preferred term by injection number.  Subjects and events are 
attributed to a given injection only if the event start date (subject to the missing date and 


 
 
 
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time imputation rules of Section 8.6.3) occurs on or after the date and time of that 
injection and not before the next injection.  
• TEAE by SOC, preferred term and protocol version 
• TEAE by SOC, preferred term and maximum severity.  At the across-SOC and preferred 
term levels of subject summarization, a subject is classified according to the highest 
severity if the subject reported one or more events; severity within an SOC is not 
summarized.  AEs with missing severity will be considered severe for this summary. 
• TEAE by SOC, preferred term and closest relationship to study treatment (Related/Not 
Related).  At each level of subject summarization, a subject is classified according to the 
closest relationship if the subject reported one or more events.  AEs with a missing 
relationship will be considered ‘related’ for this summary; events classified as 
‘possibly’, ‘probably’ or ‘definitely’ will be considered ‘related’. 
A listing of treatment-emergent SAEs (if any) will be provided, and if more than one occurs 
within any given preferred term, a summary of treatment-emergent SAEs by SOC and preferred 
term will be created. 
9.5.4. Vital Signs 
Vital signs and change from baseline will be summarized descriptively at each visit by 
treatment group.  Note that weights were not collected at the weekly ‘wound assessment and 
dressing change’ visits nor at the ‘confirmation of ulcer healing’ visit for subjects enrolled 
under protocol version D or later; weights collected at such visits from subjects enrolled prior to 
protocol version D will be included in listings only. 
9.5.5. HbA1c, Serum Chemistry and Hematology 
Shift tables (i.e., normal or abnormal at baseline versus normal or abnormal at follow-up in a 
2-by-2 contingency table) based on the normal range will be provided to assess changes in 
laboratory values from baseline to follow-up results for each scheduled follow-up visit. 
Additionally, shift tables of severity (low, normal, high) at baseline vs low, normal and high at 
each scheduled follow-up visit will also be summarized for hematology and chemistry 
parameters. Low and high severities are with respect to the lower and upper limits of normal, 
respectively, while normal is within normal limits. The counts and percentage of subjects with 
each of the 4 possible “shift” outcomes will be calculated by treatment group. 
Individual laboratory parameter values and changes from baseline will be summarized 
descriptively by treatment group at each scheduled follow-up visit. 
Laboratory values and their center-specific normal ranges will be listed and summarized using 
SI units.  For the WBC differentials, only the absolute values will be summarized; percent 
differentials, if provided by the study center, will be listed only. 


 
 
 
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9.5.6. Prior and Concomitant Medications  
Prior medications are those medications taken within 60 days of the first injection of study drug.  
Concomitant medications are those medications taken on or after the day of the initial dose of 
study drug.  All prior and concomitant medications will be assigned preferred drug names using 
WHODDE.  Prior and concomitant medications of interest will be determined by the CDRC and 
will be used to define the per-protocol populations.  
9.5.7. Retinal Fundoscopy 
Retinal fundoscopy findings in each eye (presence or absence of proliferative retinopathy, other 
finding) at screening and the 7-month follow-up and any changes from the baseline at follow-up 
will be summarized descriptively by treatment group. 
9.5.8. Pharmacokinetics 
HGF serum levels and the number of copies of VM202 in whole blood will be analyzed by an 
independent lab designated by the study sponsor.  Data will be listed only. 
10. 
INTERIM ANALYSIS 
Due to the early stopping of the study, the protocol-specified interim analysis will not be 
conducted.