Clinical trial NCT04055090
Conditions: Painful Diabetic Neuropathy Diabetic Neuropathy, Painful
Keywords: diabetic neuropathy shooting pain burning pain pins and needles pain foot pain ViroMed Helixmith Engensis VM202
Sponsor: Helixmith Co., Ltd.
Start date: 2019-02-04; Completion date: 2019-07-24
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to explore the overall safety profile and durability of efficacy of Engensis (VM202) in painful diabetic peripheral neuropathy.

All subjects still in follow-up for the VMDN-003 study or who have completed the Day 270 visit within the prior 90 days will be approached to enroll in the long-term safety extension study.

Detailed description:
In the phase III VMDN-003 study, subjects received 2 treatments of either Engensis (VM202) or placebo administered as intramuscular injections into bilateral calves on Days 0 and 14, and Days 90 and 104. Primary efficacy was evaluated 90 days following the first injection. The growth potential for Hepatocyte Growth Factor make long-term follow-up important both for safety and efficacy: in order for Engensis to be a candidate for chronic treatment of Painful Diabetic Peripheral Neuropathy, it must be demonstrated not to induce unexpected adverse events with repeated dosing; and the potential for reversal or stabilization of diabetic neuropathy using only one or two treatments of Engensis may make it especially attractive compared to current treatments which must be taken daily for the duration of the disease. A safety extension to the VMDN-003 study is therefore warranted.

Arms: arm 1: VM202, Engensis arm 2: Placebo, vehicle
Interventions: intervention 1: Long-Term Follow-Up of Patients who Received Engensis (VM202) intervention 2: Long-Term Follow-Up of Patients who Received Placebo
Intervention descriptions: intervention 1: No study drug is administered in this study. Patients who received Engensis (VM202) in the previous trial (VMDN-003) will remain blinded and were evaluated in this trial for long-term safety and efficacy. intervention 2: No study drug is administered in this study. Patients who received Placebo in the previous trial (VMDN-003) will remain blinded and were evaluated in this trial for long-term safety and efficacy.

Protocol documents:
Prot_000.pdf: 
 
 
 
Protocol VMDN-003b 
 
 
 
Protocol Title: 
Long-Term, Prospective, Non-Interventional, Safety Extension of 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 Number: 
VMDN-003b; Version C 
NCT Number: 
NCT04055090 
Document Date: 
30 July 2019 
 


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LONG-TERM, PROSPECTIVE, NON-INTERVENTIONAL, SAFETY 
EXTENSION OF 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-003b/C 
July 30, 2019 
Sponsor 
 
 
 
 
 
 
 
 
 
DISCLOSURE STATEMENT 
This document contains information that is confidential and proprietary to Helixmith Co., Ltd.  
This information is being provided to you solely for the purpose of evaluating or conducting a 
clinical study for Helixmith Co., Ltd.  You may disclose the contents of this document only to 
study personnel under your supervision who need to know the contents for this purpose and to 
your Institutional Review Board (IRB), otherwise the contents of this document may not be 
disclosed without the prior authorization from Helixmith Co., Ltd.  The foregoing shall not apply 
to disclosure required by governmental regulations or laws.  Any supplemental information that 
may be added to this document also is confidential and proprietary to Helixmith Co., Ltd and 
must be kept in confidence in the same manner as the contents of this document. 






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INVESTIGATOR’S AGREEMENT 
I, the undersigned, am responsible for the conduct of the study at the site below and agree to the 
following:   
•
I understand that this protocol is a confidential document.  I agree that the information within
it will not be disclosed to anyone without prior written authority from the sponsor, Helixmith
Co., Ltd, except to the extent necessary to conduct this study and obtain approval from the
Institutional Review Board or other approving body.
•
I understand and will conduct the study according to the protocol, any approved protocol
amendments, ICH GCP and all applicable regulatory authority requirements and national
laws.
•
I will not deviate from the protocol without prior written permission from the Sponsor and
prior review and written approval from the Institutional Review Board, except where
necessary to prevent any immediate danger to the subject.
•
I have read and understand fully the Investigator Brochure.
•
I have sufficient time to properly conduct and complete the study within the agreed study
period, and I have available an adequate number of qualified staff and adequate facilities for
the foreseen duration of the study to conduct the study properly and safely.
•
I will ensure that any staff members at my site(s) who are involved in the study conduct are
adequately trained regarding this trial’s operations, the protocol and their responsibilities. In
the case of delegating any of my study responsibilities I will provide the sponsor with a
delegation of investigators responsibilities log.
•
I understand that the study may be terminated or enrollment may be suspended at any time by
Helixmith Co., Ltd, Inc. with or without cause, or by me or my institution if it becomes
necessary to protect the best interest of the study subjects.
Principal Investigator’s Name (print) 
Title 
Address 
Signature / Date 


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STUDY SYNOPSIS 
PROTOCOL TITLE 
Long-Term, Prospective, Non-Interventional, Safety Extension of 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 
PURPOSE AND 
RATIONALE
Purpose is to explore the overall safety profile and durability of efficacy 
of VM202 in painful diabetic peripheral neuropathy.  
OBJECTIVES 
To explore the overall safety profile of VM202 over the long-term as 
well as the durability of pain relief in subjects enrolled in the VMDN-
003 trial. 
POPULATION 
This study will include subjects who were randomized and administered 
study drug in the VMDN-003 trial, and who are still currently enrolled 
or within 90 days of having completed the Day 270 visit. 
STUDY DESIGN 
All subjects still in follow-up for the VMDN-003 study or who have 
completed the Day 270 visit within the prior 90 days will be approached 
to enroll in the long-term safety extension study.   
Subjects will be requested to complete a 7-Day Daily Pain and Sleep 
Interference diary and one visit 365 ± 14 days after their VMDN-003 
Day 0 visit. 
All 24 sites in the US who recruited subjects for the VMDN-003 study 
will be invited to participate in this long-term extension trial.  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 long-term safety of IM administration of VM202 in
subjects with painful DPN in the lower extremities.
•
To evaluate the durability of efficacy of IM administration of
VM202 in subjects with painful DPN in the lower extremities.
INCLUSION
CRITERIA 
1. Subjects randomized and dosed in the VMDN-003 study;
2. Having received all intramuscular injections of study drug on Days
0, 14, 90, and 104 in the VMDN-003 study;
3. Currently in follow-up for the VMDN-003 study or having
completed Day 270 within the last 90 days prior to signing consent.


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EXCLUSION
CRITERIA 
1. Current use of an investigational drug or treatment; and
2. Unable or unwilling to give informed consent.
STUDY
PROCEDURES 
Subjects currently in follow-up in the VMDN-003 study or having 
completed Day 270 within the last 90 days will be invited to enroll in the 
safety extension.  Subjects willing to participate with be asked to 
complete a 7-Day Daily Pain and Sleep Interference diary within 14 days 
before a visit scheduled 365 ± 14 days after their Day 0 visit for the 
VMDN-003 study. 
Diaries will be collected at the visit, along with vital signs, concomitant 
medications, adverse events, and the Patient’s Global Impression of 
Change (PGIC) questionnaire. 






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ABBREVIATIONS 
AE 
Adverse Event 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CDRC 
Clinical Data Review Committee 
CFR 
Code of Federal Regulation 
CRO 
Clinical Research Organization 
CS 
Clinically Significant 
DBP 
Diastolic Blood Pressure 
DNA 
Deoxyribonucleic Acid 
DPN 
Diabetic Peripheral Neuropathy 
DSMB 
Data Safety Monitoring Board 
EDC 
Electronic Data Capturing 
ER 
Extended Release 
FDA 
Food and Drug Administration 
HGF 
Hepatocyte Growth Factor 
IBC 
Institutional Biosafety Committee 
IRB 
Institutional Review Board 
IND 
Investigational New Drug 
MRC 
Medical Research Council 
NCS 
Not Clinically Significant 
PGIC 
Patients' Global Impression of Change 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 










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1.
BACKGROUND
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.  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 to 6 million patients with diabetes have painful DPN.1,2  
The total annual cost of DPN and its complications in the U.S. is estimated to be 
between $4.6 and $13.7 billion.3-5   
Currently, there are only three drugs approved by FDA specifically for the treatment 
of the symptoms of DPN: Nucynta ER – (tapentadol), an opioid medication; 
Cymbalta – (duloxetine), a serotonin and norepinephrine reuptake inhibitor; and 
Lyrica – (pregabalin), an anticonvulsant drug.  All are prescribed for the 
management of pain associated with diabetic peripheral 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.6,7  Recent research also indicates that HGF can function as a 
neurotrophic factor.8  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,9 HGF may 
be an ideally suited candidate for the treatment this condition.  
VM202 is a DNA plasmid that contains novel genomic cDNA hybrid human 
hepatocyte growth factor (HGF) coding sequence 
 expressing two 
isoforms of HGF, 
.  VM202 has been used in phase I and II 
studies for painful diabetic peripheral neuropathy (PDPN) with significant efficacy 
on pain.   
In the phase III VMDN-003 study, subjects received 2 treatments of either VM202 
or placebo administered as intramuscular (IM) injections into bilateral calves on 
Days 0 and 14, and Days 90 and 104.  Primary efficacy was evaluated 90 days 
following the first injection.  The growth potential for HGF make long-term follow-
up important both for safety and efficacy: in order for VM202 to be a candidate for 
chronic treatment of PDPN, it must be demonstrated not to induce unexpected 
adverse events with repeated dosing; and the potential for reversal or stabilization of 
diabetic neuropathy using only one or two treatments of VM202 may make it 
especially attractive compared to current treatments which must be taken daily for 
the duration of the disease.  A safety extension to the VMDN-003 study is therefore 
warranted. 


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2.
GOOD CLINICAL PRACTICES (GCP) STATEMENT
This trial will be conducted in compliance with all applicable federal regulations pertaining 
to investigational drugs and devices including but not limited to: 21 CFR Part 50, Part 54, 
Part 56, Part 312, and GCP standards.  This trial will be conducted in compliance with the 
protocol as approved by an Institutional Review Board (IRB).  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 per each institution’s guidelines. 
3.
INVESTIGATIONAL PLAN
3.1. 
STUDY OBJECTIVES 
The objective of this safety extension study is to evaluate the long term safety and 
efficacy of IM administration of VM202 in subjects with painful DPN in the lower 
extremities.   
3.2. 
STUDY DESIGN 
This is a prospective, observational, non-interventional study for long-term follow-
up of subjects previously enrolled in the VMDN-003 study: 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 
currently enrolled or having recently completed the VMDN-003 trial will be invited 
to provide informed consent and enroll in this extension study.   
After providing consent, subjects will be asked to complete a 7-Day Daily Pain and 
Sleep Interference diary and one visit 365 ± 14 days after their VMDN-003 Day 0 
visit.  Diaries will be collected at the visit, along with vital signs, concomitant 
medications, adverse events, and the PGIC questionnaire. 
3.3. 
SUBJECT POPULATION 
Subjects currently in follow-up in the VMDN-003 study or having completed Day 
270 within the last 90 days will be invited to enroll in this safety extension study.   
3.3.1. 
INCLUSION CRITERIA 
Subjects must satisfy all of the following criteria to be included in the study: 
1. Subjects randomized and dosed in the VMDN-003 study;
2. Having received all intramuscular injections of study drug on Days 0, 14, 90, and
104 in the VMDN-003 study;
3. Currently in follow-up for the VMDN-003 study or having completed Day 270
within the last 90 days prior to signing consent.
3.3.2. 
EXCLUSION CRITERIA 
Subjects will not be eligible for the study if any of the following criteria are present: 
1. Current use of an investigational drug or treatment; and


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2. 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. 
3.4.1. 
INFORMED CONSENT 
The investigator or designee 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 1).  The subject will sign and date the informed 
consent form.  The investigator or designee will also sign and date the consent form.  
The original informed consent form will be retained with the subject records; a copy 
will be provided to the subject.   
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 the same unique identifier 
that they were given for VMDN-003 in the following format: XX-YYY-ZZZ.  XX is 
the 2 digit assigned site number, YYY is the subject ID number, and ZZZ are the 
subject initials (initials of first name/middle name (if applicable)/last name). 
3.4.3. 
DAY 270 UP TO 14 DAYS PRIOR TO SCHEDULED DAY 365 VISIT 
•
Informed consent
Study subjects may sign the informed consent form for the extension study after 
completing Day 270 assessments for study VMDN-003.  Alternatively, subjects may 
return to the research center at any time following Day 270 but no later than 14 days 
prior to their scheduled Day 365 visit to sign the informed consent form. 
3.4.4. 
DAY 365 ± 14 DAYS 
The only study visit will be scheduled 365 days ± 14 days after the subject’s 
VMDN-003 Day 0 visit. 
•
The subject will be asked to completed the Daily Pain and Sleep Interference
Diary within 14 days prior to the Day 365 visit
3.4.4.1. 
STUDY VISIT PROCEDURES 
•
Daily Pain and Sleep Interference Diary – to be completed within 14 days prior
to the visit
•
Vital Signs
•
Concomitant Medications
•
PGIC
•
Adverse event assessment


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3.5. 
STUDY COMPLETION 
3.5.1. 
COMPLETED SUBJECTS 
Each subject in the study will be considered completed when all Day 365 
assessments have been performed in accordance with the study protocol. 
3.5.2. 
NON-PARTICIPATING SUBJECTS 
Any subject eligible for the long-term safety extension may elect not to participate. 
If possible, the reason(s) for the subject not participating should be recorded on the 
study worksheets. 
Possible reasons for not participating in the extension study include the following: 
• Adverse events (AEs).
• The subject is lost to follow-up.
• Subject decision (specify).
• Investigator decision (specify).
• Other reason (specify).
3.5.3. 
PREMATURE STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study for any safety, ethical or 
administrative reason at any time. 
4.
EXAMINATIONS AND EVALUATIONS
4.1. 
CONCOMITANT MEDICATIONS 
All concomitant medications (taken since completion of Day 270 of the VMDN-003 
study) 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).
4.2. 
VITAL SIGNS 
Vital signs consisting of blood pressure (while subject is sitting), temperature, 
weight, heart rate, and respiratory rate will be measured and recorded. 
4.3. 
DAILY PAIN AND SLEEP INTERFERENCE DIARY 
Subjects will be asked to keep a Daily Pain and Sleep Interference Diary (see 
Appendix 2).  Subjects will be asked to rate their 24-hour average daily pain 
intensity score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst 
possible pain).  The effect of pain on the subject’s ability to sleep will be assessed 


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using the sleep interference score.  Like the pain intensity score, the sleep 
interference score is an 11-point numerical rating scale from 0 (pain did not interfere 
with sleep) to 10 (pain completely interfered; subject was not able to sleep due to 
pain).   
The diary will be completed within 14 days prior to the Day 365 visit.   To increase 
compliance, the Diary will be FedExed to the subject 2 weeks prior to the scheduled 
visit.  The FedEx shipping bill will become part of the subject’s source documents.  
Ten days prior to the scheduled visit, the study coordinator will call the subject to 
remind the subject of their upcoming visit at Day 365, and the requirement to 
complete the diary starting within 14 days of the visit.  The phone call will be 
documented on the source document worksheets.  One day prior to the visit, the site 
study coordinator will call the subjects to confirm their upcoming visit and to remind 
the subject to bring the completed Diary.  If the subject arrives at the clinic without 
the completed diary, the visit will be rescheduled as soon as possible.   
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. 
4.4. 
PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC) 
The patient’s global impression of change after treatment will be measured using the 
Patient’s Global Impression of Change (PGIC) questionnaire.10  This questionnaire 
measures a patient’s perception of how treatment has affected their level of activity, 
symptoms, emotions, and overall quality of life.  Each descriptor is ranked on an 
intensity scale of 1 = Very Much Improved; 2 = Much Improved; 3 = Minimally 
Improved; 4 = No Change; 5 = Minimally Worse; 6 = Much Worse 7 = Very Much 
Worse.  This test will be self-administered during study visits on Day 365.   
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 PGIC can be found in 
Appendix 3.  Note, the subject will be required to initial and date the PGIC. 
5.
EVALUATION OF ADVERSE EVENTS
5.1. 
DEFINITIONS 
An Adverse Event (AE) is the development of an untoward medical occurrence or 
the deterioration of a pre-existing medical condition following or during exposure to 
an investigational product, whether or not considered causally related to the product.  
An untoward medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver) or clinically significant abnormal results of an 
investigation (e.g., laboratory findings, electrocardiogram). 


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Conditions or diseases that are chronic but stable should not be recorded as an AE.  
Changes in a chronic condition or disease that are consistent with natural disease 
progression are NOT considered AEs and also should not be recorded on AE 
worksheets.  These medical conditions should be adequately documented on the 
appropriate page of the study worksheet (relevant medical history and/or physical 
examination).  However, medical conditions present at enrollment that worsen in 
intensity or frequency in a manner inconsistent with the natural course of the disease 
during the treatment or post-treatment periods should be reported and recorded as AEs. 
An adverse reaction means any adverse event caused by a drug.  Adverse reactions 
are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For the purposes of 
IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
A serious adverse event (SAE) is any untoward medical occurrence which: 
•
Results in death;
•
Is life-threatening;
•
Requires inpatient hospitalization (admission to hospital with a stay > 24 hours)
or prolongation of hospitalization which is not specifically required by the
protocol or is elective;
•
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.   


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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 study drug administration 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)
•
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 


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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. 
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 Day 365 follow-up safety extension 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 Day 
365 safety extension 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.   


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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 
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. 
5.5. 
ANALYSIS POPULATION 
The analysis population will be the safety population, and will include all subjects 
who sign consent for the safety extension study.  Subjects in the analysis population 


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will be analyzed according to treatment received, regardless of original treatment 
assignment.  The primary analyses of the primary and secondary endpoints will be 
based on the analysis population. 
5.6. 
STUDY ENDPOINTS 
5.6.1. 
PRIMARY ENDPOINTS 
The primary endpoint is the difference in long-term safety – defined as occurrence of 
adverse events -  observed between subjects receiving VM202 versus subjects 
receiving placebo in the VMDN-003 study. 
5.6.2. 
SECONDARY ENDPOINTS 
The secondary efficacy endpoints are: 
1.
The change in the average 24-hour pain score from baseline to the Day 365
follow-up from the Daily Pain and Sleep Interference Diary;
2.
The change in the average 24-hour pain score from Day 270 to the Day 365
follow-up from the Daily Pain and Sleep Interference Diary; and
3.
Patient’s Global Impression of Change (PGIC) at the Day 365 follow-up.
5.6.3. 
ANALYSIS METHODS 
The statistical analyses will be descriptive only and reported using summary tables, 
figures, and listings.  All summaries will be derived based on available data.  The 
average 24-hour pain score for a visit will be considered as missing if fewer than 5 of 
7 days of Daily Pain and Sleep Interference Diary entries are provided.  No 
imputation will be performed for missing values.  Summary tables will present 
results by treatment group (i.e., VM202 and Placebo) both within and across the 
randomization stratification factor (i.e., baseline use of gabapentin and/or pregabalin) 
values.  Continuous variables will be summarized using the number of non-missing 
values, mean, standard deviation, median, minimum and maximum values.  
Categorical data will be summarized using the number of observations and 
percentages.  Summary plots of efficacy data will present mean values with standard 
error bars.   
5.6.4. 
DATA SAFETY MONITORING BOARD (DSMB) 
The independent data safety monitoring board (DSMB) for the VMDN-003 study 
will periodically review a limited set of un-blinded tables and/or listings, including 
all reported AEs, as per its responsibilities described in the DSMB Charter.  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 provided to the DSMB members and other 
participants of the DSMB meeting.   


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6.
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 
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. 
7.
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. 


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8.
INSTITUTIONAL REVIEW BOARD
Prior to the initiation of the study, the protocol, the informed consent form and 
investigator’s brochure will be submitted to the IRB for approval.  By signing the 
"Statement of Investigator" form (form FDA 1572), the investigator is assuring that an IRB 
which complies with the requirements set forth in 21 CFR Part 56 will be responsible for 
the initial and continuing review of the proposed clinical study.  A copy of the IRB 
approval letter for the protocol, the informed consent, and the protocol signature page must 
be submitted to the Sponsor or its designee, prior to release of investigational supplies to 
the study site.  The approval letter must refer to the specific protocol and the informed 
consent form.  The study site must maintain an accurate and complete record of all reports, 
documents and other submissions made to the IRB concerning this protocol.  A list of the 
IRB members, their titles or occupations, and their institutional affiliation, or an IRB 
assurance number must be provided to the Sponsor or its designee prior to release of study 
supplies. 
FDA/relevant health authority regulations require that all advertisements for subject 
recruitment be approved by an IRB prior to implementation.  The complete text and format 
must be submitted to the Sponsor or its designee for approval prior to IRB submission. 
The investigator is responsible for notifying the IRB of any serious adverse events as 
required by the IRB.  
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. 
9.
INFORMED CONSENT PROCESS
It is the responsibility of the investigator or designee to inform each subject, prior to the 
screening evaluation, of the purpose of this clinical trial, including possible risks and 
benefits and document the informed consent process in the subject’s chart.  A sample 
informed consent form containing the required elements of informed consent is provided in 
Appendix 1.  Any changes made to this sample must be approved by the Sponsor or its 
designee, prior to submission to an IRB.  After approval by the Sponsor or its designee, the 
informed consent must be submitted to and approved by an IRB.  Prior to entry into the 
study or initiation of any study-related procedures, the subject must read, sign and date the 
informed consent form.  The person executing the consent must also sign and date the final 
consent form page.  One original informed consent form is to be retained by the study site 
and a copy is to be given to the subject.  The informed consent process must be 
documented in the subject’s medical record. 


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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. 
10.
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. 
11.
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.  
12.
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 
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.  


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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.  
13.
RECORD KEEPING AND RETENTION
Data generated for the study should be stored in a limited-access file area and be accessible 
only to representatives of the study site, the Sponsor and its representatives and 
FDA/relevant health authorities/regulatory agencies.  All reports and communications 
relating to study subjects will identify subjects only by initials and subject identification 
number.  Complete subject identification will be kept by the investigator.  This information 
will be treated with strict adherence to professional standards of confidentiality. 
An investigator must in reasonable time, upon request from any properly authorized officer 
or employee of FDA/relevant health authority or regulatory agency, permit such officer or 
employee to have access to requested records and reports, and copy and verify any records 
or reports made by the investigator.  Upon notification of a visit by the FDA/relevant health 
authority or regulatory agency, the investigator will contact the Sponsor or its designee 
immediately.  The investigator will also grant Sponsor representatives the same privileges 
offered to FDA/relevant health authority or regulatory agents/officers/employees. 


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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).
•
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).
•
Copy of the Study Monitoring Log
•
Clinical and non-clinical supply shipment forms
•
Copies of all pertinent correspondence pertaining to the study (except budget issues)
between the Sponsor or the CRO and the site
•
Copies of all SAEs reports submitted to the Sponsor or its designee
•
Copies of all IND Safety Reports submitted to the site by the Sponsor 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 


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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. 
14.
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. 
15.
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.   


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16.
REFERENCES
1.
Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: epidemiology, natural
history, early diagnosis, and treatment options. Pain Med 2008;9:660-74.
2.
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.
3.
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.
4.
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.
5.
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.
6.
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.
7.
Nakagami H, Kaneda Y, Ogihara T, Morishita R. Hepatocyte growth factor as potential
cardiovascular therapy. Expert Rev Cardiovasc Ther 2005;3:513-9.
8.
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.
9.
Camera A, Hopps E, Caimi G. Diabetic microangiopathy: physiopathological, clinical
and therapeutic aspects. Minerva Endocrinol 2007;32:209-29.
10.
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.


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APPENDICES 


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TABLE OF APPENDICES 
Appendix 1. 
Schedule of Evaluations ...........................................................................32 
Appendix 2. 
Sample Informed Consent ........................................................................34 
Appendix 3. 
Daily Pain and Sleep Interference Diary – One Day Sample ...................42 
Appendix 4. 
Patient’s Global Impression of Change ....................................................44 


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Appendix 1. 
Schedule of Evaluations 




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Appendix 2. 
Sample Informed Consent 


SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
LONG-TERM, PROSPECTIVE, NON-INTERVENTIONAL, SAFETY EXTENSION OF 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-003b)
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TITLE:  Long-Term, Prospective, Non-Interventional, Safety Extension of 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 
Number: VMDN-003b) 
SPONSOR: 
Helixmith Co., Ltd 
 
 
www.Helixmith.com  
Worldwide Headquarters: 
Helixmith Co., Ltd. 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
[INSERT NAME AND TITLE] 
INSTITUTION: 
[INSERT INSTITUTION NAME AND ADDRESS] 
SUBJECT INITIALS: 
[INSERT SUBJECT’S INITIALS] 
SUBJECT NUMBER: 
[INSERT SUBJECT’S UNIQUE STUDY 
NUMBER] 
You are being asked to participate in a research study sponsored by Helixmith Co., Ltd.  Before 
you decide whether to participate, it is important for you to know why the research is being done, 
and what it will involve.  Please take your time to read the following information carefully, and 
feel free to discuss your decision with your family, friends, and your primary care doctor.  Please 
ask your study doctor to explain if there is anything that is not clear or if you would like more 
information.  If you agree to take part in this study, you need to sign this consent form.  Your 
signature on this form means that you have been told about and understand the purpose of the 
study, procedures to be followed, and any benefits or risks.  Your signature on this form also 
means that you want to take part in this study.  After you agree, you will be provided with a copy 
of this signed form for your records.   


SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
LONG-TERM, PROSPECTIVE, NON-INTERVENTIONAL, SAFETY EXTENSION OF 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-003b)
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Do I have to take part? 
Taking part in this study is entirely voluntary, and you may refuse to participate or withdraw 
from the study at any time without influencing your regular medical treatment and without 
giving a reason.  A decision to withdraw at any time, or a decision not to take part, will not affect 
the standard of care you receive.  Regardless of your decision, you will still be treated for your 
medical condition.   
Why is this study being done? 
You are being considered to participate in this research study because you are currently enrolled 
or have recently completed the study titled “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”, also known as the VMDN-003 study. 
The current study is intended to help determine the long-term safety and efficacy of VM202 in 
subjects with painful diabetic neuropathy.  No additional administration of study drug will be 
performed, but you will be asked to complete one additional pain diary and return to the research 
clinic for one more visit to evaluate your pain and your current medical status. 
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? 
About 157 patients who are still enrolled in the VMDN-003 study or recently finished the 
VMDN-003 study throughout the 24 research centers in the United States will be invited to 
participate.   
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 be 
asked to fill out a daily questionnaire for a week (7 days).  You will be asked to assess your 
average pain in your feet and lower legs 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 in your feet and lower 
legs 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 complete the daily questionnaire within 14 days of a return visit to the research clinic.  
The visit will be scheduled to occur approximately 1 year from the date that you received your 
first injections of study drug for the VMDN-003 study (365 days). 


SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
LONG-TERM, PROSPECTIVE, NON-INTERVENTIONAL, SAFETY EXTENSION OF 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-003b)
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Description of the tests, procedures, and diagnostic studies to be done at the visit 
Vital signs – Your doctor will measure your weight, heart rate, blood pressure, and respiratory 
rate. 
Assessment of side effects – Your doctor will ask you about any unpleasant medical 
experiences, side effects, or discomforts that may have happened to you since completing the 
VMDN-003 study and up until this visit.   
Medication review – Discussion with your doctor of what medications and dietary supplements 
you have taken and are currently taking since you completed the VMDN-003 study.  In 
particular, your doctor will ask you about any new medications, dietary supplements, or therapies 
that you may have started for the diabetic peripheral neuropathy pain. 
Questionnaires – You will be asked to complete a short questionnaire about your current health. 
How long will I be in this research study? 
This extension study consists of one visit during which you will be explained the study and sign 
the informed consent if you agree to participate, and one visit about 1 year after the date your 
received the first injections of study drug for the VMDN-003 study.  After the 1-year visit, you 
will have completed the study. 
What do I have to do as a participant in this study? 
Participation in this study requires you to make sure that you will be able to complete the diary 
and attend the study visit.   
You also must not participate in any other clinical trial until after you complete the study visit.  
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 


SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
LONG-TERM, PROSPECTIVE, NON-INTERVENTIONAL, SAFETY EXTENSION OF 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-003b)
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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 is very little risk to participating in this study.  There is no investigational product or 
invasive procedure such as blood draws involved and it is unlikely that you will incur any harm 
from participating. However, you may discuss any concerns you have with your doctor before 
you start in the study.   
Are there benefits to taking part in this research study? 
There may be no direct benefit to you by participating in this study.  
Knowledge from this study may help us better understand how the study drug used in the 
VMDN-003 study helps treat painful diabetic neuropathy.     
What if new information becomes available? 
If additional data regarding potential safety risks become available during the study, your 
research doctor will tell you about it and discuss with you whether you want to continue in the 
study.  If you decide to withdraw from the study, your research doctor will make arrangements 
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 and study evaluations 
and procedures that are required for this research study are provided to you at no cost to you. 
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? 


SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
LONG-TERM, PROSPECTIVE, NON-INTERVENTIONAL, SAFETY EXTENSION OF 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-003b)
Protocol VMDN-003b/C 
CONFIDENTIAL 
Helixmith Co., Ltd. 
Page 39 of 45 
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. 
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 
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) 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.   


SUBJECT INFORMATION SHEET / INFORMED CONSENT FORM 
LONG-TERM, PROSPECTIVE, NON-INTERVENTIONAL, SAFETY EXTENSION OF 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-003b)
Protocol VMDN-003b/C 
CONFIDENTIAL 
Helixmith Co., Ltd. 
Page 40 of 45 
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.   
What alternatives are there to participation in this study?   
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 -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 
LONG-TERM, PROSPECTIVE, NON-INTERVENTIONAL, SAFETY EXTENSION OF 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-003b)
Protocol VMDN-003b/C 
CONFIDENTIAL 
Helixmith Co., Ltd. 
Page 41 of 45 
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-003b/C 
CONFIDENTIAL 
Helixmith Co., Ltd. 
Page 42 of 45
Appendix 3. 
Daily Pain and Sleep Interference Diary – One Day Sample 


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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-003b/C 
CONFIDENTIAL 
Helixmith Co., Ltd. 
Page 44 of 45
Appendix 4. 
Patient’s Global Impression of Change 


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Helixmith Co., Ltd. 
Page 45 of 45
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: ________________ 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan 
 
 
 
Protocol Title: 
Long-Term, Prospective, Non-Interventional, Safety Extension of 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 
 
SAP Version: 
VMDN-003b SAP; Version A 
Protocol Number: 
VMDN-003b; Version C 
NCT Number: 
NCT04055090 
Document Date: 
07 August 2019