A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of VM202 in Participants With Painful Diabetic Peripheral Neuropathy
Phase: PHASE3
Conditions: Painful Diabetic Neuropathy, Diabetic Neuropathy, Painful
Sponsor: Helixmith Co., Ltd.

 
 
 
 
 
Protocol VMDN-003 
 
Protocol Title: 
A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter 
Study to Assess the Safety and Efficacy of VM202 in Participants with 
Painful Diabetic Peripheral Neuropathy  
 
Protocol Number: VMDN-003; Version H 
 
NCT Number:  
NCT02427464 
 
Document Date: 
05 September 2019 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 3 of 137 
 
 
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 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 4 of 137 
STUDY SYNOPSIS 
PROTOCOL TITLE 
A Phase III, Double-blind, Randomized, Placebo-controlled, Multicenter 
Study to Assess the Safety and Efficacy of VM202 in Subjects with 
Painful Diabetic Peripheral Neuropathy 
STUDY PHASE 
III 
INVESTIGATIONAL
AGENT 
VM202 
DOSE 
16 mg of VM202 administered as a divided dose at Day 0 and Day 14, 
with a second treatment of 16 mg VM202 at 3 months administered as a 
divided dose at Day 90 and Day 104, for a final total dose of 32 mg 
VM202 administered per subject. 
POPULATION 
Subjects aged ≥ 18 years to ≤ 75 years diagnosed with painful diabetic 
neuropathy in both lower extremities. 
STUDY DESIGN 
A phase III, double-blind, randomized, placebo-controlled, multicenter, 
9-month study designed to assess the safety and efficacy of bilateral
intramuscular (IM) injection of VM202 in the calves of subjects with
painful diabetic peripheral neuropathy (DPN).
A total of 477 subjects will be randomized in a 2:1 ratio to one of two 
treatment groups: 
Treatment - VM202 - 318 subjects 
Control - Placebo (VM202 suspension medium) - 159 subjects 
Randomization will be stratified by current use of gabapentin and/or 
pregabalin. 
Up to 30 sites in the US and Korea will participate in the study.  Safety 
will be monitored throughout the study and assessed regularly by an 
independent Data Safety Monitoring Board (DSMB) throughout the 
study. 
STUDY
OBJECTIVES 
•
To evaluate the efficacy of IM administration of VM202 in subjects
with painful DPN in the lower extremities, when compared with
placebo, on pain.
•
To evaluate the safety of IM administration of VM202 in subjects
with painful DPN in lower extremities.

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 5 of 137 
INCLUSION
CRITERIA 
1. Age ≥ 18 years to ≤ 75 years;
2. Documented history of Type I or II diabetes with current treatment
control (glycosylated hemoglobin A1c of ≤ 10.0% at Screening) and
currently on medication for diabetes (oral, injectable and / or
insulin);
3. No significant changes anticipated in diabetes medication regimen;
4. No new symptoms associated with diabetes within the last 3 months
prior to study entry†;
5. Diagnosis of painful diabetic peripheral neuropathy in both lower
extremities;
6. Lower extremity pain for at least 6 months;
7. Visual analog scale (VAS) score of ≥ 40 mm at Initial Screening (0
mm = no pain – 100 mm very severe pain);
8. Symptoms from the Brief Peripheral Neuropathy Screening (BPNS)
is ≤ 5-point difference between legs at Initial Screening;
9. The average daily pain intensity score of the Daily Pain and Sleep
Interference Diary completed after medication wash-out is ≥ 4 with
a standard deviation ≤ 2;
10. The physical examination component of the Michigan Neuropathy
Screening Instrument Score (MNSI) is ≥ 3 at Initial Screening;
11. Subjects on gabapentin (Neurontin), pregabalin (Lyrica), duloxetine
(Cymbalta) for painful DPN at study entry† must be on stable
regimen of these treatments for at least 3 months prior to study
entry†; and
12. If female of childbearing potential, negative urine pregnancy test at
screening and using acceptable method of birth control during the
study.
EXCLUSION
CRITERIA 
1. Peripheral neuropathy caused by condition other than diabetes;
2. Other pain more severe than neuropathic pain that would prevent
assessment of DPN;
3. Progressive or degenerative neurological disorder;
4. Myopathy;
5. Inflammatory disorder of the blood vessels (inflammatory
angiopathy, such as Buerger’s disease);
6. Active infection;
7. Chronic inflammatory disease (e.g., Crohn’s disease, rheumatoid
arthritis);
8. Positive HIV or HTLV at Screening;
9. Active Hepatitis B or C as determined by Hepatitis B core antibody
(IgG and IgM; HBcAb), antibody to Hepatitis B surface antigen
(HBsAb), Hepatitis B surface antigen (HBsAg) and Hepatitis C
antibodies (Anti-HCV) at Screening;
† Study entry is defined as the date of signing informed consent. 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 6 of 137 
10. Subjects with known immunosuppression or currently receiving
immunosuppressive drugs, chemotherapy or radiation therapy;
11. Stroke or myocardial infarction within last 3 months;
12. Clinically significant laboratory values at Screening (e.g.,
Hemoglobin < 8.0 g/dL, WBC < 3,000 cells per microliter, platelet
count <75,000/mm3, Creatinine > 2.0 mg/dL; 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;
13. Ophthalmologic conditions pertinent to proliferative retinopathy or
conditions that preclude standard ophthalmologic examination;
14. Uncontrolled hypertension defined as sustained systolic blood
pressure (SBP) > 200 mmHg or diastolic BP (DBP) > 110 mmHg at
Screening;
15. 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 one 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;
16. Use of the following drugs / therapeutics is PROHIBITED.
Subjects may participate in the study if they are willing to
discontinue use of these drugs / therapeutics 7 days prior to starting
the Daily Pain and Sleep Interference Diary.  Subjects must
refrain from taking these drugs or undergoing these therapies for
the duration of the study:
•
skeletal muscle relaxants, opioids, benzodiazepines (except for
stable bedtime dose),
•
capsaicin, local anesthetic creams (except for Lidocaine cream
prior to IM injections) and patches, isosorbide dinitrate (ISDN)
spray,
•
transcutaneous electrical nerve stimulation (TENS), acupuncture
17. If not using gabapentin (Neurontin) or pregabalin (Lyrica), subjects
must agree not to start these drugs until Day 180 visit of the study.
Subjects on these medications at study entry† must maintain a stable
dose until Day 180 visit of the study;
18. If not using duloxetine (Cymbalta), any antidepressants (e.g.
amitriptyline and venlafaxine), any other antiepileptics (e.g.,
valproic acid, carbamazepine, vigabatrin), subjects must agree not
to start these drugs until Day 180 visit of the study.  Subjects on

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 7 of 137 
these medications at study entry† must maintain a stable dose until 
Day 180 visit of the study; 
19. Subjects requiring > 81 mg daily of acetylsalicylic acid; subjects
may be enrolled if willing/able to switch to ≤ 81 mg daily of
acetylsalicylic acid or to another medication;
20. Subjects requiring regular COX-2 inhibitor drug(s) or non-specific
COX-1/COX-2 inhibiting drugs, 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 until Day 180 visit of the study;
21. Major psychiatric disorder within last 6 months that would interfere
with study participation;
22. Body mass index (BMI) > 45 kg/m2 at Screening;
23. Any lower extremity amputation due to diabetic complications;
24. Use of an investigational drug or treatment in past 6 months or prior
participation in any study of VM202; and
25. Unable or unwilling to give informed consent.
STUDY
PROCEDURES 
Screening should be completed within the 90 days prior to Day 0 (day 
of injection).  Prior to screening, subjects will give informed consent 
and then be initially screened using the VAS, the symptoms portion of 
the BPNS and the entire MNSI.  Only subjects with a VAS score of ≥ 
40 mm, a ≤ 5-point difference in symptoms of the BPNS between legs 
and physical examination component of MNSI of ≥ 3 will be allowed to 
proceed with the full screening procedures.  All other assessments other 
than the completion of the Diary may be scheduled during medication 
washout.  Screening will include assessment of study eligibility, 
medical history, vital signs, physical exam, concomitant medications, 
cancer screening tests, retinal fundoscopy, viral screening, 12 lead 
EKG, serum chemistry and hematology including HbA1c, and urine 
pregnancy test (women of childbearing potential only). 
If applicable, the subject will be washed out of prohibited medications 
prior to initiation of the Daily Pain and Sleep Interference Diary; the 
Diary must be completed within 14 days prior to Day 0.  At least 5 days 
of the diary must be completed.  The average pain score of the Daily 
Pain and Sleep Interference Diary must be ≥ 4 with a standard deviation 
≤ 2 in order to be eligible for study participation.  Eligible subjects will 
be randomly assigned in 2:1 ratio to the VM202 treatment group or to 
the placebo group. 
A single treatment with VM202 is delivered as an equally divided dose 
administered two weeks apart.  Subjects will receive VM202 or placebo (VM202 
vehicle) by intramuscular injections in both legs (in the calf) on Day 0 and Day 
† Study entry is defined as the date of signing informed consent. 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 9 of 137 
HGF serum levels will be determined immediately pre-treatment on Day 0, 
immediately pre-treatment on Day 14, on Day 21, Day 60, immediately 
pre-treatment on Day 90, immediately pre-treatment on Day 104, Day 111, 
Day 150, Day 180, and Day 270.  
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 21, Day 60, at Day 90 
(pre-injection, and 2 hours [± 1 hour] post injection), at Day 104 (pre-
injection, and 2 hours [± 1 hour] post injection), Day 111, Day 150, Day 
180, and Day 270. 
Nerve conduction studies will be conducted pre-treatment on Day 0, Day 
180 and Day 270 at selected sites. 
Serum chemistry, hematology and HbA1c will be determined on Day 0, 
Day 90, Day 180, and Day 270. 
VAS, Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN), 
and Semmes-Weinstein monofilament testing will be recorded at Day 0, 
Day 90, Day 180, and Day 270.  Patients’ Global Impression of Change 
(PGIC) will be recorded at Day 90, Day 180 and Day 270.  MNSI will be 
conducted at Day 180 and Day 270 to track disease progression.   
Retinal fundoscopy will be conducted on Day 180 and Day 270.  
The Daily Pain and Sleep Interference Diary will be completed by subjects 
before the Day 90, Day 180, and Day 270 visits.   
Rescue medication (i.e., Acetaminophen [Tylenol]) taken for DPN pain 
will be dispensed on Day 0 and use of Tylenol will be documented through 
the 9-month follow-up visit.   
Adverse events, concomitant medications and vital signs will be recorded 
throughout the 9-month follow-up period, while injection site reactions will 
be assessed starting on Day 0 through Day 150. 
CONCOMITANT
MEDICATIONS
COX-1 and COX-2 inhibiting drugs, and steroids (except inhaled steroids 
or ocular steroids) 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 not 
to take any of these drugs until Day 180 visit of the study.  
Several medications used to manage neuropathic pain will be excluded 
from use during the study.  Subjects must discontinue use of the 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 10 of 137 
following drugs / therapeutics listed below.  Subjects may participate in 
the study if they are willing to discontinue use of these drugs / 
therapeutics 7 days prior to starting the Daily Pain and Sleep 
Interference Diary.  Subjects must refrain from taking these drugs or 
undergoing these therapies for the duration of the study: 
• skeletal muscle relaxants, opioids, benzodiazepines (except for stable
bedtime dose),
• capsaicin, local anesthetic creams and patches (except for Lidocaine
cream prior to IM injection), isosorbide dinitrate (ISDN) spray,
• transcutaneous electrical nerve stimulation (TENS), acupuncture
If not using gabapentin (Neurontin) or pregabalin (Lyrica), subjects must 
agree not to start these drugs for the first 6 months of the study.  Subjects 
on these medications must be on stable regimen of these treatments for at 
least 3 months at study entry† and must maintain the stable dose until 
Day 180 visit of the study. 
If not using duloxetine (Cymbalta), any antidepressants (e.g. 
amitriptyline and venlafaxine), any other antiepileptics (e.g., valproic 
acid, carbamazepine, vigabatrin) at screening, subjects must agree not to 
start these drugs until Day 180 visit of the study.  Subjects on these 
medications at study entry must maintain a stable dose until Day 180 visit 
of the study.  
Acetaminophen (Tylenol) is the only rescue medication allowed in this 
study.  Up to 3 grams / day will be allowed. 
SCHEDULE OF
EXAMINATIONS 
Screening (Day -90 to Day 0) 
Day 0 
Day 14 ± 1 day 
Day 21 ± 3 days 
Day 60 ± 3 days 
Day 90 ± 7 days 
Day 104 – 13 to15 days after Day 90 Visit 
Day 111 – 4 to 10 days after the Day 104 visit 
Day 150 ± 7 days 
Day 180 ± 7 days 
Day 270 ± 14 days 
STUDY
ENDPOINTS 
There are two primary efficacy endpoints that will be evaluated in 
sequential order.   
The first primary efficacy endpoint is the change in the average 24-hour 
pain score from baseline to the 3-month follow-up  [Day 90] obtained 
from the Daily Pain and Sleep Interference Diary.  The difference in the 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 11 of 137 
mean of the change in the average 24-hour pain score will be compared 
between the treatment group and the placebo arm to determine the 
treatment effect in the efficacy analysis populations.   
The second primary efficacy endpoint is the outcome of at least a 50% 
reduction (i.e. ≥ 50%) in the average 24-hour pain score from baseline to 
the 3-month follow-up obtained from the Daily Pain and Sleep 
Interference Diary.  The responder success rate will be compared 
between the treatment group and the placebo arm to determine the 
treatment effect in the efficacy analysis populations. 
The secondary efficacy endpoints will be based on the change in the 
average 24-hour pain score from baseline to the 6-month follow-up [Day 
180] (3 months after the Day 90 injection) obtained from the Daily Pain
and Sleep Interference Diary.  The difference in the mean of the change
in the average 24-hour pain score will be compared between the
treatment group and the placebo arm to determine the treatment effect in
the efficacy populations.  The proportion of subjects with at least a ≥
50% reduction in the average 24-hour pain score from baseline to the 6-
month follow-up [Day 180] (3 months after the Day 90 injection) will be
compared between the two study groups.
All other efficacy endpoints will be exploratory. 
SAFETY 
Any subject who receives study injections (VM202 or placebo) will be 
included in the safety analysis population.  Adverse events (including 
serious adverse events, and adverse events leading to treatment 
discontinuation) throughout the 9-month follow-up will be described 
according to severity and to their relationship with the study drug and 
injection procedure.  Descriptive statistics (N, mean, median, SD, 
minimum and maximum values, where applicable) will be used to 
characterize continuous safety parameters. Categorical variables will be 
summarized by counts and by percentage of subjects in corresponding 
categories. 
All subjects will undergo testing as presented in the American Cancer 
Society Cancer Screening Guidelines as part of their screening to rule out 
cancer. 
PHARMACO-
KINETICS
HGF serum levels will be determined immediately pre-treatment on Day 
0, immediately pre-treatment on Day 14, on Day 21, Day 60, 
immediately pre-treatment on Day 90, immediately pre-treatment on Day 
104, Day 111, Day 150, Day 180 and Day 270.  
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 21, Day 60, at 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 12 of 137 
Day 90 (pre-injection, and 2 hours [± 1 hour] post injection), at Day 104 
(pre-injection, and 2 hours [± 1 hour] post injection), Day 111, Day 150, 
Day 180, and Day 270. 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 17 of 137 
ABBREVIATIONS 
AE 
Adverse Event 
ABI 
Ankle Brachial Index 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale 
ALT 
Alanine Transaminase (SGPT) 
Anti-HCV 
Hepatitis C antibodies 
AST 
Aspartate Transaminase (SGOT) 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPI-DPN 
Brief Pain Inventory for Diabetic Peripheral Nephropathy 
BPNS 
Brief Peripheral Neuropathy Screening  
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 
cm 
Centimeter(s) 
CR 
Controlled Release 
 
 
CRO 
Clinical Research Organization 
CS 
Clinically Significant 
DBP 
Diastolic Blood Pressure 
DIP 
Distal Interphalangeal 
DLT 
Dose Limiting Toxicities 
DNA 
Deoxyribonucleic Acid 
DPN 
Diabetic Peripheral Neuropathy 
DSMB 
Data Safety Monitoring Board 
EDC 
Electronic Data Capturing 
EFFS 
Efficacy Analysis Set 
EKG 
Electrocardiogram 
ER 
Extended Release 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FVC 
Forced Vital Capacity 
HBV 
Hepatitis B Virus 
HBcAb 
Hepatitis B core antibody (IgG and IgM) 
HBsAb 
Antibody to Hepatitis B surface antigen  
HBsAg 
Hepatitis B surface antigen 
HCT 
Hematocrit 
HCV 
Hepatitis C Virus 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
Hgb 
Hemoglobin 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 18 of 137 
HGF 
Hepatocyte Growth Factor 
HIV 
Human Immunodeficiency Virus 
HTLV 
Anti-Human T-Cell Lymphotropic Virus 
IBC 
Institutional Biosafety Committee 
IRB 
Institutional Review Board 
IND 
Investigational New Drug 
ISDN 
Isosorbide dinitrate 
ITT 
Intent-to-Treat 
LLOQ 
Lower limit of quantitation 
mITT 
Modified Intent-to-Treat 
mm 
millimeters 
MNSI 
Michigan Neuropathy Screening Instrument 
MRC 
Medical Research Council 
NCS 
Not Clinically Significant 
NCV 
Nerve Conduction Velocity 
NIH 
National Institutes of Health 
OBA 
Office of Biotechnology Activities 
PAD 
Peripheral Arterial Disease 
PGIC 
Patients' Global Impression of Change 
PI 
Principal Investigator 
PP 
Per Protocol 
qPCR 
Quantitative Polymerase Chain Reaction 
RBC 
Red Blood Cells 
RCT 
Randomized Controlled Trial 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SGPT 
Serum Glutamic Pyruvic Transaminase (same as ALT) 
SNRI 
Serotonin–Norepinephrine Reuptake Inhibitors 
SOP 
Standard Operating Procedure 
SSRI 
Selective Serotonin Reuptake Inhibitors 
TAR 
Treatment Authorization Request 
TBI 
Toe Brachial Index 
TCA 
Tricyclic Anti-depressants 
TcPO2
Transcutaneous Pressure of Oxygen 
TENS 
Transcutaneous Electrical Nerve Stimulation 
VAS 
Visual Analog Scale  
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cells 
WFI 
Water for Injection 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 23 of 137 
1.
BACKGROUND
1.1. 
DIABETES 
Approximately 29.1 million adults in the United States have diabetes mellitus, a 
metabolic disorder of multiple causes characterized by chronic hyperglycemia and 
disorders of carbohydrate, fat, and protein metabolism.  Diabetes can result from 
defects in insulin secretion (type 1), insulin action (type 2), or a combination of these 
factors, and is associated with a high level of morbidity and mortality.  The total 
estimated cost of diabetes in 2012 was $245 billion, including $176 billion in excess 
medical expenditures and $69 billion in reduced national productivity.†    
1.1.1. 
DIABETIC PERIPHERAL NEUROPATHY 
Diabetic peripheral neuropathy (DPN) is one of the most commonly encountered 
neuropathic pain syndromes in clinical practice, and is a particularly debilitating
complication of diabetes.  When symptomatic, it is associated with continuous or 
paroxysmal pain described by patients as shooting, stabbing, or electric in nature.1  
The pain can either be triggered by an external stimulus or be independent of 
external input.  Unlike other painful sensations which signal a warning in response to 
a harmful stimulus, neuropathic pain is maladaptive.  DPN accounts for significant 
morbidity by predisposing the foot to ulceration and lower extremity amputation.2-4   
According to both the American Diabetes Association and the National Institute of 
Diabetes and Digestive and Kidney Disease, 60 to 70 percent of diabetics will 
eventually develop some form of diabetic neuropathy.  Today, it is estimated that 3 -
6 million patients with diabetes have painful DPN.5,6  The total annual cost of DPN 
and its complications in the U.S. is estimated to be between $4.6 and $13.7 billion.7-9  
If current health trends persist unabated, the costs associated with diabetic 
neuropathy will rise sharply over the coming decades. 
1.1.2. 
PATHOPHYSIOLOGY OF DIABETIC PERIPHERAL NEUROPATHY 
DPN manifests as three broad categories: sensory, motor and autonomic.  The most 
prevalent form is somatic or sensorimotor neuropathy.  Symptoms often exhibit a 
distal symmetric pattern, beginning distally at the base of the toes and ascending 
proximally up the lower leg as the disease progresses.  Symptoms are described as 
burning, tingling, stabbing and a pins-and-needles sensation in a stocking and glove 
distribution.  Patients may also display muscle weakness, lack of coordination and 
ataxia, and loss of pain perception.  Loss of protective sensation can lead to the 
formation of foot ulcerations, infections, and amputations.  
Despite being the focus of current research, the sequence of physiological events that 
result in this condition is poorly understood.  The pathogenesis of diabetic 
neuropathy likely involves the interplay of hyperglycemia, ischemia, and oxidative 
stress.10  Vascular dysfunction, driven by metabolic change, is thought to play a 
† From: National Diabetes Statistics Report, 2014 http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-
report-web.pdf 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 24 of 137 
crucial role in the progression of diabetic neuropathy.11-15  Figure 1 portrays the 
relationship of hyperglycemia to oxidative stress, metabolic alterations, vascular 
dysfunction and neural damage.  
Figure 1. The neurodestructive effects of hyperglycemia 
Increased polyol pathway flux. Hyperglycemia causes increased levels of 
intracellular glucose in nerves, leading to saturation of the normal glycolytic 
pathway.  Extra glucose is shunted into the polyol pathway and converted to sorbitol 
and fructose by the enzymes aldose reductase and sorbitol dehydrogenase. 
Accumulation of sorbitol and fructose lead to reduced nerve myoinositol, decreased 
membrane Na+/K+-ATPase activity, impaired axonal transport, and structural 
breakdown of nerves, causing abnormal action potential propagation.16 
Non-enzymatic protein glycation. Advanced glycation end products are the result of 
nonenzymatic addition of glucose or other saccharides to proteins, lipids, and 
nucleotides.  In diabetes, excess glucose accelerates advanced glycation end product 
generation that leads to intracellular and extracellular protein cross-linking and 
protein aggregation.  Activation of the advanced glycation end product receptor 
alters intracellular signaling and gene expression, releases proinflammatory 
molecules, and results in an increased production of reactive oxygen species that 
contribute to diabetic microvascular complications. 
Oxidative Stress. Glucose can cause significant oxidative stress and damage when 
present in excess in the body.  Under physiological conditions, aerobic respiration is 
associated with the formation of a small amount of free radicals (ROS).  In a 
hyperglycemic state, however, particularly in endothelial cells which do not have the 
ability to limit glucose entry into the cell, glucose accumulation exceeds the levels 
that glycolytic enzymes can handle.17  The flood of excess glucose into endothelial 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 25 of 137 
cells is shunted into alternate metabolic pathways (e.g. polyol pathway, 
glycosylation, hexosamine pathway, the diacylglycerol activation of protein kinase C 
[PKC], etc.).  These pathways, particularly PKC, produce significantly larger 
amounts of ROS than aerobic respiration, overwhelming compensatory antioxidant 
mechanisms.18-25  The resulting hyperglycemic oxidative stress contributes to 
endothelial dysfunction by inhibiting endothelial nitric oxide (NO) production and 
by initiating and promoting the deposition of modified lipids in the subendothelium.  
These factors accelerate atherosclerotic macrovascular disease, and is associated 
with the development of apoptosis in neurons and supporting glial cells.15 26 
Vascular Damage. Nervous tissue depends on adequate blood flow to deliver 
nutrients and remove metabolic waste.  Normally, the capillary basement membrane 
allows the passage of nutrients into the cell and permits the removal of waste 
products.  In patients with prolonged hyperglycemia, glucose is more likely to be 
deposited in the basement membrane, thus decreasing its permeability.  Decreased 
permeability results in the buildup of toxic metabolites, resulting in poor cellular 
metabolism, further free radical formation, apoptosis and a decline in vascularization 
of nervous tissues. 
1.2. 
CURRENT TREATMENT OPTIONS 
Currently, there are no approved drugs or interventional strategies known to halt or 
reverse the progression of DPN.  Treatments target pain reduction, physical function 
improvement, reduction of psychological distress, and quality of life improvements.5 
1.2.1. 
PREVENTIVE TREATMENT
Glycemic control. It is generally agreed that long-term complications of both type 1 
and type 2 diabetes can be reduced by tight glycemic control.  To date, this is the 
only intervention specifically shown to arrest or postpone the onset and severity of 
peripheral neuropathy.27-29   
Modifiable risk factors. The incidence of neuropathy is also associated with 
potentially modifiable cardiovascular risk factors, including an elevated triglyceride 
level, a high body mass index (BMI), smoking, and hypertension.30   
Foot care. Patients with diabetes also need to be educated about foot care and 
footwear, and about protection of hyposensitive areas and pressure points, to prevent 
the occurrence of ulcers and to decrease the risk of bone infection.31   
1.2.2. 
MEDICAL MANAGEMENT
There are only two drugs approved by FDA specifically for the treatment of the 
symptoms of DPN: Cymbalta – (duloxetine), a serotonin and norepinephrine 
reuptake inhibitor; and Lyrica – (pregabalin), an anticonvulsant drug.  Both are 
prescribed for the management of pain associated with diabetic peripheral 
neuropathy.  Table 1 presents the Diabetic Peripheral Neuropathic Pain Consensus 
Treatment Guidelines Advisory Board’s recommendations for first- and second-tier 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 27 of 137 
1.2.4. 
UNMET CLINICAL NEED 
Peripheral neuropathy is a serious complication of diabetes.  This form of 
neuropathy carries a high risk of pain, trophic changes and autonomic dysfunction.  
Treatment of DPN is based on either pathogenetic mechanisms or symptomatic 
relief. A number of clinical trials have established symptomatic treatment but for 
pathogenetic mechanisms, the only proven treatment strategy is strict glycemic 
control.  Clearly, it would be desirable to prevent, impede, or reverse the disrupting 
and often life-threatening manifestations of peripheral neuropathy by stimulating 
growth or regeneration of peripheral nerve axons.  
1.3. 
HGF FOR THE TREATMENT OF DIABETIC NEUROPATHY 
Hepatocyte growth factor (HGF) has been shown to be a potent angiogenic growth 
factor, stimulating the growth of endothelial cells and migration of vascular smooth 
muscle cells.35,36  It is a multi-functional mesenchyme-derived cytokine with potent 
angiogenic and anti-apoptotic effects 35-38  HGF stimulates DNA, RNA and protein 
synthesis by endothelial cells in a dose-dependent manner and attenuates high D-
glucose-induced endothelial cell death. 35,37  HGF has also been shown to upregulate 
vascular endothelial growth factor (VEGF) expression, and has demonstrated greater 
mitogenic activity than that of VEGF alone in human aortic endothelial cells in 
vitro.39,40  
Recent research also indicates that HGF can function as a neurotrophic factor.41  
Sympathetic neurons co-express bioactive HGF, its cognate receptor (the Met 
receptor), and localized exogenous HGF has been shown to promote the growth (but 
not survival) of sympathetic neurons,42-46 and to induce the formation of collateral 
vessels and increased blood flow both in rat diabetic and non-diabetic hind limb 
ischemia models.47,48  It is proposed that administration of HGF may promote axonal 
growth and regeneration.  As loss of microvasculature in diabetic neuropathy has 
also been implicated in acceleration of neuronal loss and pain symptoms,49 HGF 
may be an ideally suited candidate for the treatment this condition.  Exogenous 
VEGF has been studied in this patient population, but with limited success.50-53 
The challenge associated with delivering a targeted sustained dose of exogenous 
HGF is in overcoming the instability of HGF in blood circulation and its rapid 
clearance by the liver; HGF has an in vivo half-life of less than 15 minutes.54,55  
One approach to increasing HGF in ischemic tissues is to develop a gene transfer 
strategy that would allow for persistent expression of HGF protein in vivo.  Although 
plasmid DNA is one of the least efficient gene transfer systems currently in use, the 
fact that it is associated with limited persistence and no propensity for genomic 
integration, (particularly in skeletal muscle tissue) makes it an attractive option for 
local targeted delivery. 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 29 of 137 
Eligible subjects were randomized 2:2:1 to the low dose VM202 
mg VM202 / leg, 
mg total, n=
, high dose VM202 (
 mg VM202 / leg,
 mg total, n=
), or 
placebo (normal saline, n=21).  Key findings from the phase II VM202 study 
included: 
•
VM202 injections were well tolerated:
•
Other than Grade 1 injection site reactions (pain, itching and / or swelling),
which all resolved before the 3-month visit, there were no adverse events
deemed related to the study drug or study injections.
•
There were no unanticipated serious adverse events.
•
Ten subjects experienced thirteen serious adverse events over the course of
the study (10/103, 9.7%).  There was no significant difference in the
incidence of SAEs across treatment groups.  All SAEs except one in the
Placebo group (Melanoma) were resolved at study exit.
•
None of the withdrawals (n=7) were due to a study related adverse event.
•
Pain reduction reported in Low Dose VM202 Group was clinically meaningful:
•
Reductions in pain (as measured by the 7 Day Pain and Sleep Interference
Diary which rated pain on a 0 – 10 point scale) were of similar magnitude to
those experienced in the studies of Cymbalta and Lyrica (see medical
reviews in respective NDAs).
•
Mean reduction in pain for the Low Dose Group (8 mg VM202 / leg, total
dose 16 mg VM202) at 3 months was -3.03 points as compared to a -1.53
point reduction in the Placebo arm, for a net treatment effect of -1.5 points (p
= 0.033)
•
Studies that demonstrated a significant reduction in pain for both Cymbalta
and Lyrica showed a net pain reduction of -1 – -1.3 (includes range of both
the BOCF and LOCF analyses in medical reviews).
•
Patients in the Low Dose Group that were not on Gabapentin and Pregabalin
experienced greater reductions in pain at 3 months.  The net pain reduction
was -2.37 (p = 0.006).
•
48.4% of subjects in the Low Dose arm experienced a ≥ 50% reduction in
pain at 3 Months, as compared to 17.6% of Placebo patients (p = 0.06), and
29.3% - 38.3% of patients in the three successful studies of Lyrica (using
same definition for ‘responder’).  The Cymbalta studies used a less stringent
definition of responder (≥ 30% reduction in pain), so we did not have the
ability to directly compare the results.
A pivotal phase III study of VM202 in patients with DPN is warranted. 
1.5. 
PRECLINICAL DATA 
The non-clinical safety of VM202 has been evaluated for general toxicity following 
single intramuscular and intravenous doses in rats.  In addition, the general toxicity 
of VM202 following multiple intermittent (weekly or monthly) intramuscular doses 
has been evaluated in rabbits and rats, respectively.  The potential for genomic 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 30 of 137 
integration at the injection site as well as the potential for distribution to and 
persistence of VM202 in reproductive tissues was evaluated in rats. The ability of 
VM202 to induce humoral immune responses was evaluated following intramuscular 
administration with or without adjuvant in mice.  All species utilized for these 
studies (mouse, rat, and rabbit) were shown in in vivo experiments to be able to 
express the plasmid following intramuscular injection.  
An ischemic heart disease efficacy study in a Yorkshire swine model demonstrated 
that intramyocardial administration of VM202 increased the capillary density and 
regional perfusion in ischemic myocardium and improved ischemic left ventricular 
function.  An ischemic heart disease efficacy study in rats demonstrated that 
histologically identifiable capillaries increased following intramuscular 
administration of VM202 (versus pCK and pCK-VEGF165; p< 0.001). 
Collectively, VM202 has been well-tolerated in all studies conducted to date, with 
the only evidence of toxicity consisting of mild, transient injection site irritation in 
rats at a dose level 11 times the clinical dose of 8 mg / leg (0.11 mg/kg for a 70 kg 
subject).  There has been no evidence of systemic toxicity in any study and human 
HGF has not been detected in the sera of rats or rabbits following intramuscular 
injection [lower limit of quantitation (LLOQ) = 125 pg/mL].  There is no evidence 
of genomic integration, potential germ cell transmission, or immunostimulatory 
effects following intramuscular administration of VM202 to animals.  
Therefore, the nonclinical efficacy and safety studies support the clinical 
investigation of VM202 in subjects with painful diabetic peripheral neuropathy. 
1.6. 
CLINICAL DATA 
VM202 was/is being evaluated in seven clinical trials in the US. 
1.6.1. 
PHASE I STUDY IN CRITICAL LIMB ISCHEMIA 
VM202 was evaluated for treatment of critical limb ischemia (CLI) in a prospective, 
dose-escalation Phase I study.  The study consisted of four (4) cohorts of three (3) 
‘no-option’ CLI subjects.  Subjects received mg,  mg, mg, or 
mg VM202.  
For each dose cohort, VM202 was administered as local intramuscular injections 
with half of the dose administered at Day 0 of the study and the second half 
administered 2 weeks later.  Preliminary efficacy (hemodynamic assessments), 
safety and tolerability were evaluated at Baseline (screening) and at designated time 
points throughout the study.  Clinical evaluations were conducted at baseline, Days 
15, 28, 59, 91, 180, and 365.  All dose cohorts were followed for a year from the 
time of the first dose of study drug administration. 
Between March of 2007 and October of 2008, twelve (12) subjects participated in 
the study (median age, 72 years, 53% male and 75% were a current or former 
smoker).  No deaths occurred during the 12 month follow up, but one subject 
underwent a major amputation.  Median ankle/brachial index (ABI) and toe brachial 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 31 of 137 
index (TBI) significantly increased from 0.35 to 0.52 (p=0.005) and 0.15 to 0.24 
(p=0.01) at 12 months follow-up.  Transcutaneous pressure of oxygen (TcPO2) 
showed an improvement trend (increase).  A significant reduction in pain was 
reported by nine of eleven subjects, with median visual analog scale (VAS) 
decreasing from 58 to 16 (p=0.03) at 6 months follow-up.  VAS score reduction 
tracked well with the hemodynamic data.   
In general, there was more improvement over baseline in Cohort II ( mg VM202) 
than in any other cohort.  Cohort I (  mg of VM202) also experienced a significant 
reduction in pain and modest improvement in hemodynamic measurement.  
Interestingly, 2 subjects in each of these cohorts had diabetes, possibly suggesting 
some benefit of VM202 in this subpopulation.  Doses of aspirin above 81 mg daily 
may have an inhibitory effect on the therapeutic activity of VM202.   
VM202 appears to be well tolerated at doses as high as 
mg.  There were no 
unexpected adverse events in the study.  None of the serious adverse events (SAEs) 
were directly attributable to VM202 (eight SAEs in five subjects, 5/12, 41.7%).  
There was one amputation caused by osteomyelitis which was assessed as unrelated 
to VM202.  Results from this study were published in Gene Therapy in 2011.64 
1.6.2. 
PHASE II STUDY IN CRITICAL LIMB ISCHEMIA 
VM202 was evaluated for treatment of CLI in a prospective, double-blind, placebo-
controlled, multicenter Phase II study.  A total of 50 eligible ‘no-option’ CLI 
subjects with a Rutherford Scale score of 4 or 5 were randomized in 2:2:1 ratio to a 
low dose of VM202, high dose of VM202 or placebo.  Subjects received a final dose 
of  mg VM202, 
 mg VM202 or placebo by IM injections in the affected, 
unilateral calf on Days 0, 14, 28, and 42.  All subjects were 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.   
Efficacy was evaluated in the Efficacy Population (n = 50, defined as subjects that 
received all study injections).  Improvements were statistically significant for wound 
healing in both treatment groups.   
• Ulcers improved most in the high dose group when compared to placebo.  The
average decrease in wound area in the high dose group was 2.8 cm2 (SD 0.3 cm2).
Nine of the 14 ulcers present at baseline in the high dose group completely healed
(9/14, 64.3%); all but one ulcer that did not completely heal showed
improvement.
• Fourteen of 27 (14/27, 51.9%) ulcers in the low dose group healed; of the 13 that
did not completely heal, 8 (8/13, 61.5%) improved (average decrease 1.3 cm2, SD
1.1 cm2).
• Only one ulcer present at baseline in the placebo group healed (1/9, 11.1%).  The
average increase in wound area in the placebo group was 4.3 cm2 (SD 12.6 cm2).
Improvements in skin perfusion (as measured by TcPO2) in both treatment groups 
were also significantly improved in the dorsum foot when compared to placebo in 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 32 of 137 
both treatment arms (low dose, p = 0.0299; high dose, p = 0.0681; treatment groups 
combined, p = 0.0475).     
By the 3-month study visit, all three study arms experienced a reduction in pain with 
sustained reductions over the 12 month follow-up period, but only the two treatment 
arms had a statistically significant reduction compared to baseline.  There was a 
greater relative reduction in pain from baseline in the high dose group at 6 and 9 
months (-21.8, p=0.008, and -33.4, p=0.0018, respectively).   
ABI and TBI trended towards improvement over the course of the study in all three 
study arms, but there were no statistically significant differences between treatment 
groups.   
There was no statistically significant difference in Rutherford scores across 
treatment groups at any time, but a pairwise comparison to baseline in the low dose 
group demonstrated a statistically significant improvement at 6, 9 and 12 months (p 
= 0.0016, p = 0.0012, p = 0008, respectively).   
When considering the biological activity of VM202, amputation rates were lower in 
the low dose and high dose groups (2.5%) as compared to the placebo group (20%). 
Intramuscular injections of VM202 in the lower leg were well tolerated.  There were 
no unexpected adverse events in the study.  Overall, 26 subjects experienced 67 
serious adverse events over the course of the study (26/52, 50%).  With the 
exception of thrombosis in the high dose group (placebo = 0%, low dose = 0%, high 
dose = 15%), there was no significant difference in the incidence of SAEs across 
treatment groups.  One incident of peroneal deep vein thrombosis was categorized as 
possibly related to the study injection.  All other SAEs were deemed unrelated to the 
study drug / placebo.  The majority of SAEs were related to the natural progression 
of peripheral arterial disease (PAD).   
In conclusion, VM202 significantly improved wound healing, improved skin 
perfusion (as measured by TcPO2), and reduced pain.  Positive trends were seen in 
Rutherford classification and in measureable pressures (ABI/TBI).  There appeared 
to be a significant dose response.  The number and types of adverse events seen in 
this study were consistent with those reported in the literature for other 
interventional studies in patients with CLI.  VM202 continues to demonstrate an 
excellent safety profile.
1.6.3. 
PHASE I/II STUDY IN SUBJECTS WITH PAINFUL DPN 
VM202 was evaluated for treatment of DPN in a prospective, dose-escalation Phase 
I study.  The study consisted of three (3) cohorts of four (4) subjects.  Subjects 
received  mg,  mg, or 
 mg VM202 unilaterally in a calf.  For each dose cohort, 
VM202 was administered as local intramuscular injections with half of the dose 
administered at Day 0 of the study and the second half administered 2 weeks later.   

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 33 of 137 
Preliminary efficacy (hemodynamic assessments), safety and tolerability were 
evaluated at Baseline (screening) and at designated time points throughout the study.  
All 3 dose cohorts were followed for one year from the time of the first dose of study 
drug administration.  Between June 2010 and March 2011, twelve (12) subjects were 
enrolled in the study, and enrollment and follow-up are complete.   
Ten out of 12 subjects (10/12, 83%) experienced a reduction in pain at their 6-month 
visit.  One subject each in Cohort I and Cohort II did not experience a reduction in 
pain.  At 6 months, mean change in VAS was -8.2 in Cohort I, -31.6 in Cohort II and 
-25 in Cohort III.
At 12 months, 9 out of 12 subjects (9/12, 75%) experienced a reduction in pain.  The 
same 2 subjects, one each in Cohort I and Cohort II did not experience a reduction in 
pain, and one subject in Cohort III returned to baseline levels at 12 months.  At 12 
months, mean change in VAS was -12.0 in Cohort I, -32.8 in Cohort II and -18.5 in 
Cohort III.  VAS scores also tracked well with other quality of life measures (Brief 
Pain Inventory for Diabetic Peripheral Nephropathy [BPI-DPN]).   
Intramuscular injections of VM202 appear to be well tolerated at doses as high as 
 
mg in subjects with DPN.  There were no incidents of dose limiting toxicities (DLT).  
There have been no serious or unexpected adverse events in the study.   The level of 
VM202 DNA was below the LLOQ in all 12 subjects by day 90.  Circulating HGF 
levels remained relatively constant throughout the study, suggesting that the plasmid 
remained active only at the injection site.  Results from this study were published in 
Molecular Therapy in 2013.63
1.6.4. 
PHASE II STUDY IN SUBJECTS WITH PAINFUL DPN 
VM202 was evaluated for treatment of DPN in a multi-center, phase II, double-
blind, randomized, placebo-controlled, study.  The study enrolled subjects with DPN 
with significant pain at study entry.  Pain was evaluated at initial screening using the 
VAS.  A score of ≥ 4 cm (scale 0 - 10cm) was required for continued screening.  
Pain levels were confirmed by completion of a Daily Pain and Sleep Interference 
Diary after prohibited medication wash-out.  DPN was verified, as in other studies, 
symptomatically, using the Michigan Neuropathy Screening Instrument (MNSI).  
The Brief Peripheral Neuropathy Screening (BPNS) was used to confirm bilateral 
involvement.   
Eligible subjects were randomized 2:2:1 to the low dose VM202 ( mg VM202 / leg, 
mg total, n=40), high dose VM202 (
 mg VM202 / leg, 
mg total, n=
), or 
placebo (normal saline, n=21).  Clinical assessments were performed at Day 0 
(baseline), Day 14, Day 21, Day 30, Day 60, 3 Months, 6 Months, and 9 Months.   
Subjects that received VM202 injections improved more than subjects that received 
only placebo injections in most efficacy measures.  Subjects in the low dose VM202 
arm improved the most in all efficacy measures.  Improvements were statistically 
significant when compared to placebo at 3 months for the mean reduction in pain (as 

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 34 of 137 
measured by the 7 Day Pain and Sleep Interference Diary, p = 0.033), and were of 
similar magnitude as improvements demonstrated in studies of pregabalin.   
48.4% of subjects in the low dose VM202 arm experienced a ≥ 50% reduction in 
pain at 3 months, as compared to 17.6% of placebo subjects (p = 0.06).  The low 
dose VM202 arm demonstrated significant improvements as measured by the BPI-
DPN quality of life measure at 3 months and 6 months in both sections of this 
instrument: pain severity, p = 0.064 and p = 0.053, respectively; and pain 
interference, p = 0.046, p = 0.046, respectively.   
The low dose VM202 arm showed significant improvements in the questionnaire 
portion of the MNSI at 6 months (p = 0.024).  Although there were no significant 
differences between study groups in the physical assessment portion of the MNSI, 
when the monofilament testing was examined, as a stand-alone evaluation, there was 
an improvement trend in the low dose VM202 arm at 6 months, with continued 
improvement at 9 months.  The low dose VM202 group maintained or improved 
sensitivity in the foot two-fold over placebo.   
An important, unanticipated finding in the study was that subjects not on pregabalin 
or gabapentin during the study experienced even greater improvements in pain 
reduction at all time-points for both doses of VM202 (although the low dose VM202 
was still superior to the high dose VM202).   
Intramuscular injections of VM202 were well tolerated.  No deaths or unanticipated 
adverse events were reported.  Over the course of the study, ten (10) subjects in the 
as-treated (safety) population experienced 13 SAEs.  Four subjects in the high dose 
VM202 group experienced 5 SAEs (4/43, 9.3%); 3 subjects in the low dose VM202 
group experienced 3 SAEs (3/39, 7.7%); and 3 subjects in the placebo group 
experienced 5 SAEs (3/21, 14.3%).  All SAEs were classified as unrelated to study 
drug / placebo.   
A total of 45 Grade 1 minor injection site reactions (i.e., pain, itching, erythema, 
and/or bruising) were reported.  Over the course of the study, 202 non-serious 
adverse events (AEs) were reported for 69 subjects (69/103, 67%).  Most non-
serious AEs (150/202, 74%) were resolved at study closure and the majority of the 
non-serious AEs (126/202, 62%) were considered mild in severity.   
Copies of VM202 in whole blood were greatly reduced or completely negative 
within one week after final VM202 dosing (Day 21).  Serum HGF levels remained 
relatively constant throughout the study.   
The results from this study suggest that VM202 provides the same magnitude of pain 
relief as reported with pregabalin or gabapentin.  A pivotal study in subjects with 
DPN is warranted.   

Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
Page 35 of 137 
1.6.5. 
PHASE I/II STUDY IN SUBJECTS WITH AMYOTROPHIC LATERAL
SCLEROSIS (ALS) 
Helixmith Co., Ltd is currently conducting a Phase I/II, open label, single center 
study to assess the safety and tolerability of VM202 in 18 subjects diagnosed with 
clinically definite, clinically probable, or clinically probable-laboratory supported 
ALS.  Enrollment is complete and follow-up is ongoing.  Prior to injections on Day 
0, subjects were assessed using the Revised Amyotrophic Lateral Sclerosis 
Functional Rating Scale (ALSFRS-R), the Medical Research Council (MRC) scale 
for muscle strength testing, dynamometry, forced vital capacity (FVC), and muscle 
circumference.   
All subjects received a total of 
 mg of VM202 IM in the upper limbs (abductor 
pollicis brevis, first dorsal interosseous, biceps, deltoid, extensor carpi radialis, 
flexor carpi ulnaris, and flexor carpi radialis) and lower limbs (quadriceps, 
gastrocnemius, and tibialis anterior).  VM202 was administered over the course of 
four visits: Day 0, Day 7, Day 14, and Day 21.  As in all previous VM202 studies, 
final dose of VM202 for each target muscle group is divided and administered 2 
weeks apart.  However, in order to reduce the injection burden on the ALS subject, 
injection of the upper limbs will be done on separate visits from injection of the 
lower limbs.   
Post-injection, ALSFRS-R, FVC and muscle strength (as determined by the MRC 
scale) were/will be assessed at Day 30, Day 60, Day 90, at 6 months and 9 months.  
Muscle circumference and dynamometry will be conducted on Day 60, Day 90, at 6 
months, and 9 months.  Subjects will be followed up at 12, 18, 24, and 36 months by 
phone to assess survival. 
As of September 9, 2015, all subjects had reached the 9-month follow-up visit, and 
long-term follow-up through 36 months to determine vital status is ongoing.  One 
subject died prior to the 9-month visit, and 2 subjects died following the 9-month 
visit; all 3 subjects died due to respiratory failure associated with ALS.  Four 
additional SAEs that required hospitalization were reported.  All deaths and SAEs 
were classified as unrelated to the study drug.  Injection site reactions have been 
limited to pain, and/or bruising.   
1.6.6. 
CLINICAL EXPERIENCE CONCLUSIONS 
Data collected to date data support the feasibility and safety of intramuscular 
injections of VM202 in subjects with critical limb ischemia and DPN.  Results 
suggest that this therapeutic approach may improve functional outcomes and provide 
symptomatic relief.  VM202 is rapidly eliminated from circulation, and appears to 
remain active only at the injection site.  The incidence of complications did not 
appear to be significantly different between treatment cohorts.  Continued study of 
VM202 in subjects with CLI and DPN is warranted.   

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 36 of 137 
1.7. 
STUDY AND DOSE RATIONALE  
Diabetic peripheral neuropathy, by definition, is a bilateral neuropathy.  Treating 
only one leg may confound patient-reported pain levels and quality of life measures.  
Based on the excellent safety profile of VM202 observed in the phase I and phase II 
CLI studies and the safety and preliminary efficacy data from the phase I/II studies 
of VM202 injections in subjects with DPN, we propose continued bilateral treatment 
in this phase III study.   
 
One dose of VM202 will be tested against placebo (VM202 vehicle).  The total dose 
of VM202 per leg will remain within the dosing scheme of the phase II study (
 mg 
/ leg, for a total of 
mg / subject).  However, instead of two treatments of 
intramuscular injections in the calf (on Day 0 and Day 14), as performed in the prior 
DPN studies, subjects will receive VM202 or placebo (VM202 vehicle) by 
intramuscular injections in both legs (in the calf) on Day 0, and Day 14, followed by 
a second treatment on Day 90 and Day 104.  Studies have shown that copies of 
VM202 in whole blood were greatly reduced or completely negative within one 
week after final VM202 dosing (Day 21).  Serum HGF levels remained relatively 
constant throughout the study.  The phase II DPN study showed greater 
improvements at 3 months than 6 months indicating that the effects of VM202 
attenuate over time justifying a second treatment in the current study. 
 
As in all prior/ongoing studies, VM202 will be delivered in a solution of 
 mg 
VM202 / mL.  Subjects will be treated with an overall final dose of 
mg VM202 or 
placebo, dosages well within those supported by the body of pharmacology and 
toxicology safety studies of VM202.  No toxicities were reported in the phase II 
DPN study.  Safety studies in rabbit, rat and mouse models demonstrate that doses 
approximately 2½ (
mg/
kg) to 30 (
mg/
kg) times the clinical dose (
 mg) 
proposed in this study are safe and resulted in no toxicities. 
 
 
 
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. 
 
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 37 of 137 
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 subjects with painful DPN in lower extremities.   
 
 
3.2. 
STUDY DESIGN 
This is a phase III, double-blind, randomized, placebo-controlled, multicenter, 9-
month study designed to assess the safety and efficacy of VM202 in subjects with 
painful DPN.  Subjects with painful DPN will be screened for study eligibility after 
giving informed consent.   
 
Initial Screening Activities. Prior to screening, subjects will provide informed 
consent and then be initially screened using the VAS, the symptoms portion of the 
BPNS and the MNSI.  Only subjects with a VAS score of ≥ 40 mm, a ≤ 5-point 
difference in symptom of BPNS between legs and MNSI score of ≥ 3 will be 
allowed to proceed with the full screening procedures.  
 
Screening. If the VAS, BPNS and MNSI criteria are met, the rest of screening will 
proceed.  If applicable, the subject will be washed out of prohibited medications.  
During medication wash-out, screening procedures consisting of assessment of study 
eligibility, a complete medical history, vital signs, physical exam, concomitant 
medications, cancer screening tests, viral screening, 12 lead EKG, retinal 
fundoscopy, serum chemistry, hematology, including HbA1c, and urine pregnancy 
test (women of childbearing potential only) may occur. 
 
If applicable, the subject will be washed out of prohibited medications 14 days prior 
to initiation of the 7-day Daily Pain and Sleep Interference Diary.  The Daily Pain 
and Sleep Interference Diary must be completed within 14 days of the first 
injections.  Subjects will be asked to rate their 24-hour average daily pain intensity 
score using an 11-point numerical scale with 0 = no pain – 10 = worst pain possible, 
and to evaluate how much their pain interferes with sleep (also an 11 point numerical 
rating scale from 0 (did not interfere with sleep) to 10 (completely interfered with 
sleep; subject was not able to sleep due to pain).  The subject must record at least 
five assessments of the 24-hour average daily pain intensity score during the seven-
day period.  The mean baseline 24-hour will represent the baseline reference value.  
The average daily pain intensity score of the Daily Pain and Sleep Interference Diary 
must be ≥ 4 with a standard deviation ≤ 2 in order to be eligible for study 
participation.   
 
Data from the Daily Pain and Sleep Interference Diary at screening and BPI-DPN on 
Day 0 will represent the baseline reference values.   
 
All screening assessments should occur within the 90 days prior to Day 0 (day of 
first injections), and the diary must be completed within 14 days prior to Day 0. 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 40 of 137 
• Day 104 – 16 injections of 0.5mL of VM202 vehicle / calf  
 
1 to 3 hours post injection on Day 90 and Day 104, vital signs, and blood draw for 
determination of copies of VM202 will be performed, and the occurrence of 
injection site reactions and adverse events will be assessed.   
 
HGF serum levels will be determined immediately pre-treatment on Day 0, 
immediately pre-treatment on Day 14, on Day 21, Day 60, immediately pre-
treatment on Day 90, immediately pre-treatment on Day 104, Day 111, Day 150, 
Day 180 and Day 270.  
 
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 21, Day 60, at Day 90 (pre-injection, and 2 
hours [± 1 hour] post injection), at Day 104 (pre-injection, and 2 hours [± 1 hour] 
post injection), Day 111, Day 150, Day 180 and Day 270. 
 
Serum chemistry, hematology and HbA1c will be determined on Day 0, Day 90, Day 
180, and Day 270.   
 
VAS, BPI-DPN, and Semmes Weinstein monofilament testing will be recorded at 
Day 0, Day 90, Day 180, and Day 270.  Patients’ Global Impression of Change 
(PGIC) will be recorded at Day 90, Day 180 and Day 270.  MNSI will be conducted 
at Day 180 and Day 270 to track disease progression. 
 
The Daily Pain and Sleep Interference Diary will be completed by subjects before 
the Day 90, Day 180, and Day 270 visits.  
 
Nerve conduction will be conducted on Day 0, Day 180 and Day 270 at select sites.  
Retinal fundoscopy will be conducted at Day 180 and Day 270.  Rescue medication 
(i.e., Acetaminophen [Tylenol]) taken for DPN pain will be dispensed on Day 0 and 
use will be documented throughout the 9-month follow-up visit.     
 
Adverse events, concomitant medications and vital signs will be recorded throughout 
the 9-month follow-up period, while injection site reactions will be assessed through 
Day 150. 
 
A summary of the schedule of evaluations and visits can be found in Appendix 1. 
 
 
3.3. 
SUBJECT POPULATION 
A total of 477 evaluable subjects with DPN meeting the following study entry 
criteria will be enrolled.  
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 41 of 137 
3.3.1. 
INCLUSION CRITERIA 
Subjects must satisfy all of the following criteria to be included in the study: 
 
1. 
Age ≥ 18 years to ≤ 75 years; 
2. 
Documented history of Type I or II diabetes with current treatment control 
(glycosylated hemoglobin A1c of ≤ 10.0% at Screening) and currently on  
medication for diabetes (oral, injectable and / or insulin); 
3. 
No significant changes anticipated in diabetes medication regimen; 
4. 
No new symptoms associated with diabetes within the last 3 months prior to 
study entry†; 
5. 
Diagnosis of painful diabetic peripheral neuropathy in both lower extremities; 
6. 
Lower extremity pain for at least 6 months; 
7. 
Visual analog scale (VAS) score of ≥ 40 mm at Initial Screening (0 mm = no 
pain – 100 mm very severe pain);  
8. 
Symptoms from the Brief Peripheral Neuropathy Screening (BPNS) is ≤ 5-
point difference between legs at Initial Screening;  
9. 
The average daily pain intensity score of the Daily Pain and Sleep Interference 
Diary completed after medication wash-out is ≥ 4 with a standard deviation ≤ 
2;  
10. The physical examination component of the Michigan Neuropathy Screening 
Instrument Score (MNSI) is ≥ 3 at Screening; 
11. Subjects on gabapentin (Neurontin), pregabalin (Lyrica), duloxetine 
(Cymbalta) for painful DPN at study entry† must be on stable regimen of these 
treatments for at least 3 months prior to study entry†; and  
12. 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. 
Peripheral neuropathy caused by condition other than diabetes; 
2. 
Other pain more severe than neuropathic pain that would prevent assessment of 
DPN; 
3. 
Progressive or degenerative neurological disorder; 
4. 
Myopathy; 
5. 
Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as 
Buerger’s disease); 
6. 
Active infection; 
7. 
Chronic inflammatory disease (e.g., Crohn’s disease, rheumatoid arthritis);  
8. 
Positive HIV or HTLV at Screening; 
9. 
Active Hepatitis B or C as determined by 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) at Screening; 
 
† Study entry is defined as the date of signing informed consent. 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 42 of 137 
10. Subjects with known immunosuppression or currently receiving 
immunosuppressive drugs, chemotherapy or radiation therapy; 
11. Stroke or myocardial infarction within last 3 months; 
12. Clinically significant laboratory values at Screening (e.g.,  Hemoglobin < 8.0 
g/dL, WBC < 3,000 cells per microliter, platelet count <75,000/mm3, Creatinine 
> 2.0 mg/dL; 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; 
13. Ophthalmologic conditions pertinent to proliferative retinopathy or conditions 
that preclude standard ophthalmologic examination 
14. Uncontrolled hypertension defined as sustained systolic blood pressure (SBP) > 
200 mmHg or diastolic BP (DBP) > 110 mmHg at Screening; 
15. 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 one 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; 
16. Use of the following drugs / therapeutics is PROHIBITED.  Subjects may 
participate in the study if they are willing to discontinue use of these drugs / 
therapeutics 7 days prior to starting the Daily Pain and Sleep Interference 
Diary.  Subjects must refrain from taking these drugs or undergoing these 
therapies for the duration of the study: 
 
• 
skeletal muscle relaxants, opioids, benzodiazepines (except for stable 
bedtime dose), 
• 
capsaicin, local anesthetic creams (except for Lidocaine cream prior to IM 
injection) and patches, isosorbide dinitrate (ISDN) spray,  
• 
transcutaneous electrical nerve stimulation (TENS), acupuncture 
 
17. If not using gabapentin (Neurontin) or pregabalin (Lyrica), subjects must agree 
not to start these drugs until Day 180 visit of the study. Subjects on these 
medications at study entry† must maintain a stable dose until Day 180 visit of 
the study; 
18. If not using duloxetine (Cymbalta), any antidepressants (e.g. amitriptyline and 
venlafaxine), any other antiepileptics (e.g., valproic acid, carbamazepine, 
vigabatrin), subjects must agree not to start these drugs until Day 180 visit of 
the study. Subjects on these medications at study entry† must maintain a stable 
dose until Day 180 visit of the study; 
19. Subjects requiring > 81 mg daily of acetylsalicylic acid; subjects may be 
enrolled if willing/able to switch to ≤ 81 mg daily of acetylsalicylic acid or to 
another medication; 
20. Subjects requiring regular COX-2 inhibitor drug(s) or non-specific COX-
1/COX-2 inhibiting drugs, or steroids (except inhaled steroids or ocular 
steroids); subjects may be enrolled if willing/able to undergo medication wash-

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 43 of 137 
out prior to the first dosing and to refrain from taking these drugs until Day 180 
visit of the study; 
21. Major psychiatric disorder in within last 6 months that would interfere with 
study participation; 
22. Body mass index (BMI) > 45 kg/m2 at Screening; 
23. Any lower extremity amputation due to diabetic complications; 
24. Use of an investigational drug or treatment in past 6 months or prior 
participation in any study of VM202; and 
25. 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 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 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-YYY-ZZZ.  XX is the 2 digit assigned site number, YYY 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 11-001-JSD.  Subject ID numbers will 
not be re-used (e.g., if the subject is determined to be a screen failure).    
 
3.4.3. 
SCREENING (DAY -90 TO DAY 0) 
Prior to screening, subjects will give informed consent and then be initially screened 
using the VAS, the symptoms portion of the BPNS and the MNSI.  Only subjects 
with a VAS score of ≥ 40 mm, a ≤ 5-point difference in symptom of BPNS between 
legs and MNSI physical assessment score of ≥ 3 will be allowed to proceed with the 
full screening procedures.  
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 44 of 137 
If the VAS, BPNS and MNSI criteria are met, the rest of screening will proceed. If 
applicable, the subject will be washed-out of prohibited medications.  During 
medication wash-out and prior to randomization, subject eligibility will be assessed 
as follows: 
 
• Evaluation of Eligibility Criteria  
• Medical History 
• Concomitant Medications 
• Vital Signs  
• Physical Exam, including height 
• EKG 
• Retinal Fundoscopy 
• Serum Chemistry and Hematology 
• HbA1c 
• Urine pregnancy test (for women of childbearing potential only) 
• Cancer screening should be conducted per the current American Cancer Society 
Guidelines for the Early Detection of Cancer.  Testing should also include: pap 
smear and mammogram if not performed within past 12 months (females only); 
chest X-ray or chest CT scan (if the subject has a previous history of tobacco use, 
a CT scan will be performed instead of X-ray) within 3 months prior to study 
entry†; for subjects ≥ 50 years old, fecal occult blood test.  Note, subjects with 
medical history and/or family history of colon cancer in any first degree relative 
are excluded unless they have undergone a colonoscopy within past 12 months 
with negative findings.     
• Viral screening – HIV, Anti-Human T-Cell Lymphotropic Virus (HTLV), 
Positive Hepatitis B or C as determined by 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), at Screening 
• Following medication washout (if applicable) and within 14 days prior to Day 
0 (first injections). Subjects will keep a Daily Pain and Sleep Interference Diary 
for 7 days.  They will be asked to rate their 24-hour average daily pain intensity 
score using an 11-point numerical scale with 0 mm = no pain – 100 mm worst 
possible pain, and to evaluate how much their pain interferes with sleep (also 
using an 11-point numerical rating scale from 0 (did not interfere with sleep) to 
10 (completely interfered with sleep; subject was not able to sleep due to pain).  
The subject must record at least five assessments of the 24-hour average daily 
pain intensity score during the seven-day period.  The mean 24-hour scores at 
Screening will represent the baseline reference value.  In case less than five 
assessments are recorded, a new Daily Pain and Sleep Interference Diary will be 
provided and the Day 0 visit will be rescheduled to allow completion of the 
Diary.  The average pain score of the Daily Pain and Sleep Interference Diary 
must be ≥ 4 with a standard deviation ≤ 2 in order to be eligible for study 
participation.   
 
 
† Study entry is defined as the date of signing informed consent. 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 45 of 137 
3.4.4. 
RESCUE MEDICATION 
The only allowed rescue medication is Tylenol.  On Day 0, the site will dispense 
extra strength Tylenol (500 mg) provided by the Sponsor.  The subject will be 
instructed to take 2 tabs every 6 hours as needed for DPN pain for a maximum of 6 
tabs (3 grams) / day.  The study-issued Tylenol is only to be used for DPN pain, and 
the subject is not to use any other source of acetaminophen or Tylenol for DPN pain. 
The subject will be provided with a diary to record their pain level (VAS, 0 mm = no 
pain – 100 mm very severe pain) before use, the date and time of use, and the 
amount of Tylenol used.  The subject will be asked to return the diary and the bottle 
of rescue medication at each visit.  At each visit, the site will count how many tabs 
were taking between visits and will dispense additional bottles as needed. 
 
3.4.5. 
(PROHIBITED) CONCOMITANT MEDICATIONS 
 
3.4.5.1. 
MEDICATION THAT MAY INTERFERE WITH VM202 BIOACTIVITY 
COX-1 and COX-2 inhibiting drugs, and steroids (except inhaled steroids or ocular 
steroids) 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 until Day 
180 visit of the study.  The subject needs to be advised that common over the 
counter medications excluded include: Bayer (> 81mg), Excedrin, Aleve, Advil 
(Motrin, ibuprofen).  A full list of the excluded medications, including the washout 
period, can be found in Appendix 3. 
 
Subjects taken gabapentin (Neurontin) and / or pregabalin (Lyrica) at study entry† 
must be on stable dosing regimen for at least 3 months prior to study entry. †  It is not 
allowed to increase the dosage of either of these medications until Day 180 visit of 
the study.  If a subject is not taking gabapentin and / or pregabalin at study entry†, 
the subject must agree not to start these drugs until Day 180 visit of the study. 
 
3.4.5.2. 
MEDICATIONS THAT MAY INTERFERE WITH ASSESSMENT OF VM202 
EFFECT ON PAIN 
Subjects must discontinue use of the following drugs / therapeutics listed below.  
Subjects may participate in the study if they are willing to discontinue use of these 
drugs / therapeutics 7 days prior to starting the Daily Pain and Sleep Interference 
Diary.  Subjects must refrain from taking these drugs or undergoing these therapies 
for the duration of the study: 
 
• skeletal muscle relaxants, opioids, benzodiazepines (except for stable bedtime 
dose), 
• capsaicin, local anesthetic creams (except for Lidocaine cream prior to IM 
injection) and patches, isosorbide dinitrate (ISDN) spray,  
• transcutaneous electrical nerve stimulation (TENS), acupuncture 
 
 
† Study entry is defined as the date of signing informed consent. 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 46 of 137 
If not using duloxetine (Cymbalta), any antidepressants (e.g. amitriptyline and 
venlafaxine), any other antiepileptics (e.g., valproic acid, carbamazepine, vigabatrin) 
at screening, subjects must agree not to start these drugs until Day 180 visit of the 
study.  Subjects on these medications at study entry† must maintain a stable dose 
until Day 180 visit of the study.  
 
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 on Screening Log.  Screen failures will be replaced. 
 
3.4.6. 
TREATMENT ASSIGNMENT 
After providing written informed consent, potential study participants will undergo 
Screening assessments.  The site will log in into the electronic data capturing (EDC) 
system and enter the screening assessments.  If the site selects that the subject meets 
all inclusion and exclusion criteria, the EDC will indicate whether the subject can be 
treated, and will send a separate notification to the Pharmacist, the drug depot and 
the unblinded Pharmacy Monitor with the subject ID, randomly assigned kit number, 
and randomly assigned study treatment.  The Investigator or designee will coordinate 
with the Pharmacist and schedule the Day 0 visit.  
 
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.  Randomization will be stratified by current use 
of gabapentin and/or pregabalin. 
 
The drug depot will prepare and send the appropriate kit with associated dose 
preparation worksheets and treatment assignment notification to the Pharmacy.  The 
Pharmacist or designee will keep the notification and dose preparation worksheets in 
a secure location with access limited to Pharmacy personnel responsible for 
preparing the syringes with assigned study treatment. 
 
After study initiation, randomly assigned VM202 and VM202 vehicle (placebo) will 
be provided to the site’s pharmacy by the drug depot for each eligible subject.  
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. 
 
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 prepares the vials according to the 
instructions (which vials to reconstitute with water for injection [WFI].  The site 
pharmacist and select individuals (but excluding study monitors and study director) 
will be unblinded to the treatment assignments.  The subject and study personnel, 
including core lab, principal investigator, co-investigators, study coordinators, study 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 47 of 137 
monitors and study director will remain blinded until all data has been entered into 
the database and the database is locked.  
 
IN CASE OF EMERGENCY ONLY, i.e. SERIOUS ADVERSE EVENT (SAE) 
AND ONLY WHEN THIS INFORMATION INFLUENCES THE SUBJECT'S 
MANAGEMENT, the Investigator may contact the Pharmacist or unblinded 
Pharmacy Monitor to unblind the study medication assignment.  The date and reason 
for unblinding will be documented by the Investigator on the Unblinding Form, and 
a copy of this form will be provided to the unblinded Pharmacy Monitor.  
 
3.4.8. 
DAY -7 (-7 DAYS) 
• Daily Pain and Sleep Interference Diary 
 
3.4.9. 
DAY 0 – 1ST INJECTIONS 
 
3.4.9.1. 
PRE-INJECTION (WITHIN 4 HRS PRIOR TO INJECTIONS) 
• Concomitant Medications 
• Changes in medical history 
• Vital Signs 
• VAS 
• Brief Pain Inventory for Diabetic Neuropathy (BPI-DPN) 
• Semmes-Weinstein Monofilament Testing 
• Nerve Conduction (testing may be performed anytime between randomization 
and/ or on Day 0) 
• Serum Chemistry and Hematology 
• HbA1c 
• Serum HGF  
• Copies of VM202 in whole blood 
 
3.4.9.2. 
1ST DOSE OF VM202 OR PLACEBO 
Sixteen (16) IM injections of randomly assigned study medication in each calf for a 
total of 32 injections will be administered. 
 
3.4.9.3. 
POST-INJECTION (2 HOURS ± 1 HOUR POST INJECTION) 
• Vital Signs 
• Copies of VM202 in whole blood 
• Injection site assessment 
• Adverse event assessment 
 
3.4.10. 
DAY 14 ± 1 DAY – 2ND INJECTIONS 
 
3.4.10.1. 
PRE-INJECTION (WITHIN 4 HOURS PRIOR TO THE INJECTIONS) 
• Concomitant Medications  
• Vital Signs 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 48 of 137 
• Serum HGF  
• Copies of VM202 in whole blood  
• Tylenol Usage 
• 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 each calf for a 
total of 32 injections will be administered. 
 
3.4.10.3. 
POST-INJECTION (2 HOURS ± 1 HOUR POST INJECTION) 
• Vital Signs 
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 
 
3.4.11. 
DAY 21 ± 3 DAYS 
• Concomitant Medications  
• Vital Signs 
• Copies of VM202 in whole blood 
• Serum HGF  
• Tylenol Usage 
• Injection site assessment 
• Adverse event assessment 
 
3.4.12. 
DAY 60 ± 3 DAYS 
• Concomitant Medications  
• Vital Signs 
• Copies of VM202 in whole blood 
• Serum HGF 
• Tylenol Usage 
• Injection site assessment 
• Adverse event assessment 
 
3.4.13. 
DAY 90 ± 7 DAYS – 3RD INJECTIONS 
• Daily Pain and Sleep Interference Diary – to be completed within 14 days prior 
to the visit 
 
3.4.13.1. 
PRE-INJECTION (WITHIN 4 HRS PRIOR TO INJECTIONS) 
• VAS 
• Semmes-Weinstein monofilament testing 
• BPI-DPN 
• PGIC 
• Vital Signs 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 49 of 137 
• Concomitant Medications 
• Serum Chemistry and Hematology 
• HbA1c 
• Serum HGF  
• Copies of VM202 in whole blood 
• Tylenol Usage 
• Injection site assessment 
• Adverse event assessment 
 
3.4.13.2. 
3RD DOSE OF VM202 OR PLACEBO 
Sixteen (16) IM injections of randomly assigned study medication in each calf for a 
total of 32 injections will be administered. 
 
3.4.13.3. 
POST-INJECTION (2 HOURS ± 1 HOUR POST INJECTION) 
• Vital Signs 
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 
 
 
3.4.14. 
DAY 104 (13-15 DAYS AFTER DAY 90 VISIT) – 4TH INJECTIONS 
 
3.4.14.1. 
PRE-INJECTION (WITHIN 4 HOURS PRIOR TO THE INJECTIONS) 
• Concomitant Medications  
• Vital Signs 
• Serum HGF  
• Copies of VM202 in whole blood  
• Tylenol Usage 
• Injection site assessment 
• Adverse event assessment 
 
3.4.14.2. 
4TH DOSE OF VM202 OR PLACEBO 
Sixteen (16) IM injections of randomly assigned study medication in each calf for a 
total of 32 injections will be administered. 
 
3.4.14.3. 
POST-INJECTION (2 HOURS ± 1 HOUR POST INJECTION) 
• Vital Signs 
• Copies of VM202 in whole blood  
• Injection site assessment 
• Adverse event assessment 
 
3.4.15. 
DAY 111 (4-10 DAYS AFTER DAY 104 VISITS) 
• Concomitant Medications  
• Vital Signs 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 50 of 137 
• Serum HGF 
• Copies of VM202 in whole blood 
• Tylenol Usage 
• Injection site assessment 
• Adverse event assessment 
 
3.4.16. 
DAY 150 (5 MONTHS) ± 7 DAYS 
• Concomitant Medications  
• Vital Signs 
• Serum HGF 
• Copies of VM202 in whole blood 
• Tylenol Usage 
• Injection site assessment 
• Adverse event assessment 
 
3.4.17. 
DAY 180 (6 MONTHS) ± 7 DAYS 
• Daily Pain and Sleep Interference Diary – to be completed within 14 days prior 
to the visit 
• Retinal Fundoscopy (testing may be performed anytime within the visit window) 
• Concomitant Medications  
• Vital Signs 
• VAS 
• MNSI 
• Semmes-Weinstein monofilament testing 
• BPI-DPN 
• PGIC 
• Nerve Conduction (testing may be performed anytime within the visit window) 
• Serum Chemistry and Hematology 
• HbA1c  
• Serum HGF 
• Copies of VM202 in whole blood 
• Tylenol Usage 
• Adverse event assessment 
 
3.4.18. 
DAY 270 (9 MONTHS) ± 14 DAYS 
• Daily Pain and Sleep Interference Diary – to be completed within 14 days prior 
to visit 
• Retinal Fundoscopy (testing may be performed anytime within the visit window) 
• Concomitant Medications  
• Vital Signs 
• VAS 
• MNSI 
• Semmes-Weinstein monofilament testing 
• BPI-DPN 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 51 of 137 
• PGIC 
• Nerve Conduction (testing may be performed anytime within the visit window) 
• Serum Chemistry and Hematology 
• HbA1c 
• Serum HGF 
• Copies of VM202 in whole blood 
• Tylenol Usage  
• Adverse event assessment 
 
 
 
3.5. 
STUDY COMPLETION 
 
3.5.1. 
COMPLETED SUBJECTS 
Each subject in the study will be considered completed when all assessments through 
9 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 (AEs) necessitating discontinuation from the study (pre-
treatment). 
• 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 (investigational 
treatment) prior to the 90-day visit in order to achieve a 477 subject dataset with 90 
day data (primary efficacy endpoint). 
 
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.   
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 54 of 137 
 
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 complete medical history will be obtained at Baseline.  All positive and negative 
findings will be carefully documented on the study worksheets.  Any 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 
history to include all events and interventions prior to study enrollment.  Other 
potential causes of peripheral neuropathy will be excluded (e.g., alcohol 
consumption, renal failure, liver disease, hypothyroidism, collagen vascular diseases, 
vasculitis, osteoarthritis of the ankle or foot, gout, bursitis, fasciitis, and B-12 or 
folate deficiency).  
 
4.1.2. 
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: 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 55 of 137 
 
1. 
For subjects ≥ 50 years old, fecal occult blood test.  A positive fecal occult 
blood test (current or reported within the past 12 month) 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.  For subjects with medical history and/or family history of colon 
cancer in any first degree relative, must have documentation of a negative 
colonoscopy performed within past 12 months. 
2. 
Chest X-ray or chest CT scan within 3 months prior to study entry†: (if the 
subject is currently using tobacco or has a previous history [within 15 years] of 
tobacco use, a CT scan will be performed instead of X-ray). 
3. 
Mammogram within 1 year prior to study entry† (females ≥ 40 years only)  
4. 
Papanicolaou (Pap) smear within 1 year prior to study entry† – (females ≥ 21 
years only except for women who had a complete hysterectomy [removal of 
uterus and cervix] and females ≥ 70 years with 3 normal pap smears and no 
abnormal pap smear during the last 10 years). 
 
4.1.4. 
VIRAL SCREENING 
The local laboratory will be responsible for Screening viral testing and assays to 
include: HIV-1, HIV-2, HTLV, and HBV and HCV as determined by Hepatitis B 
core antibody (IgG and IgM; HBcAb), antibody to Hepatitis B antigen (HBsAb), 
Hepatitis B surface antigen (HBsAg) and Hepatitis C antibodies (Anti-HCV). 
 
4.1.5. 
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.  
 
4.1.6. 
BRIEF PERIPHERAL NEUROPATHY SCREENING (BPNS) 
Symptoms of BPNS will be assessed at initial screening in order to evaluate the 
bilateral extent of DPN (see Appendix 11). 
 
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; 
 
 
† Study entry is defined as the date of signing informed consent. 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 56 of 137 
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. 
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 180 and Day 270.  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. 
 
4.2.2. 
CONCOMITANT MEDICATIONS 
Concomitant medications will be recorded at each visit using the trade name or 
generic name as described in Section 3.7. 
 
4.2.3. 
VITAL SIGNS 
Vital signs consisting of blood pressure (while subject is sitting), temperature, 
weight, heart rate, and respiratory rate will be measured and recorded at Screening 
and at every visit through the 9-month follow-up.   
 
4.2.4. 
SERUM CHEMISTRY, HEMATOLOGY AND HBA1C 
Evaluation of serum chemistry and hematology will be conducted at Screening, Day 
0, Day 90, Day 180 (6 months) and Day 270 (9 months).  Evaluations will be 
conducted by a local laboratory at each site. 
 
Serum chemistry evaluations will include: calcium, glucose, sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline 
phosphatase, albumin, and total protein. 
 
Hematology evaluations will include: complete blood count (CBC): red blood cells 
(RBC); hemoglobin (Hgb), hematocrit (HCT), platelets and white blood cells (WBC) 
with differential.  Abnormal readings do not necessarily constitute an adverse event; 
the results need to be reviewed in the context of the subject’s health. 
 
HbA1c will be determined at Screening, Day 0, Day 90, Day 180 (6 months) and 
Day 270 (9 months) at a local laboratory at each site.  Laboratory testing by visit is 
provided in Appendix 1. 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 59 of 137 
arrives at the clinic without the completed diary, the visit will be rescheduled as soon 
as possible.   
 
Optionally at the Day 90, Day 180 (Month 6) and Day 270 (Months 9) visits only 
(not at Screening): if the subject states that the Diary was completed and it is a 
hardship for the subject to reschedule the visit (e.g., distance or transportation 
issues), the site may provide a completed FedEx shipping bill to the subject so the 
subject can send the completed Diary to the site using FedEx.   
 
Upon completion of the Diary, the study coordinator will check the Diary for 
completeness.  Any omissions or ambiguous answers will be clarified by the subject 
prior to leaving the clinic.  Note, the subject will be required to initial each page of 
the diary. 
 
4.2.9. 
MICHIGAN NEUROPATHY SCREENING INSTRUMENT 
The Michigan Neuropathy Screening Instrument (MNSI) will be conducted at 
Screening in order to confirm the diagnosis of diabetic peripheral neuropathy and at 
Day 180 (6 months) and Day 270 (9 months) to track disease progression.52-54  The 
MNSI is comprised of a subject questionnaire (15 questions) and of a physical 
evaluation which includes a foot inspection, vibration sensation testing, muscle 
stretch reflexes, and monofilament testing.  The MNSI forms and instructions can be 
found in Appendix 5.  Upon completion of the MNSI questionnaire, the study 
coordinator will check the questionnaire for completeness.  Any omissions or 
ambiguous answers will be clarified by the subject prior to leaving the clinic.  Note, 
the subject will be required to initial and date the MNSI questionnaire. 
 
4.2.10. 
SEMMES WEINSTEIN MONOFILAMENT TEST 
The Semmes-Weinstein monofilament test will be conducted at Day 0, 90 Days, 
Day 180 (6 months) and Day 270 (9 months).  Testing will be performed on the 
plantar aspect of great toe, first, third and fifth metatarsal heads of each foot.  The 
Semmes Weinstein monofilament test instructions can be found in Appendix 6. 
 
4.2.11. 
BRIEF PAIN INVENTORY FOR SUBJECTS WITH DIABETIC PERIPHERAL 
NEUROPATHY (BPI-DPN) 
The brief pain inventory (BPI-DPN) 55,56 will be self-administered during site visits 
on Day 0 before the treatment (injection), on Day 90 before the treatment (injection), 
and at 180 and 270 days.  The Questionnaire includes numeric rating scale that 
assesses the severity of pain, its impact on daily functioning, and other aspects of 
pain (e.g. location of pain, relief from medications).  The questionnaire was modified 
to distinguish between pain due to DPN and pain due to other causes.  Upon 
completion of the questionnaire, the study coordinator will check the questionnaire 
for completeness.  Any omissions or ambiguous answers will be clarified by the 
subject prior to leaving the clinic.  The full Questionnaire can be found in 
Appendix 8.  Note, the subject will be required to initial and date the BPI-DPN. 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 62 of 137 
• 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; 
• 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 AES 
All AEs, regardless of severity, occurring following the first study drug 
administration on Day 0 and the 9-month follow-up visit of the study by a subject 
must be recorded on the AE worksheet.  This will include the following information: 
 
• Description of the AE 
• Date of onset 
• Duration 
• Frequency 
• Severity 
• Seriousness (yes/no) 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 63 of 137 
• 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 (intramuscular injection) and / or the underlying disease 
using the following criteria: 
 
Not related: An adverse event that is not related to the use of the test article or 
administration procedure.   
 
Possibly related: An adverse event that might be due to the use of the test article or 
administration procedure.  An alternative explanation, e.g., concomitant study 
product(s), concomitant disease(s), is inconclusive.  The relationship in time is 
reasonable; therefore, a causal relationship cannot be excluded.   
 
Probably related: An adverse event that might be due to the use of the test article or 
administration procedure.  The relationship in time is suggestive.  An alternative 
explanation is less likely, e.g., concomitant drug(s), concomitant disease(s). 
 
Definitely related: An AE that is due to the use of the test article or administration 
procedure.  The event cannot be reasonably explained by an alternative explanation – 
e.g., concomitant drug(s), concomitant disease(s).  
 
5.2.2. 
AE INTENSITY 
The intensity of the AE/SAE will be defined by the following criteria: 
 
Mild: 
The AE is noticeable to the subject but does not interfere with 
routine activity. 
Moderate: 
The AE is discomforting and interferes with routine activity. 
Severe: 
The AE significantly limits the subject’s ability to perform 
routine activities despite symptomatic therapy. 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 64 of 137 
5.3. 
REPORTING/RECORDING OF AES 
Throughout the course of the study, all efforts will be made by the investigator to 
remain alert to possible AEs.  The first concern will be the safety of the subject, and 
for providing appropriate medical intervention.  The period of observation for 
collection of AEs starts during the first intramuscular injection procedure (Day 0) 
until the 9 month follow-up visit.  Any AE should be recorded on the appropriate 
study worksheet. 
 
 
5.4. 
REPORTING / RECORDING OF SAES 
 
5.4.1. 
INVESTIGATOR’S RESPONSIBILITY 
SAEs will be recorded following the first study drug administration through the 9-
month follow-up visit.  Any serious adverse event or unexpected adverse event that 
occurs during this investigation, whether or not related to the study medication, must 
be reported as soon as possible but no later than 3 working days after the investigator 
first learns of the event to the Sponsor and the designated CRO by completing the 
SAE form and the AE information in the EDC and selecting appropriate criteria that 
classifies the AE as serious and/or unexpected.  In order to have the Investigator’s 
signature on file, the signed SAE form needs to be uploaded to the EDC at the time 
of initial data entry.    
 
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.  This information must be recorded in the subject’s medical 
record and then entered into the EDC.  Copies of related source documentation such 
as results/reports, hospitalization records, and other relevant information must be 
obtained if possible. 
 
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 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 65 of 137 
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. 
 
 
 
6. 
STATISTICAL CONSIDERATIONS 
 
Detailed statistical methods are described in the Statistical Analysis Plan (SAP). 
 
6.1. 
SAMPLE SIZE CALCULATION 
The sample size for the primary efficacy endpoints is calculated based on the 
hypothesis for the primary efficacy endpoints.  The primary efficacy endpoints are as 
follows: 
 
1. The change in the average pain score from baseline to the 3-month follow-up 
obtained from the Daily Pain and Sleep Interference Diary. 
2. The outcome of at least a 50% reduction (i.e. ≥ 50%) in the average pain score 
from baseline to the 3-month follow-up obtained from the Daily Pain and 
Sleep Interference Diary. 
 
The statistical hypotheses for the first primary efficacy endpoint are: 
 
H0: µt = µp versus Ha: µt ≠ µp, (I) 
 
where µt and µp are the mean pain change from baseline to 3-month follow-up for 
the VM202 and Placebo groups, respectively.  A negative mean value means a 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 67 of 137 
second primary efficacy endpoint will not be performed unless the null hypothesis 
of the first primary efficacy endpoint is rejected, no adjustment on the 
significance level is performed. 
• The randomization ratio for the VM202 group and the placebo group is 2:1. 
 
Based on the items above, the sample sizes calculated for the VM202 group and 
placebo group are 286 and 143 subjects, respectively, for first statistical hypotheses; 
those for second statistical hypotheses are 212 VM202 subjects and 106 placebo 
subjects.  Therefore, 286 VM202 subjects and 143 placebo subjects are needed for 
data analyses.  With a dropout rate of 10%, at least 477 subjects should be 
randomized in order to have 318 VM202 subjects and 159 placebo subjects. 
 
In order to control the type I error, the statistical hypotheses for the two secondary 
efficacy endpoints will be formally evaluated only if the statistical tests for the two 
primary efficacy endpoints are statistically significant (i.e. p-value < 0.05). 
 
 
6.2. 
ANALYSIS POPULATION 
 
6.2.1. 
INTENT-TO-TREAT POPULATION (ITT) 
This subset includes all subjects who were randomized on the VMDN-003 study.2  
All baseline characteristics will be summarized based on ITT.  Subjects in the ITT 
will be analyzed according to original treatment assignment, regardless of actual 
treatment received.  The primary analyses of the primary and secondary efficacy 
endpoints 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 that meet the following: 
 
2 Per FDA/ICH E9 Statistical Guidance, pg. 29:  
“In some situations, it may be reasonable to eliminate from the set of all randomized subjects any subject who 
took no trial medication. The intention-to-treat principle would be preserved despite the exclusion of these 
patients provided, for example, that the decision of whether or not to begin treatment could not be 
influenced by knowledge of the assigned treatment. In other situations it may be necessary to eliminate 
from the set of all randomized subjects any subject without data post randomization. No analysis should be 
considered complete unless the potential biases arising from these specific exclusions, or any others, are 
addressed.”   
Helixmith is aware of 7 subjects in VMDN-003 who were randomized in error (did not meet Inclusion / Exclusion 
criteria or who were randomized without PI oversight).  These 7 subjects were subsequently withdrawn before 
receiving study medication and without knowledge of treatment assignment.  Details are summarized in a Note-to-
File, July 12, 2019, which was prepared according to Helixmith SOP QA-002. 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 68 of 137 
 
• 
Received at least one dose of study medication;  
• 
Correctly completed the Daily Pain and Sleep Interference Diary at the 3-
month follow-up;  
• 
Satisfies inclusion/exclusion criteria 
 
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 and secondary efficacy endpoints. 
 
6.2.4. 
PER PROTOCOL (PP) POPULATION 
The Per Protocol population is a subset of mITT.  It includes all mITT subjects who 
meet all of the following criteria: 
 
• 
Subject absent of any major protocol deviations  
• 
Additional criteria, if any, will be established before unblinding the 
randomization code by the independent CDRC that is masked to the treatment 
information of each study subject. 
 
6.3. 
STUDY ENDPOINTS 
 
6.3.1. 
PRIMARY ENDPOINTS 
There are two primary efficacy endpoints that will be evaluated in sequential order. 
The primary efficacy endpoints are: 
 
1. 
The change in the average 24-hour pain score from baseline to the 3-month 
follow-up [Day 90] obtained from the Daily Pain and Sleep Interference Diary. 
2. 
The outcome of at least a 50% reduction (i.e. ≥ 50%) in the average 24-hour 
pain score from baseline to the 3-month follow-up obtained from the Daily 
Pain and Sleep Interference Diary. 
 
6.3.2. 
SECONDARY EFFICACY ENDPOINTS 
The key secondary efficacy endpoints are: 
 
1. 
The change in the average 24-hour pain score from baseline to the 6-month 
follow-up [Day 180](3 months after the Day 90 injection) obtained from the 
Daily Pain and Sleep Interference Diary. 
 
2. 
The outcome of at least a 50% reduction (i.e. ≥ 50%) in the 24-hour average 
pain score from baseline to the 6-month follow-up [Day 180] (3 months after 
the Day 90 injection) obtained from the Daily Pain and Sleep Interference 
Diary. 
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 69 of 137 
6.3.3. 
EXPLORATORY EFFICACY ENDPOINTS 
• The outcome of at least a 20%, 30%, 40%, or 60% reduction in the average pain 
score from baseline to the 3-month follow-up obtained from the Daily Pain and 
Sleep Interference Diary. 
• The outcome of at least a 20%, 30%, 40%, or 60% reduction in the average pain 
score from baseline to the 6-month follow-up obtained from the Daily Pain and 
Sleep Interference Diary. 
• Change in the average pain score from baseline to the 9-month follow-up (Day 
270) obtained from the Daily Pain and Sleep Interference Diary. 
• The outcome of at least a 20%, 30%, 40%, or 60% reduction in the average pain 
score from baseline to the 9-month follow-up obtained from the Daily Pain and 
Sleep Interference Diary. 
• Change in VAS for Pain from baseline to the 3-month, 6-month and 9-month 
follow-up visits. 
• Michigan Neuropathy Screening Instrument (MNSI) physical assessment and 
history changes from baseline to the 6-month and 9-month follow-up. 
• Average sleep interference score change from baseline to the 3-month, 6-month, 
and 9-month follow-up obtained from the Daily Pain and Sleep Interference 
Diary. 
• BPI-DPN pain interference and severity changes from baseline to the 3-month, 
6-month, and 9-month follow-up. 
• Patient’s Global Impression of Change (PGIC) at the 3-month, 6-month, 9-month 
follow-up. 
• Semmes-Weinstein monofilament testing changes from baseline to the  
3-month, 6-month, and 9-month follow-up. 
 
6.3.4. 
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 safety summaries will be derived based on 
available data.  No imputation will be performed for missing values. 
 
6.3.5. 
PHARMACOKINETICS 
HGF serum levels will be determined immediately pre-treatment on Day 0, 
immediately pre-treatment on Day 14, on Day 21, Day 60, immediately pre-
treatment on Day 90, immediately pre-treatment on Day 104, Day 111, Day 150, 
Day 180, and Day 270.  
 
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 21, Day 60, at Day 90 (pre-injection, and 2 
hours [± 1 hour] post injection), at Day 104 (pre-injection, and 2 hours [± 1 hour] 
post injection), Day 111, Day 150, Day 180 and Day 270. 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 70 of 137 
6.3.6. 
DATA SAFETY MONITORING BOARD (DSMB) AND INTERIM ANALYSES 
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. 
 
No interim efficacy analyses are planned. 
 
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 
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. 
 
 
 
 
7. 
ACCESS TO STUDY DOCUMENTS AND STUDY MONITORING 
The Sponsor has designated consultants 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 the study 
worksheets used for data entry in the EDC system to verify the accuracy and completeness 
of the information contained in those reports in preparation for retrieval.  Study worksheets 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 71 of 137 
and source documents must contain all data entered in the EDC system.  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 
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. 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 72 of 137 
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.  
 
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 1 month of study 
completion or termination.  This report should include: any deviations from the protocol, 
the number of participants evaluated, the number of participants who withdrew or were 
withdrawn and the reasons for withdrawal, any significant adverse events and the 
investigator's summation of the study. 
 
 
 
10. INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) 
The 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.   
 
If a potential clinical site does not receive any NIH funding (either directly or indirectly) 
and does not have an institutional IBC, they can participate in the study if they issue a 
certification statement to that effect.  The certification statement will be submitted to the 
OBA. 
 
 
 
11. INFORMED CONSENT PROCESS 
It is the responsibility of the investigator to inform each 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 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 73 of 137 
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 
confidential information for any purpose without first obtaining the consent of Sponsor in 
writing.  Such consent shall be deemed to have been given for disclosure to any person for 
whom the investigator is responsible at his/her center, but only so far as required for the 
purposes of the study, and, in the case of disclosures to staff, only if such staff are bound by 
obligations of confidentiality no less strict than those set out herein. 
 
 
 
13. PROTOCOL AMENDMENTS 
The Sponsor will document modifications to the protocol in the form of a written 
amendment.  Protocol modifications that impact 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.  If the site elects to use the worksheets, 
appropriate worksheets will be completed and initialed or signed where indicated at each 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 74 of 137 
examination.  All worksheets will be completed in a legible manner in black/blue ink.  
Alternatively, the site may elect to use their own source documents.  It is expected there 
will be source data for all entries in the EDC. 
 
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.  
The study worksheets and data entered in the EDC system will be audited by the Study 
Monitor. 
 
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 
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 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 75 of 137 
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. 
 
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 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 76 of 137 
• Copies of all IND Safety Reports submitted to the site by the Sponsor or 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 
Sponsor.  At the end of the study, a clinical study report will be written by the Sponsor or 
its designee.   
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 77 of 137 
18. REFERENCES 
 
1. 
Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning 
and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc 2006;81:S12-25. 
2. 
Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of 
painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes care 2006;29:1518-22. 
3. 
Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: Mechanisms to 
management. Pharmacol Ther 2008;120:1-34. 
4. 
Mehra M, Merchant S, Gupta S, Potluri RC. Diabetic peripheral neuropathy: resource 
utilization and burden of illness. Journal of medical economics 2014;17:637-45. 
5. 
Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: epidemiology, natural 
history, early diagnosis, and treatment options. Pain Med 2008;9:660-74. 
6. 
Hartsfield CL, Korner EJ, Ellis JL, Raebel MA, Merenich J, Brandenburg N. Painful 
diabetic peripheral neuropathy in a managed care setting: patient identification, 
prevalence estimates, and pharmacy utilization patterns. Population health management 
2008;11:317-28. 
7. 
Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of 
diabetic peripheral neuropathy in the US. Diabetes care 2003;26:1790-5. 
8. 
Tolle T, Xu X, Sadosky AB. Painful diabetic neuropathy: a cross-sectional survey of 
health state impairment and treatment patterns. Journal of diabetes and its complications 
2006;20:26-33. 
9. 
Sadosky A, Mardekian J, Parsons B, Hopps M, Bienen EJ, Markman J. Healthcare 
utilization and costs in diabetes relative to the clinical spectrum of painful diabetic 
peripheral neuropathy. Journal of diabetes and its complications 2014. 
10. 
Yagihashi S, Yamagishi S, Wada R. Pathology and pathogenetic mechanisms of diabetic 
neuropathy: correlation with clinical signs and symptoms. Diabetes Res Clin Pract 
2007;77 Suppl 1:S184-9. 
11. 
Kles KA, Vinik AI. Pathophysiology and treatment of diabetic peripheral neuropathy: the 
case for diabetic neurovascular function as an essential component. Curr Diabetes Rev 
2006;2:131-45. 
12. 
Yokoyama H, Yokota Y, Tada J, Kanno S. Diabetic neuropathy is closely associated with 
arterial stiffening and thickness in Type 2 diabetes. Diabet Med 2007;24:1329-35. 
13. 
Coppini DV, Spruce MC, Thomas P, Masding MG. Established diabetic neuropathy 
seems irreversible despite improvements in metabolic and vascular risk markers--a 
retrospective case-control study in a hospital patient cohort. Diabet Med 2006;23:1016-
20. 
14. 
Kasalova Z, Prazny M, Skrha J. Relationship between peripheral diabetic neuropathy and 
microvascular reactivity in patients with type 1 and type 2 diabetes mellitus -- neuropathy 
and microcirculation in diabetes. Exp Clin Endocrinol Diabetes 2006;114:52-7. 
15. 
Kim B, Feldman EL. Insulin resistance in the nervous system. Trends in endocrinology 
and metabolism: TEM 2012;23:133-41. 
16. 
Figueroa-Romero C, Sadidi M, Feldman EL. Mechanisms of disease: The oxidative stress 
theory of diabetic neuropathy. Rev Endocr Metab Disord 2008;9:301-14. 
17. 
Kumagai AK. Glucose transport in brain and retina: implications in the management and 
complications of diabetes. Diabetes/metabolism research and reviews 1999;15:261-73. 
18. 
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 
2001;414:813-20. 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 78 of 137 
19. 
de MBS, da Fonseca LJ, da SGG, Rabelo LA, Goulart MO, Vasconcelos SM. Oxidative 
stress as an underlying contributor in the development of chronic complications in 
diabetes mellitus. International journal of molecular sciences 2013;14:3265-84. 
20. 
Yanagida K, Maejima Y, Santoso P, et al. Hexosamine pathway but not interstitial 
changes mediates glucotoxicity in pancreatic beta-cells as assessed by cytosolic Ca2+ 
response to glucose. Aging 2014;6:207-14. 
21. 
Tang WH, Martin KA, Hwa J. Aldose reductase, oxidative stress, and diabetic mellitus. 
Frontiers in pharmacology 2012;3:87. 
22. 
Vedantham S, Ananthakrishnan R, Schmidt AM, Ramasamy R. Aldose reductase, 
oxidative stress and diabetic cardiovascular complications. Cardiovascular & 
hematological agents in medicinal chemistry 2012;10:234-40. 
23. 
Gray SP, Di Marco E, Okabe J, et al. NADPH oxidase 1 plays a key role in diabetes 
mellitus-accelerated atherosclerosis. Circulation 2013;127:1888-902. 
24. 
Naudi A, Jove M, Ayala V, et al. Cellular dysfunction in diabetes as maladaptive 
response to mitochondrial oxidative stress. Experimental diabetes research 
2012;2012:696215. 
25. 
Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular 
mechanisms to functional significance and therapeutic opportunities. Antioxidants & 
redox signaling 2010;12:537-77. 
26. 
Ziegler D, Sohr CG, Nourooz-Zadeh J. Oxidative stress and antioxidant defense in 
relation to the severity of diabetic polyneuropathy and cardiovascular autonomic 
neuropathy. Diabetes care 2004;27:2178-83. 
27. 
Genuth S. Insights from the diabetes control and complications trial/epidemiology of 
diabetes interventions and complications study on the use of intensive glycemic treatment 
to reduce the risk of complications of type 1 diabetes. Endocr Pract 2006;12 Suppl 1:34-
41. 
28. 
Martin CL, Albers J, Herman WH, et al. Neuropathy among the diabetes control and 
complications trial cohort 8 years after trial completion. Diabetes care 2006;29:340-4. 
29. 
Intensive blood-glucose control with sulphonylureas or insulin compared with 
conventional treatment and risk of complications in patients with type 2 diabetes 
(UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-53. 
30. 
Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. 
N Engl J Med 2005;352:341-50. 
31. 
Farber DC, Farber JS. Office-based screening, prevention, and management of diabetic 
foot disorders. Prim Care 2007;34:873-85, vii-viii. 
32. 
Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves 
symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes care 2006;29:2365-
70. 
33. 
Chaudhry V, Russell J, Belzberg A. Decompressive surgery of lower limbs for 
symmetrical diabetic peripheral neuropathy. Cochrane Database Syst Rev 
2008:CD006152. 
34. 
Bigam DL, Shapiro AJ. Pancreatic Transplantation: Beta Cell Replacement. Curr Treat 
Options Gastroenterol 2004;7:329-41. 
35. 
Bussolino F, Di Renzo MF, Ziche M, et al. Hepatocyte growth factor is a potent 
angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 
1992;119:629-41. 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 79 of 137 
36. 
Nakagami H, Kaneda Y, Ogihara T, Morishita R. Hepatocyte growth factor as potential 
cardiovascular therapy. Expert Rev Cardiovasc Ther 2005;3:513-9. 
37. 
Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J 
Biochem 1996;119:591-600. 
38. 
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. 
39. 
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. 
40. 
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. 
41. 
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. 
42. 
Giacobini P, Messina A, Wray S, et al. Hepatocyte growth factor acts as a motogen and 
guidance signal for gonadotropin hormone-releasing hormone-1 neuronal migration. J 
Neurosci 2007;27:431-45. 
43. 
Kato N, Nemoto K, Nakanishi K, et al. Nonviral gene transfer of human hepatocyte 
growth factor improves streptozotocin-induced diabetic neuropathy in rats. Diabetes 
2005;54:846-54. 
44. 
Koike H, Morishita R, Iguchi S, et al. Enhanced angiogenesis and improvement of 
neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin 
synthase gene. FASEB J 2003;17:779-81. 
45. 
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. 
46. 
Tonges L, Ostendorf T, Lamballe F, et al. Hepatocyte growth factor protects retinal 
ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in 
vivo. Journal of neurochemistry 2011;117:892-903. 
47. 
Taniyama Y, Morishita R, Hiraoka K, et al. Therapeutic angiogenesis induced by human 
hepatocyte growth factor gene in rat diabetic hind limb ischemia model: molecular 
mechanisms of delayed angiogenesis in diabetes. Circulation 2001;104:2344-50. 
48. 
Taniyama Y, Morishita R, Aoki M, et al. Therapeutic angiogenesis induced by human 
hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical 
study for treatment of peripheral arterial disease. Gene therapy 2001;8:181-9. 
49. 
Camera A, Hopps E, Caimi G. Diabetic microangiopathy: physiopathological, clinical 
and therapeutic aspects. Minerva Endocrinol 2007;32:209-29. 
50. 
Murakami T, Arai M, Sunada Y, Nakamura A. VEGF 164 gene transfer by 
electroporation improves diabetic sensory neuropathy in mice. The journal of gene 
medicine 2006;8:773-81. 
51. 
Quattrini C, Jeziorska M, Boulton AJ, Malik RA. Reduced vascular endothelial growth 
factor expression and intra-epidermal nerve fiber loss in human diabetic neuropathy. 
Diabetes care 2008;31:140-5. 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 80 of 137 
52. 
Tremolada G, Lattanzio R, Mazzolari G, Zerbini G. The therapeutic potential of VEGF 
inhibition in diabetic microvascular complications. Am J Cardiovasc Drugs 2007;7:393-
8. 
53. 
Krishnan ST, Quattrini C, Jeziorska M, Malik RA, Rayman G. Neurovascular factors in 
wound healing in the foot skin of type 2 diabetic subjects. Diabetes care 2007;30:3058-
62. 
54. 
Kawaida K, Matsumoto K, Shimazu H, Nakamura T. Hepatocyte growth factor prevents 
acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci U S A 
1994;91:4357-61. 
55. 
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. 
56. 
Wolff JA, Dowty ME, Jiao S, et al. Expression of naked plasmids by cultured myotubes 
and entry of plasmids into T tubules and caveolae of mammalian skeletal muscle. J Cell 
Sci 1992;103 ( Pt 4):1249-59. 
57. 
Wolff JA, Budker V. The mechanism of naked DNA uptake and expression. Adv Genet 
2005;54:3-20. 
58. 
Malecki M, Kolsut P, Proczka R. Angiogenic and antiangiogenic gene therapy. Gene 
therapy 2005;12 Suppl 1:S159-69. 
59. 
Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events. In: 
CBER, ed. Rockville; 2006. 
60. 
Considerations for Plasmid DNA Vaccines for Infectious Disease Indications. In: CBER, 
ed. Rockville; 2007. 
61. 
Pyun WB, Hahn W, Kim DS, et al. Naked DNA expressing two isoforms of hepatocyte 
growth factor induces collateral artery augmentation in a rabbit model of limb ischemia. 
Gene therapy 2010;17:1442-52. 
62. 
Hahn W, Pyun WB, Kim DS, et al. Enhanced cardioprotective effects by coexpression of 
two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic 
heart disease model. The journal of gene medicine 2011;13:549-55. 
63. 
Ajroud-Driss S, Christiansen M, Allen JA, Kessler JA. Phase 1/2 Open-label Dose-
escalation Study of Plasmid DNA Expressing Two Isoforms of Hepatocyte Growth 
Factor in Patients With Painful Diabetic Peripheral Neuropathy. Molecular therapy : the 
journal of the American Society of Gene Therapy 2013;21:1279-86. 
64. 
Henry TD, Hirsch AT, Goldman J, et al. Safety of a non-viral plasmid-encoding dual 
isoforms of heypatocyte growth factor in critical limb ischemia patients: a phase I study. 
Gene therapy 2011. 
65. 
Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on 
subjective outcome measures. Journal of manipulative and physiological therapeutics 
2004;27:26-35. 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 81 of 137 
 
 
 
APPENDICES 
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 82 of 137 
 
 
TABLE OF APPENDICES 
 
 
Appendix 1. Schedule of Evaluations and Visits & Laboratory Tests by Visit ......................... 83 
Appendix 2. Sample Informed Consent ..................................................................................... 87 
Appendix 3. Medications Excluded from Use During the Study ............................................ 105 
Appendix 4. Continued Stable Use of Specific Medications/Treatments during the Study .... 108 
Appendix 5. Michigan Neuropathy Screening Instrument ...................................................... 110 
Appendix 6. Semmes Weinstein Monofilament Testing ......................................................... 115 
Appendix 7. Test Article Administration................................................................................. 118 
Appendix 8. Brief Pain Inventory for Subjects with Diabetic Peripheral  Neuropathy (BPI-
DPN) ............................................................................................................. 120 
Appendix 9. Visual Analog Scale ............................................................................................ 123 
Appendix 10. Daily Pain and Sleep Interference Diary - One Day Sample ............................ 125 
Appendix 11. Symptoms of Brief Peripheral Neuropathy Screening ...................................... 127 
Appendix 12. Patient’s Global Impression of Change ............................................................ 129 
Appendix 13. Nerve Conduction Testing (at select sites only) ................................................. 131 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 83 of 137 
 
 
 
 
Appendix 1. 
Schedule of Evaluations and Visits & Laboratory Tests by Visit 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 87 of 137 
 
 
 
 
Appendix 2. 
Sample Informed Consent 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 89 of 137 
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 and, you are experiencing painful diabetic peripheral 
neuropathy (DPN) in both lower extremities [legs].   
 
The specific events that result in painful diabetic peripheral neuropathy are not well understood, 
but high blood sugar, reduced blood flow in the limbs, and changes in the blood vessels are 
thought to result in damage to the nerves in the affected areas.  Stimulating the growth of new 
blood vessels may stimulate growth or regeneration of nerves and may reduce pain. Researchers 
have discovered that a protein called hepatocyte growth factor (HGF) that your body naturally 
produces in small amounts can cause the growth of new blood vessels and protect nerves.  
Unfortunately, your body only makes a small amount of this protein and not always in the areas 
where you need it.  Researchers have found a way to increase the amount of HGF in your legs.  
They have isolated the genes responsible for directing the production of HGF, and have designed 
a product that can be injected into your leg. 
 
In the research study, the HGF gene will be injected into your calf muscle cells to evaluate if it 
changes your pain related to diabetic neuropathy.  The product being used in this study is called 
VM202.  VM202 is an experimental drug that is not yet approved by regulatory authorities (the 
US Food and Drug Administration [FDA]).  VM202 is a plasmid (a small piece of DNA), which 
includes the HGF genes.   
 
VM202 has been used in two studies (a small feasibility study and a larger study) in the United 
States in subjects with painful diabetic neuropathy; in a study in Korea in subjects with coronary 
artery disease and in two other studies in the United States in subjects with critical limb ischemia 
(decreased blood flow to the legs).  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 reduce pain related to 
diabetic neuropathy.   
 
This study is intended to help determine the safety and efficacy of VM202 in subjects with 
painful diabetic neuropathy.  VM202 will be injected into both your calf muscles using a syringe 
with a fine needle.     
 
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 90 of 137 
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 Co., Ltd.  [insert PRINCIPAL INVESTIGATOR 
NAME] is being paid by Helixmith Co., Ltd Co., Ltd. to conduct this study.  Together with your 
doctor, Helixmith Co., Ltd 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 477 patients will take part in this study at up to 30 hospitals in the United States and 
Korea.   
 
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 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 each calf at the Day 0, Day 14, Day 90 and Day 104 visits.  The 
contents of the injections depend on your study group:  
 
• VM202 Treatment Group – if you are selected for this group, you will receive 32 mg of 
VM202 over the course of the four injection visits (8 mg of VM202 at the Day 0 visit, 8 mg 
of VM202 at the Day 14 visit, 8 mg of VM202 at the Day 90 visit, and 8 mg of VM202 at the 
Day 104 visit).  At all 4 injection visits, you will receive 16 injections of 0.5 mL of VM202 
in each 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 VM202 vehicle (ingredients of VM202 
without the genetic material which mainly contains sterile salt solution).  At all 4 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 91 of 137 
injection visits, you will receive 16 injections of 0.5 mL of saline in each 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.   
 
Before your first treatment, you will be asked to fill out a daily questionnaire for a week (7 days).  
You will be asked to rate your pain on a scale of 0 - 10 (with 0 = no pain, and 10 = worst 
possible pain) every day.  You will also be asked to describe if your pain interfered with your 
sleep on a scale of 0 - 10 (with 0 = pain did not interfere with sleep, and 10 = pain completely 
interfered; I was not able to sleep due to pain).  You will not be able to receive injections if you 
do not complete this diary. 
 
What tests, procedures, and diagnostic studies will be done during this study?  
There are 11 visits which span 9 months total time from visit #2 to visit #11.  Depending on the 
visit, different tests will be done.  Visit #1 may actually take more than one visit to accomplish 
depending on how many tests can be scheduled on that first day, but is usually completed within 
a few weeks before the first injection procedure (Visit #2).  Below is a detailed description of 
each of the required visits and the laboratory tests, procedures, and evaluations that will be done 
during the visits.   
 
Description of the tests, procedures, and diagnostic studies to be done  
 
Medical history – Discussion with your doctor of your medical history, including diabetes 
history and any changes that have happened.   
 
Physical exam – Your doctor will examine you.  This exam includes taking your sitting blood 
pressure, temperature, 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 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; 
if you are currently taking any of these medications, you will be asked to stop taking these 
medications for the duration of the study. 
 
Rescue Medication – You will be given extra strength Tylenol (500mg) for DPN pain and a 
Tylenol diary for use during the study.  It is important to only use this bottle of Tylenol for DPN 
pain and no other (pain) indications.  You are allowed to take 2 tabs every 6 hours as needed for 
DPN pain for a maximum of 6 tabs (3 grams) / day.  Every time you take Tylenol, please record 
your pain level before use, the date and time of use, and the amount of Tylenol used on the 
Tylenol diary provided to you.  At each visit, please return the diary and the bottle of Tylenol 
even if you have not taken any Tylenol.  At each visit, the site will count how many tabs you 
have taken between visits and will dispense additional bottles of Tylenol and/or diary pages as 
needed. 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 92 of 137 
Assessment of neuropathy – Assessment by your doctor of the condition of your feet and legs, 
your reflexes, and sensitivity to touch. 
 
Injection site reaction assessment – Assessment by your doctor of any pain or other reaction at 
the locations where VM202 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.   
 
Questionnaires – You will be asked to complete short questionnaires about feeling/pain in your 
legs and feet. 
 
Nerve Conduction Studies (Select Sites Only – Omit section if not applicable) - You will be 
asked to lie on a table or bed so your muscles are relaxed.  The skin over the areas to be tested is 
cleaned.  Several flat metal disc electrodes are attached to your skin with tape or a paste.  A 
shock-emitting electrode is placed directly over the nerve, and a recording electrode is placed 
over the muscles controlled by that nerve.  Several quick electrical pulses are given to the nerve, 
and the time it takes for the muscle to contract in response to the electrical pulse is recorded.  
The speed of the response is called the conduction velocity.  When the test is done, the electrodes 
are removed.  You will be able to feel the electrical pulses; note, a very low-voltage electrical 
current is used, and each pulse is very quick (less than a split-second).  
 
Pain and Sleep Interference Diary - You will be asked to assess your average pain in your feet 
and lower legs for 7 days.  You will also be asked to assess to what degree your pain in your feet 
and lower legs interferes with your sleep. 
 
Cancer screening – Cancer screening includes pap smear and mammogram if not performed 
within past 12 months (females only); 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 medical history and/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; and X-ray or CT scan of chest. 
 
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 6 month and 9 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 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 93 of 137 
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 or plan to 
become pregnant during the course of the trial.   
 
12 Lead EKG – An electrocardiogram (EKG) is a measurement of your heart’s electrical 
activity that is traced and sent to a machine, which can be read by your doctor.  This procedure is 
not painful and involves lying as still as possible for a few minutes with sticky pads (electrodes) 
on your chest, arms and legs which are connected through wires to the EKG machine.  This test 
typically takes approximately 15 to 20 minutes. 
 
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).  
 
Below is a list of each visit and the specific tests that will be done: 
 
Visit # 1: Screening/Baseline Evaluations 
Screening is a process of evaluating your initial health status and assessing the status of your 
pain related to diabetic neuropathy.  Screening is usually completed within 2-3 months before the 
first study injections if you qualify for this study.  If you agree to take part in this research study, 
you will first sign this consent form, and then undergo screening.  Screening will involve the 
following procedures:  medical history, physical exam, vital signs, medication review, 
completion of questionnaires, assessment of neuropathy, cancer screening, retinal fundoscopy; 
blood tests including a viral screen; urine pregnancy test (if you are a female of childbearing 
age), 12 lead EKG, and completion of a pain and sleep interference diary. 
 
Please note:  If any of your viral test results are positive you may need to have a second test done 
to make sure the results are the same.  The doctor or his/her nurse will tell you how to find 
medical help and counseling as needed, and you will not be able to take part in this study.  The 
study sponsor will not pay for the cost of the repeat tests, or any other follow-up medical care, or 
counseling for a positive or abnormal test result.   
 
It takes approximately one to two weeks to get all of the initial test results.  After your doctor has 
reviewed the results of these tests he/she will determine whether you are eligible for participation 
in the study.  If you are eligible for the study and you do wish to continue, you will be assigned 
by chance (randomly) to receive VM202 or the placebo control group.  You will then be 
scheduled for the first set of injections which will be done at your next visit (Visit #2).    
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 94 of 137 
Visit # 2 – First Injection Procedure (injections of VM202 or placebo into both calf 
muscles) 
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  update of 
any changes in your medical history, medication review, completion of questionnaires, nerve 
conduction (select sites), vital signs, 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 each 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 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 both 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:  
medication review, vital signs, blood tests for HGF and VM202, injection site reaction 
assessment, and assessment of side effects. 
 
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 each 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. 
 
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 95 of 137 
After Injection Procedure:  
After the injection procedure is performed, the following tests and/or evaluations will be done:  
vital signs, blood tests for VM202, injection site reaction assessment, and assessment of side 
effects. 
 
Before you go home you will receive detailed discharge instructions.  
 
Visit # 4 – 21 Days after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: medication review, vital signs, blood 
tests for HGF and VM202, injection site reaction assessment and assessment of side effects. 
 
Visit # 5 – 60 Days after the First Injection Procedure 
At this visit, the following tests or evaluations will be done: medication review, vital signs, blood 
tests for HGF and VM202, injection site reaction assessment and assessment of side effects. 
 
Visit # 6 –Third Injection Procedure (injections of VM202 or placebo into both calf 
muscles; 90 Days after the First Injection Procedure) 
You will be asked to fill out the 7-day Pain and Sleep Interference Diary before this visit and to 
bring the diary with you for this visit.   
 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  
medication review, completion of questionnaires, assessment of neuropathy, review of your 
completed diary entries, vital signs, blood tests including HGF and VM202, injection site 
reaction assessment, and assessment of side effects. 
 
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 each 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 tests for VM202, and assessment of side 
effects. 
 
Before you go home you will receive detailed discharge instructions.  
 
Visit # 7 – Fourth and Final Injection Procedure (injections of VM202 or placebo into both 
calf muscles; 13 to 15 Days after the Third Injection Procedure) 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 96 of 137 
Before Injection Procedure:  
The following tests will be performed before you have your injection procedure done:  
medication review, vital signs, blood tests including for HGF and VM202, injection site reaction 
assessment, and assessment of side effects. 
 
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 each 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, blood tests for VM202, injection site reaction assessment, and assessment of side 
effects. 
 
Before you go home you will receive detailed discharge instructions.  
 
Visit # 8 – 4-10 Days after the Fourth Injection Procedure 
At this visit, the following tests or evaluations will be done:  medication review, vital signs, 
blood tests for HGF and VM202, injection site reaction assessment and assessment of side 
effects. 
 
Visit # 9 – 5 Months after the First Injection Procedure 
At this visit, the following tests or evaluations will be done:  medication review, vital signs, 
blood tests for HGF and VM202, injection site reaction assessment and assessment of side 
effects. 
 
Visit # 10 – 6 Months after the First Injection Procedure 
You will be asked to fill out the 7-day Pain and Sleep Interference Diary before this visit and to 
bring the diary with you for this visit.  At this visit, the following tests or evaluations will be 
done: retinal fundoscopy, medication review, vital signs, nerve conduction (select sites), blood 
tests including for HGF, VM202, completion of questionnaires, assessment of neuropathy, and 
assessment of side effects. 
 
Visit # 11 – 9 Months after the First Injection Procedure 
You will be asked to fill out the 7-day Pain and Sleep Interference Diary before this visit and to 
bring the diary with you for this visit.  At this visit, the following tests or evaluations will be 
done: retinal fundoscopy, medication review, vital signs, nerve conduction (select sites), blood 
tests including for HGF, VM202, completion of questionnaires, assessment of neuropathy, and 
assessment of side effects. 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 97 of 137 
After you have completed your 9-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 medications with you using the following directions: 
 
• You are allowed to continue taking Lyrica (pregabalin) and/or gabapentin (Neurontin), 
and/or Cymbalta (duloxetine) during the study if you have been taking these medications 
for more than 3 months prior to Screening, but you are not allowed to start these 
medications or increase the dosage of either these medications until Day 180 visit of the 
study. 
 
• Some medications have pain reduction as a side effect.  If you are using any 
antidepressants (e.g. amitriptyline and venlafaxine), or any other antiepileptics (e.g., 
valproic acid, carbamazepine, vigabatrin) at Screening, you must maintain a stable dose 
of these medications until Day 180 visit of the study and you are not allowed to start 
these drugs until Day 180 visit of the study.   
 
• The following therapies are not allowed during the study: 
o skeletal muscle relaxants 
o opioids 
o benzodiazepines (except for stable bedtime dose) 
o capsaicin 
o local anesthetic creams and patches (except for Lidocaine cream prior to study 
drug injections) 
o isosorbide dinitrate (ISDN) spray  
o transcutaneous electrical nerve stimulation (TENS) 
o acupuncture 
 
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, 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 and Advil (ibuprofen), Aleve (naproxen), and 
Excedrin (aspirin/acetaminophen/caffeine). Your doctor will review these medications 
with you to make sure you understand which medications are prohibited during the study. 
 
If the study doctor or you feel that you cannot adhere to these directions, please do not 
sign up for study participation. 
 
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 98 of 137 
How long will I be in this research study? 
Your last follow up visit will be approximately 9 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 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 99 of 137 
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 cancer screening 
Cancer screening includes pap smear and mammogram if not performed within past 12 months 
(females only); for subjects 50 years of age or older, fecal occult blood test; and X-ray or CT 
scan of chest within the past 3 months.  

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 100 of 137 
 
Possible risks include a small amount of radiation exposure from a chest X-ray (or chest CT 
scan, if you have a history of smoking) and mammogram (if you are female), discomfort 
associated with pap smear and mammography (if you are female).   
 
Risks from Nerve Conduction Studies (Select Sites Only – Omit if not applicable) 
There is no chance of problems with nerve conduction studies.  Nothing is put into your skin, so 
there is no chance of infection.  The voltage of electrical pulses is not high enough to cause an 
injury.  You may experience some discomfort or pain for a few seconds during nerve 
stimulation.  The discomfort will end as soon as the stimulation is over. 
 
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 
the pain related to your diabetic neuropathy will improve.    
 
Knowledge from this study may help us better understand how to treat people with painful 
diabetic neuropathy.     
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 101 of 137 
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 Co., Ltd. pays for this research.  However, if taking part in this study leads to 
procedures or care not included in this study, it may lead to added costs for you or your 
insurance company.   
 
What happens if I am injured because I took part in this research study? 
In the event of an injury resulting from your participation in this study, you will be provided with 
appropriate medical care.  However, the costs incurred may, ultimately, be borne by your 
medical insurance.  Further information concerning this and your rights as a research subject can 
be obtained from [INSERT NAME OF PRINCIPAL INVESTIGATOR] or by phone [INSERT 
PHONE NUMBER] or by mail [INSERT MAILING ADDRESS].   
 
What are my rights if I take part in this research study? 
You have the right to refuse to sign this consent.  Taking part in this research study does not take 
away any other rights or benefits you might have if you did not take part in the study.  Taking 
part in this study does not give you any special privileges.  You will not be penalized in any way 
if you decide not to take part or if you stop after you start the study.  Specifically, you do not 
have to be in this study to receive or continue to receive medical care from your doctor.  If you 
stop the study you would still receive medical care for your condition although you would not be 
able to get the VM202 product.   
 
For any questions pertaining to your rights as a research subject, you may contact [PROVIDE 
CONTACT NAME] of the Institutional Review Board [PROVIDE NAME OF IRB AND 
CONTACT PHONE NUMBER].   
 
What about confidentiality? 
The personal information obtained about you during the course of this study will remain 
confidential.  When recording the results of the study you will be referred to only by a unique 
subject identifier code number and your initials.  Except when required by law, you will not be 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 102 of 137 
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.   

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 103 of 137 
 
What alternatives are there to participation in this study?   
Currently, there are no approved drugs or treatment strategies known to stop or reverse the 
progression of diabetic peripheral neuropathy.  Treatments goals are to reduce pain, improve 
physical function, reduce psychological distress, and improve quality of life.  Good glycemic 
control is the only factor shown to slow the progress of neuropathy symptoms.  Lowering your 
triglyceride level, losing weight (if you are overweight), stopping smoking (smokers only) and 
reducing blood pressure have also shown to reduce diabetic neuropathy symptoms. 
 
If you choose not to take part in this study, other commonly prescribed medicines may be 
available for treatment of your diabetic neuropathy.  You do not have to take part in this study to 
receive treatment for your condition.  Your doctor may suggest that you use a topical over the 
counter medication for pain relief (such as lidocaine or capsaicin) and may suggest taking 
nutritional supplements such as α-lipoic acid (a chemical found naturally in various plants such 
as spinach and broccoli). 
 
There are only two drugs approved by FDA specifically for the treatment of the (nerve) pain 
associated with DPN: Cymbalta – (duloxetine); and Lyrica - (pregabalin).  In addition, 
gabapentin (Neurontin) may be prescribed.   
 
 

SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
 
A PHASE III DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF VM202 IN SUBJECTS WITH PAINFUL DIABETIC PERIPHERAL 
NEUROPATHY (PROTOCOL VMDN-003) 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 104 of 137 
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.   
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 105 of 137 
 
 
 
 
Appendix 3. 
Medications Excluded from Use During the Study 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 107 of 137 
  
WASHOUT OF OPIOIDS AND OTHER THERAPIES 
 
Subjects must refrain from taking these drugs or undergoing these therapies for the duration of 
the study since these therapies may interfere with assessment of VM202 effect on pain: 
 
• skeletal muscle relaxants 
• opioids (e.g., morphine, oxycodone, tramadol [Ultram], methadone, fentanyl etc.) 
• benzodiazepines (except for stable bedtime dose), 
• capsaicin 
• local anesthetic creams (except for Lidocaine cream prior to IM injection) and patches 
• isosorbide dinitrate (ISDN) spray,  
• transcutaneous electrical nerve stimulation (TENS) 
• acupuncture 
 
Subjects must discontinue use of these therapies seven (7) days prior to starting the Daily Pain 
and Sleep Interference Diary at Screening. 
 
Subject must agree to remain off of these medications/treatments until completion of the 9-
month follow-up visit. 
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 108 of 137 
 
 
 
 
Appendix 4. 
Continued Stable Use of Specific Medications/Treatments during the Study 
 
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 109 of 137 
 
 
 
 
During the study, subjects must be on a stable regimen for painful DPN.  If subjects are using 
any of the following medications at Screening, they must continue the use of these medications 
at the same regimen for the first 6 months of the study: 
• Gabapentin (Neurontin) 
• Pregabalin (Lyrica) 
• Duloxetine (Cymbalta) 
• Any antidepressants (e.g. amitriptyline and venlafaxine) 
• Any anti-epileptics (e.g., valproic acid, carbamazepine, vigabatrin) 
If the subject is not using any of these medications, subjects must agree not to start any of these 
medications for the first 6 months of the study.   
 
 
Moreover, in order to meet inclusion criterion #11, subjects must be on a stable regimen of the 
following medications for painful DPN for at least 3 months prior to study entry (date of 
signing the informed consent): 
• Gabapentin (Neurontin) 
• Pregabalin (Lyrica) 
• Duloxetine (Cymbalta) 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 110 of 137 
 
 
 
 
Appendix 5. 
Michigan Neuropathy Screening Instrument 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 111 of 137 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 112 of 137 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 113 of 137 
 
How to Use the Michigan Neuropathy Screening Instrument 
 
 
History.  The history questionnaire is self-administered by the subject.  Responses are added to 
obtain the total score.  Responses of “yes” to items 1-3, 5-6, 8-9, 11-12, 14-15 are each counted 
as one point.  A “no” response on items 7 and 13 counts as 1 point.  Item #4 is a measure of 
impaired circulation and item #10 is a measure of general aesthenia and are not included in 
scoring.  To decrease the potential for bias, all scoring information has been eliminated from the 
subject version.  
 
Upon completion of the questionnaire, the study coordinator will check the questionnaire for 
completeness.  Note, the subject will be required to initial and date the questionnaire. 
 
Physical Assessment.  For all assessments, the foot should be warm (>30°C).   
 
Foot Inspection:  The feet are inspected for evidence of excessively dry skin, callous formation, 
fissures, frank ulceration or deformities.  Deformities include flat feet, hammer toes, overlapping 
toes, hallux valgus, joint subluxation, prominent metatarsal heads, medial convexity (Charcot 
foot) and amputation.    
 
Vibration Sensation:  Vibration sensation should be performed with the great toe unsupported.  
Vibration sensation will be tested bilaterally using a 128 Hz tuning fork placed over the dorsum 
of the great toe on the boney prominence of the distal interphalangeal (DIP) joint.  Subjects, 
whose eyes are closed, will be asked to indicate when they can no longer sense the vibration 
from the vibrating tuning fork.  In general, the examiner should be able to feel vibration from the 
hand-held tuning fork for 5 seconds longer on his distal forefinger than a normal subject can at 
the great toe (e.g. examiner’s DIP joint of the first finger versus subject’s toe).  If the examiner 
feels vibration for 10 or more seconds on his or her finger, then vibration is considered 
decreased.  A trial should be given when the tuning fork is not vibrating to be certain that the 
subject is responding to vibration and not pressure or some other clue.  Vibration is scored as 1) 
present if the examiner senses the vibration on his or her finger for < 10 seconds, 2) reduced if 
sensed for ≥ 10 or 3) absent (no vibration detection.)   
 
Muscle Stretch Reflexes: The ankle reflexes will be examined using an appropriate reflex 
hammer (e.g. Trommer or Queen square).  The ankle reflexes should be elicited in the sitting 
position with the foot dependent and the subject relaxed.  For the reflex, the foot should be 
passively positioned and the foot dorsiflexed slightly to obtain optimal stretch of the muscle.  
The Achilles tendon should be percussed directly.  If the reflex is obtained, it is graded as 
present.  If the reflex is absent, the subject is asked to perform the Jendrassic maneuver (i.e., 
hooking the fingers together and pulling).  Reflexes elicited with the Jendrassic maneuver alone 
are designated “present with reinforcement.”  If the reflex is absent, even in the face of the 
Jendrassic maneuver, the reflex is considered absent. 
 
Monofilament Testing:  For this examination, it is important that the subject’s foot be supported 
(i.e., allow the sole of the foot to rest on a flat, warm surface).  The filament should initially be 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 114 of 137 
prestressed (4-6 perpendicular applications to the dorsum of the examiner’s first finger).  The 
filament is then applied to the dorsum of the great toe midway between the nail fold and the DIP 
joint.  Do not hold the toe directly.  The filament is applied perpendicularly and briefly, (<1 
second) with an even pressure.  When the filament bends, the force of 10 grams has been 
applied.  The subject, whose eyes are closed, is asked to respond yes if he/she feels the filament.   
Eight correct responses out of 10 applications is considered normal: one to seven correct 
responses indicates reduced sensation and no correct answers translates into absent sensation.   
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 115 of 137 
 
 
 
 
Appendix 6. 
Semmes Weinstein Monofilament Testing  
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 116 of 137 
Directions for use of Semmes – Weinstein Monofilament Testing 3 
1. Assess integrity of monofilament (no bends/breaks). 
2. Show the monofilament to the client. Place the end of the monofilament on his/her hand 
or arm to show that the testing procedure will not hurt. 
3. Ask the client to turn his/her head and close his/her eyes or look at the ceiling. 
4. Hold the monofilament perpendicular to the skin. 
 
 
5. Place the end of the monofilament on the sole of the foot. Ask the subject to say ‘yes’ 
when he/she feels you touching his/her foot with the monofilament. DO NOT ASK THE 
SUBJECT, “did you feel that?” If the subject does not say ‘yes’ when you touch a given 
testing site, continue on to another site. When you have completed the sequence RETEST 
the area(s) where the subject did not feel monofilament. 
6. Push the monofilament until it bends, then hold for 1-3 seconds. 
7. Lift the monofilament from the skin. Do not brush or slide along the skin. 
8. Repeat the sequence randomly at each testing site on the foot (see pictures below). 
ALL TESTING IS PERFORMED BILATERALLY (ON BOTH FEET) 
Sites on the sole of the foot for monofilament testing 
 
 
Dorsal aspect of the great toe for monofilament testing 
The same location used for the MNSI assessment will be tested, specifically, filaments are 
applied to the dorsum of the great toe midway between the nail fold and the DIP joint.   
 
Testing with the monofilaments begins with filaments in the normal threshold level and 
progresses to filaments of increasing pressure until touch is identified by the subject.  The 
smallest monofilament (lowest grams) that can be felt by the subject should be indicated for each 
 
3 Use of Semmes-Weinstein Monofilament Testing – Nursing Best Practices Guidelines 
http://pda.rnao.ca/content/use-semmes-weinstein-monofilament (downloaded 14Oct14) 
PLANTAR ASPECT OF GREAT TOE, 
FIRST, THIRD AND FIFTH 
METATARSAL HEADS OF EACH FOOT  

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 118 of 137 
 
 
 
 
 
Appendix 7. 
Test Article Administration 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 120 of 137 
 
 
 
 
Appendix 8. 
Brief Pain Inventory for Subjects with Diabetic Peripheral  
Neuropathy (BPI-DPN) 
 
 
 
 
 
Upon completion of the questionnaire, the study coordinator will check the BPI-DPN for 
completeness.  Note, the subject will be required to initial and date the BPI-DPN. 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 121 of 137 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 122 of 137 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 123 of 137 
 
 
 
 
 
 
Appendix 9. 
Visual Analog Scale 
 
 
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 124 of 137 
 
The VAS will be completed by the subject.  The subject should be asked: “How do you 
currently rate your pain in your legs (below the knee – this includes pain in your feet)?”   
 
The subject should be instructed to indicate his or her current level of pain in their legs by 
placing a single vertical line perpendicular to the horizontal line of the scale ensuring that the 
two lines intersect.  Additionally, the subject should be instructed to not use a check mark, “x” or 
circle that would intersect the horizontal line of the scale multiple times.  Ensure the subject 
understands that the mark must be only one line that is perpendicular to and intersects the scale 
line.  The subject should complete the VAS with a fine or medium point pen; felt tip pens and 
pencils should not be used.   
 
 
 
 
 
Note, the subject will be required to initial and date the VAS.  The VAS should be checked for 
accuracy and completeness immediately after it is completed by the subject.  If the subject’s 
mark does not intersect the line or intersects the line more than once, reinstruct the subject to 
modify his or her mark so it meets the appropriate criteria.  Any corrections should be 
accompanied by the subject’s initial and date.   
 
For Day 0 and Day 90, all corrections MUST be completed prior to injections; do NOT have the 
subject correct the scale after injections.  Instead, use the data collected prior to dosing. 
 
The VAS score (0 to 100mm) will be calculated by measuring the distance from the left end of 
the line (“No Pain”) along the scale to the mark made by the subject.  If the mark made by the 
subject intersects the horizontal line of the scale multiple times and was not corrected, measure 
to the middle point between the two marks.  If the mark made by the subject does not intersect 
the line of the scale and was not corrected, project the location of the mark vertically to a point 
on the line of the scale for the measurement.  
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 125 of 137 
 
 
 
 
Appendix 10. Daily Pain and Sleep Interference Diary - One Day Sample 
 
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 126 of 137 
Please complete one form (a + b + c) each day starting on the day indicated by the clinic 
around 8 pm every night.  
 
Question 1a: indicate the day of the week, the date and time. 
Return the completed forms to the clinic at your next visit. 
 
Please circle a number from 0 to 10 that best describes your status using a fine or medium 
point pen. 
 
1a.  ___________ DAY  (Day of week)       Date:  _ _ / _ _ _ / _ _ _ _       Time: ___ ___ am / pm (circle one)                                         
                                                                                                                     DD       MMM        YYYY                      
 
 
1b.  Please rate your average pain in your legs (below the knee, this includes pain in your foot) 
during the past 24 hours.                                                                                                                                            
 
                         0          1           2           3           4           5           6           7            8          9          10 
                    No                                                        Moderate                                                     Worst  
Pain                                                            Pain                                                   possible pain  
   
 
 
 
1c.  Please rate how much your pain in your legs (below the knee, this includes pain in your foot) 
interfered with sleep during the past night.                                                                         
 
                         0           1           2          3           4           5           6           7            8           9         10 
                 Did not                                                                                                                    Completely 
                interfere                                                                                                                 interfered with 
              with sleep                                                                                                                        sleep 
 
 
 
 
 
Patient’s Initials: ______________________________     
 
The study coordinator will check the diary for completeness.  Any omissions or ambiguous 
answers will be clarified by the subject prior to leaving the clinic.  Note, the subject will be 
required to initial and date each page of the diary. 
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 127 of 137 
 
 
 
 
Appendix 11. Symptoms of Brief Peripheral Neuropathy Screening 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 128 of 137 
INSTRUCTIONS FOR RECORDING SUBJECTIVE ELICITED SYMPTOMS: 
 
• Ask the subject to rate the severity of each symptom listed in question 1a-1c on a scale of 01 
(mild) to 10 (most severe) for right and left feet, legs. 
• Enter the score for each symptom in the column marked Presence/Severity. 
• If a symptom has been present in the past, but not since the last visit, enter ‘00-Currently 
Absent.’ 
• If the symptom has never been present, enter ‘11-Always Been Normal.’ 
 
 
Always 
Been 
Normal 
Currently
Absent 
Mild  --------------------------------------------------------------  Severe 
11 
00 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
 
 
1. SYMPTOMS 
 
 
 
 
 
 
 
 
 
 
 
 
     PRESENCE/SEVERITY 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          Right 
 
   Left 
  
a. Pain, aching, or burning in feet, legs: ……………………………….… 
 
  
b. “Pins and needles” in feet, legs: …………………………………….…
 
 
  
c. Numbness (lack of feeling) in feet, legs: ……………………………… 
 
 
d.   Total points (add a + b + c excluding any scores of 11)………… 
 
 
AT SCREENING, THE DIFFERENCE IN TOTAL SCORE BETWEEN LEGS SHOULD 
BE ≤ 5 POINTS IN ORDER TO BE ELIGIBLE.  
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 129 of 137 
 
 
 
 
Appendix 12. Patient’s Global Impression of Change 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 130 of 137 
 Patient Global Impression of Change (PGIC) Scale 
 
Since the start of the study, my overall status is: 
 
Check () one box only: 
 
Very Much Improved 
 1 
Much Improved 
 2 
Minimally Improved 
 3 
No Change 
 4 
Minimally Worse 
 5 
Much Worse 
 6 
Very Much Worse 
 7 
 
 
 
 
 
Patient’s Initials: ______________________________                     Date: ________________ 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 131 of 137 
 
 
 
 
Appendix 13. Nerve Conduction Testing (at select sites only) 
 
 
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 132 of 137 
 
NERVE CONDUCTION4 - GENERAL INSTRUCTIONS 
 
Overview:  These studies will examine nerve conduction velocity (NCV) and the response 
amplitude for a distal sensory nerve (i.e., sural nerve) and for a distal motor nerve (i.e., peroneal 
nerve).  These measures will be determined using standard surface electrophysiologic 
procedures. 5      
 
The key analysis will be a comparison of mean NCV measures at baseline, and Day 180: 
• NCV will be measured in m/sec to the nearest 0.1 m/sec 
• Sensory amplitude will be measured in µV to the nearest 0.1 µV 
• Motor amplitude in mV to the nearest 0.1 mV.   
 
Recording procedures, distances, electrode placements, limb temperature, instrument calibration, 
units of measurement and waveform display and will be standardized across sites.  All 
electrophysiologic procedures will be reviewed by a Central Reading site at the Laboratory for 
Behavioral Neurophysiology – Albert Einstein College of Medicine in NY. 
 
 
Skin Preparation 
The skin where recording, stimulating, and ground electrodes are placed will be cleaned and 
lightly abraded at each stimulation and recording site. 
 
Temperature Probe 
Skin temperature will be measured at a mid-calf site in each patient at each recording session.   
If necessary, the skin will be gradually warmed using a Hydroculator or warming pads. 
 
Equipment 
The equipment used for electrophysiology at each site will need to meet the following criteria:  
calibration, capacity for data averaging, capacity for appropriate data printing and display with 
units of measurement.  Units that measure motor NCV from a site off the muscle will not be 
accepted. 
 
 
 
 
4 Manual of Nerve Conduction Studies – Second Edition.  Ralph M. Buschbacher, Nathan D. Prahlow 
5 Electrodiagnosis in Diseases of the Nerves and Muscle: Principles and Practice - J. Kumura, 1981 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 133 of 137 
SURAL NERVE SENSORY NERVE CONDUCTION STUDY 
 
Position: 
This study is performed in the side-lying position. 
 
Recording Electrodes 
Commercially available disposable electrodes. 
• 
Active electrode (A): Placement immediately behind the lateral malleolus.  The 
electrode should be placed over the sural nerve on a line that goes from the triceps sural 
tendon to the prominence of the lateral malleolus perpendicular to the sural nerve. 
• 
Reference electrode (R): The reference electrode is placed 4.0 cm distal to the active 
electrode along the course of the nerve. 
 
Ground Electrode 
The ground electrode should be placed on the calf between the active recording electrode and 
the stimulating electrode. 
 
 
Stimulation Point  
The cathode (C) is placed 14.0 cm proximal to the active recording electrode in the midline or 
slightly lateral to the midline of the posterior lower leg.  The anode (A) is proximal.  In patients 
that are short, the distance between the cathode and recording electrode can be reduced, 
however, in this circumstance the selected distance (e.g., 12 cm) must remain constant across 
visits for that subject.   
 
 

 
 
 
Protocol VMDN-003/H 
CONFIDENTIAL 
Helixmith Co., Ltd 
 
 
Page 136 of 137 
 
Stimulation Point 2 (S2) 
Proximal stimulation site (Fibular head) 
The cathode (C) is placed over the nerve where it runs immediately below the fibula and 
enters the anterior compartment.  The anode (A) is proximal. 
 
Stimulation Point 3 (S3) 
Proximal stimulation site (Knee) 
The cathode (C) is placed over the nerve in the popliteal fossa approximately 10 cm proximal 
to the head of the fibula.  The cathode is placed just medial to the tendon of the long head of 
the biceps femoris muscle.  The anode (A) is proximal. 
 
Recommended Machine Settings: 
• 
Sensitivity 2.0 mV/division; it may be necessary to use a different display sensitivity 
to ensure the response is a minimum of two divisions high. 
• 
Low frequency filter: 2-3 Hz 
• 
High frequency filter: 10 kHz 
• 
Sweep speed: 5 msec/division 
 
Procedure:  
A. 
Stimulate the nerve at the ankle, fibular head, and the knee. 
B. 
When a supramaximal response is obtained, record the response. 
C. 
Mark the responses with the cursors. If the instrument automatically marks the 
responses, make sure they are done correctly.  Change the cursors if necessary. 
D. 
Measure and record the appropriate distances.  Measure the distance between the active 
recording electrode and the cathode of the stimulator.  
(1) Measure the distance between the active electrode at the ankle and the site of the 
stimulating cathode electrode.  
(2) Measure the distance between the ankle and the fibular head.  
(3) Measure the distance between the ankle and the knee. 
Do not measure the distance between fibular head and knee. 
E. 
Record the temperature before and after the nerve conduction is completed. 
 
 
Print Waveforms  
Print a copy of the waveform.  Make sure the copy has the following information: name of 
nerve, side studied, date, patient ID number, and patient initials. 
 
Complete Worksheets 
Complete the worksheets.  Follow directions carefully and make sure that all information is 
transcribed correctly.