An Adaptive, Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of Engensis in Participants With Painful Diabetic Peripheral Neuropathy
Phase: PHASE3
Conditions: Diabetic Neuropathy, Painful
Sponsor: Helixmith Co., Ltd.

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Protocol Title:
An Adaptive, Phase 3, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study to Assess the Safety and 
Efficacy of Engensis in Participants with Painful Diabetic Peripheral 
Neuropathy
Protocol Number:
VMDN-003-2
Version Number:
6.0
Approval Date:
28 Jan 2022
Compound: 
Engensis 
Study Phase:
3
Short Title: 
Phase 3 Study to Assess Safety and Efficacy of Engensis in Painful 
Diabetic Peripheral Neuropathy
Acronym:
REGAiN-1A
DISCLOSURE STATEMENT
This study will be conducted in compliance with the protocol, US Code of Federal Regulations 
applicable to clinical studies, principles of ICH Good Clinical Practice, the Declaration of 
Helsinki, and all applicable regulatory requirements. This protocol is the confidential 
information of Helixmith and is intended solely for the guidance of the clinical investigation. 
This protocol may not be disclosed to parties not associated with the clinical investigation or 
used for any purpose without the prior written consent of Helixmith.

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Table of Contents
1.
Protocol Summary....................................................................................................10
Synopsis.....................................................................................................................10
Study Schema.............................................................................................................15
Schedule of Activities (SoA) ......................................................................................16
2.
INTRODUCTION ....................................................................................................22
Study Rationale ..........................................................................................................22
Background ................................................................................................................23
2.2.1.
Pathophysiology of Diabetic Peripheral Neuropathy ...................................................23
2.2.2.
Current Treatment Options .........................................................................................25
2.2.3.
Unmet Clinical Need ..................................................................................................26
2.2.4.
Hepatocyte Growth Factor for the Treatment of Diabetic
Neuropathy.................................................................................................................26
2.2.5.
Engensis .....................................................................................................................27
2.2.6.
Nonclinical Data.........................................................................................................28
2.2.7.
Clinical Data...............................................................................................................28
Benefit/Risk Assessment ............................................................................................29
2.3.1.
Risk Assessment.........................................................................................................29
2.3.2.
Benefit Assessment.....................................................................................................32
2.3.3.
Overall Benefit/Risk Conclusions ...............................................................................32
3.
OBJECTIVES AND ENDPOINTS..........................................................................33
4.
STUDY DESIGN ......................................................................................................36
Overall Design............................................................................................................36
4.1.1.
First Treatment Cycle .................................................................................................36
4.1.2.
Second Treatment Cycle .............................................................................................37
Scientific Rationale for Study Design .........................................................................37
Participant Input into Design ......................................................................................38
Justification for Dose..................................................................................................38
End of Study Definition..............................................................................................38
Study Completion.......................................................................................................38
Completed Participants...............................................................................................38
5.
STUDY POPULATION ...........................................................................................39
Inclusion Criteria........................................................................................................39

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Exclusion Criteria.......................................................................................................39
Number of Participants...............................................................................................42
Enrollment, Randomization, and Treatment Assignment.............................................42
5.4.1.
Enrollment Adjudication Process................................................................................42
Participant Identification.............................................................................................44
Screen Failures ...........................................................................................................44
Rescreening................................................................................................................44
Lifestyle Considerations .............................................................................................44
5.8.1.
Meals and Dietary Restrictions ...................................................................................44
5.8.2.
Caffeine, Alcohol, and Tobacco..................................................................................45
5.8.3.
Supplements ...............................................................................................................45
5.8.4.
Activity ......................................................................................................................45
6.
STUDY INTERVENTION.......................................................................................46
Study Intervention(s) Administered ............................................................................46
6.1.1.
Engensis .....................................................................................................................46
6.1.2.
Placebo.......................................................................................................................46
6.1.3.
Summary of Study Intervention Characteristics...........................................................47
Preparation/Handling/Storage/Accountability .............................................................47
6.2.1.
Engensis Preparation ..................................................................................................47
6.2.2.
Storage of Engensis and Placebo.................................................................................47
6.2.3.
Product Accountability ...............................................................................................48
Measures to Minimize Bias.........................................................................................48
6.3.1.
Randomization............................................................................................................48
6.3.2.
Stratification...............................................................................................................48
6.3.3.
Blinding......................................................................................................................49
6.3.4.
Maintenance of the Blind............................................................................................49
Study Intervention Compliance...................................................................................50
Concomitant Therapy .................................................................................................50
6.5.1.
Rescue Medicine ........................................................................................................50
Dose Interruption........................................................................................................50
Prohibited and Restricted Medications and Procedures ...............................................51
6.7.1.
Medications That May Interfere with Engensis Bioactivity .........................................51

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6.7.2.
Medications and Procedures That May Interfere with Assessment 
of Pain........................................................................................................................51
Prior and Concomitant Medications, Treatments, and Procedures ...............................51
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION ..................................................................53
Discontinuation of Study Intervention ........................................................................53
Participant Discontinuation/Withdrawal/Early Termination from 
the Study ....................................................................................................................53
Lost to Follow-up .......................................................................................................54
8.
STUDY ASSESSMENTS AND PROCEDURES.....................................................55
Screening Activities....................................................................................................55
8.1.1.
Screening Days -52 to -7.............................................................................................55
8.1.2.
Screening Days (-7 to 0) .............................................................................................57
Participant Training ....................................................................................................57
8.2.1.
Accurate Pain Reporting.............................................................................................57
8.2.2.
Placebo Response Reduction ......................................................................................57
Efficacy Assessment and Procedures ..........................................................................57
8.3.1.
Brief Pain Inventory for Diabetic Painful Neuropathy.................................................57
8.3.2.
Quality of Life/Participant Reported Outcome Measures ............................................58
8.3.3.
Bedside Sensory Testing.............................................................................................59
8.3.4.
Michigan Neuropathy Screening Instrument ...............................................................59
Safety Assessments ....................................................................................................60
8.4.1.
Physical Examinations................................................................................................60
8.4.2.
Medical History and Familial History of Cancer .........................................................60
8.4.3.
12-Lead Electrocardiograms .......................................................................................60
8.4.4.
Ultrasound of Right and Left Lower Legs...................................................................61
8.4.5.
Vital Signs..................................................................................................................61
8.4.6.
Clinical Laboratory Assessments ................................................................................61
8.4.7.
Retinal Fundoscopy....................................................................................................63
Adverse Events and Serious Adverse Events ..............................................................64
8.5.1.
Time Period and Frequency for Collecting AE, TEAE, SAE, and 
TESAE Information....................................................................................................64
8.5.2.
Method of Reporting AEs, TEAEs, SAEs, TESAEs, and AESIs .................................64
8.5.3.
SAE Reporting to the Sponsor or Designee.................................................................64

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8.5.4.
Adverse Events of Special Interest..............................................................................65
8.5.5.
Follow-up of AEs/TEAEs, SAEs/TESAEs, and AESIs...............................................67
8.5.6.
Regulatory Reporting Requirements for SAEs/TESAEs..............................................67
8.5.7.
Pregnancy and Contraception......................................................................................68
8.5.8.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs.........................................................................................69
Immunogenicity Assessments.....................................................................................69
9.
STATISTICAL CONSIDERATIONS.....................................................................70
Sample Size Determination.........................................................................................70
Populations for Analyses ............................................................................................70
9.2.1.
Intent-To-Treat Population .........................................................................................70
9.2.2.
Safety Population........................................................................................................70
9.2.3.
Modified Intent-to-Treat Population ...........................................................................70
9.2.4.
Per Protocol (PP) Population.......................................................................................71
Statistical Analyses.....................................................................................................71
9.3.1.
Primary Endpoint(s)....................................................................................................71
9.3.2.
Secondary Endpoints ..................................................................................................71
9.3.3.
Exploratory Efficacy Endpoints ..................................................................................72
9.3.4.
Safety Analyses ..........................................................................................................72
9.3.5.
Interim Analysis .........................................................................................................72
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS................................................................................................74
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................74
10.1.1.
Regulatory and Ethical Considerations........................................................................74
10.1.2.
Financial Disclosure ...................................................................................................75
10.1.3.
Participant Selection and Informed Consent Process...................................................76
10.1.4.
Data Protection and Confidentiality ............................................................................76
10.1.5.
Committee Structure...................................................................................................78
10.1.6.
Data Quality Assurance ..............................................................................................79
10.1.7.
Data Management.......................................................................................................82
10.1.8.
Recordkeeping and Retention .....................................................................................82
10.1.9.
Study and Site Start and Closure.................................................................................84
10.1.10. Publication Policy.......................................................................................................84

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10.1.11. Insurance ....................................................................................................................84
Appendix 2. Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................85
10.2.1.
Definition of AE.........................................................................................................85
10.2.2.
Definition of TEAE ....................................................................................................86
10.2.3.
Definition of SAE/TESAE..........................................................................................86
10.2.4.
Recording and Follow-Up of AE/TEAE and/or SAE/TESAE .....................................87
10.2.5.
Reporting of SAEs/TESAEs .......................................................................................89
Appendix 3. Grading of Injection Site Reactions.........................................................90
Appendix 4. Prohibited Medications and Procedures ..................................................91
Appendix 5. Abbreviations and Definitions ................................................................92
10.5.1.
Abbreviations .............................................................................................................92
10.5.2.
Definitions..................................................................................................................96
Appendix 6. Hospital Anxiety and Depression Scale (HADS).....................................98
Appendix 7. Brief Pain Inventory for Participants with Diabetic 
Peripheral Neuropathy (BPI-DPN)............................................................................100
Appendix 8. Patient Global Impression of Change....................................................102
Appendix 9. Short Form Health Survey (SF-36) Example.........................................103
Appendix 10. EuroQol Health Utilities Index (EQ-5D).............................................108
Appendix 11. Bedside Sensory Testing (BST) ..........................................................111
Appendix 12. Michigan Neuropathy Screening Instrument .......................................114
Appendix 13. Protocol Amendment History..............................................................118
11.
REFERENCES .......................................................................................................125

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List of Tables
Table 1
Potential Risks of Clinical Significance ..........................................................29
Table 2
Injection and Dosing Schedule - First Treatment Cycle: Days 0 and 14...........36
Table 3
Injection and Dosing Schedule – Second Treatment Cycle: Days 90 and 104..37
Table 4
Components of Engensis.................................................................................46
Table 5
Components of the Placebo.............................................................................46
Table 6
Injection Site Reaction Grading ......................................................................90
Table 7
Prohibited Medications – Steroids ..................................................................91
Table 8
Prohibited Medications and Procedures – Opioids and Other Therapies..........91
List of Figures
Figure 1
The Neurodestructive Effects of Hyperglycemia.............................................24
Figure 2
VM202 Construct...........................................................................................27
Figure 3
Randomization Process...................................................................................43

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1.
Protocol Summary
The following sections present an overview of the study, the study schema, and the schedule of 
activities. A list of abbreviations is presented in Section 10.5, Appendix 5.
Synopsis
Protocol Title:
An Adaptive, Phase 3, Double-blind, Randomized, Placebo-controlled, 
Multicenter Study to Assess the Safety and Efficacy of Engensis in Participants with Painful 
Diabetic Peripheral Neuropathy
Short Title:
Phase 3 Study to Assess Safety and Efficacy of Engensis in Painful Diabetic 
Peripheral Neuropathy
Rationale:
The purpose of this study is to evaluate the efficacy and safety of intramuscular (IM)
administration of Engensis on pain in Participants with painful diabetic peripheral neuropathy 
(DPN) in the feet and lower legs, as compared to Placebo, as a second Phase 3, well-controlled 
study, sufficient in supporting the efficacy and safety of Engensis.
Engensis contains the active pharmaceutical ingredient VM202, a novel genomic complementary 
deoxyribonucleic acid (cDNA) hybrid human hepatocyte growth factor (HGF) coding sequence 
(HGF-X7) expressing two isoforms of HGF, HGF728 and HGF723, being developed for treatment 
of painful DPN.
Diabetic peripheral neuropathy, by definition, is a bilateral neuropathy. Based on the safety 
profile of Engensis observed in the Phase 1 and Phase 2 critical limb ischemia (CLI) studies and 
the Phase 1/2, 2, and 3 DPN studies in addition to the preliminary efficacy data from the Phase 
1/2 and 2 studies of Engensis injections in Participants with DPN, we propose continued bilateral 
treatment in this Phase 3 study, as treating only one leg may confound patient-reported pain
levels and quality-of-life measures.
Engensis will be tested against Placebo. The total dose of Engensis plasmid DNA to be delivered 
per leg uses the same dosing schedule of administration as was conducted in a Phase 2 and one
Phase 3 DPN study: 16 mg per leg (total of 32 mg) per Participant. As in the prior Phase 3 study
(Protocol VMDN-003), Participants will receive Engensis or Placebo by IM injections in both 
legs (in the calf gastrocnemius muscles) in the first Treatment Cycle on Day 0 and Day 14, 
followed by a second Treatment Cycle on Day 90 and Day 104.

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Objectives
Endpoints

Changes in Michigan Neuropathy 
Screening Instrument (MNSI) assessments 
from Baseline to Day 90 and to Day 180
for Engensis compared to Placebo

Changes in the 36-Item Short Form Health 
Survey (SF-36) from Baseline to Day 90 
and to Day 180 for Engensis compared to 
Placebo

Changes in the EuroQol Health Utilities 
Index (EQ-5D) from Baseline to Day 90 
and to Day 180 for Engensis compared to 
Placebo

Changes in the means of the daily use of 
rescue medication from Day 0 to Day 90, 
from Day 0 to Day 180, and from Day 90 
to Day 180 for Engensis compared to 
Placebo
Overall Design
VMDN-003-2 is an adaptive Phase 3, double-blind, randomized, placebo-controlled, multicenter 
study designed to assess the efficacy and safety of Engensis (containing the active 
pharmaceutical ingredient VM202) in Participants with painful DPN. 
Following completion of the informed consent process, Screening activities (during 45 days
[from Day -52 to Day -7] prior to Day 0) will determine which Participants meet all-but-one 
eligibility criteria, which are assessed by an adjudication procedure, followed by completion of a 
7-day eDiary prior to Day 0. Eligible participants will be enrolled and randomly assigned in a 
double-blind fashion and in a 1:1 ratio on Day 0 to either Engensis or Placebo.
During Screening, medical history and familial cancer history, demographics, vital signs, height, 
body mass index (BMI), waist size, physical examination, retinal fundoscopy (by an 
ophthalmologist or experienced optometrist), 12-lead electrocardiogram (ECG), ultrasound of 
the right and left gastrocnemius muscles (to guide IM Study Injections), laboratory assessments, 
estimated glomerular filtration rate (eGFR), HBA1c levels, viral screening, a record of all 
concomitant medications and procedures, urine drug analysis, and urine pregnancy test for 
females of childbearing potential will be conducted. 
In addition, the following procedures will be conducted during Screening: Hospital Anxiety and 
Depression Scale (HADS), Accurate Pain Reporting (APR) and Placebo Response Reduction 
(PRR), Michigan Neuropathy Screening Instrument (MNSI), and cancer screening tests.
During 7 days before Day 0 and randomization, Participants must complete the full Brief Pain 
Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) on an electronic diary (eDiary) for 
determining the Average Daily Pain Scores (ADPSs) for at least 5 out of the 7 days. Adverse 
event (AE) assessments will start upon completion of the consent process at the start of 
Screening.

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At any time prior to dosing on Day 0, Bedside Sensory Testing (BST) should be administered. 
Following randomization, and prior to the first IM injections of Engensis or Placebo on Day 0, 
the partial BPI-DPN, and quality of life instruments will be completed. Blood will be collected 
for testing of selected cytokines, anti-HGF antibodies, and laboratory assessments.
All Participants will receive sixteen (16) 0.5-mL IM injections of Engensis or Placebo in each 
calf gastrocnemius muscle at each of two Visits during two Treatment Cycles: Treatment Cycle 1 
on Day 0 and Day 14, and Treatment Cycle 2 on Day 90 and Day 104. At 2 hours (± 1 hour)
after completion of IM injections of Engensis or Placebo on Days 0 and 14 and Days 90 and 104, 
vital signs and blood draw for cytokine levels will be performed.
Treatment-emergent adverse event (TEAE) assessment, including injection site reactions, will 
start as of randomization (Day 0) and continue throughout the study.
Follow-up Study Visits will be conducted on Days 28, 60, 150, and 180 or early termination 
(ET). Vital signs will be recorded at all Study Visits. At the Day 180 Visit (end of study), the 
following assessments will be conducted: the full BPI-DPN (performed for 7 days prior to the 
Day 180 Visit), MNSI, BST, Patient Global Impression of Change (PGIC), and the quality of life 
assessments (36-item Short Form Health Survey [SF-36] and EuroQol Health Utilities Index
[EQ-5D]), urine drug analysis, urine pregnancy status (females only), retinal fundoscopy, 
physical examination, concomitant medications and procedures, and anti-HGF antibodies. Blood 
will be drawn for determination of serum chemistry, lipid profile, hematology, and HbA1c
levels.
The purpose of this study is to assess the efficacy and safety of Engensis compared to Placebo as 
measured by changes in the means of the Average Daily Pain Scores (ADPSs) of the BPI-DPN, 
selected blood cytokines, BST, and assessments of injection site reactions, physical examination, 
laboratory assessments, vital signs, TEAEs, and treatment-emergent serious adverse events 
(TESAEs).
Study and Treatment Duration:
Screening will occur up to 52 days prior to Baseline (Day 0) and Participants will be followed 
from Day 0, the day of first Study Injections, to Day 180/ET.
Visit Frequency:
Consented Participants will be seen and evaluated for enrollment during Screening (up to 
52 days prior to Baseline, Day 0). There are 8 visits to the Clinical Site during the study from 
Day 0 to Day 180 for Study Injections and follow-up.
Intervention Groups and Duration:
Two treatment groups of Participants (Engensis or Placebo) will be in the study for 180 days.
Number of Participants (N = 152 to approximately 250):
The target sample size is a minimum of 152 Participants and the maximum sample size is 
250 Participants based on the proposed adaptive design analysis. The final sample size of 
Participants to be enrolled and evaluated will be determined by the independent Data Monitoring 
Committee (DMC). An interim analysis will be conducted after approximately 50% of 
Participants in the target sample (i.e., 76 Participants) have completed the primary efficacy 
endpoint at Day 180 or have withdrawn prematurely. The DMC will make a recommendation 
based on an unblinded (comparative) power analysis.

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Data Safety Monitoring Board:
The independent DSMB will periodically review a limited set of unblinded (noncomparative) 
tables and/or listings, including all reported AEs, TEAEs, AESIs, SAEs, and TESAEs. 
Study Schema

 
 
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4.
Vital Signs and Weight: Vital signs will be measured at Screening, pre- and 2 hours (± 1 hour) post-dose at Study Injection Visits during Treatment Cycle 1 
(Days 0 and 14) and Treatment Cycle 2 (Days 90 and 104), and at all other Study Visits (Days 28, 60, 150, and 180 or Early Termination). After the Participant
has rested in the seated position for 5 minutes, vital signs will be collected, including temperature, sitting blood pressure, heart rate, respiratory rate, and oxygen 
saturation on room air. The method of temperature measurement should be according to the Site’s policy and should be consistently applied. Weight will be 
collected pre-dose at Study Injection Visits (Days 0, 14, 90, and 104).
5.
Height, Body Mass Index (BMI), and Waist Size will be collected only at Screening.
6.
Complete Physical Examinations will be performed at Screening, and pre-dose on Day 0, 14, 90, and 104, and on Days 28, 60, 150, and 180; and at the last 
Visit if the Participant discontinues prior to Day 180. The examination will include the following: head, eyes, ears, nose, and throat (HEENT); heart; lungs; 
abdomen; extremities; lymph nodes; neurological; and skin/integumentary systems. Any abnormalities should be categorized as clinically significant (CS) or not 
clinically significant (NCS), and the CS abnormalities should be recorded as adverse events using appropriate medical terminology, except at Screening. 
7.
Cancer Screening Tests will include the following (note that past history refers to years before Screening):

Mammogram for breast cancer for female Participants aged 45 to 54 years, if not performed within the past 12 months; or if not performed within the past 
24 months for female Participants aged ≥ 55 years. If the mammogram results are negative for cancer, the Participant will be allowed to enter the study.

Primary human papillomavirus (HPV) test for cervical cancer for female Participants aged 25 to 65 years, if not performed within the past 5 years; if 
primary HPV test is not available, an HPV test in combination with cytology (PAP) if not performed within the last 5 years, or cytology (PAP) alone if 
not performed within the past 3 years. If the test results are negative for cervical cancer, the Participant will be allowed to enter the study.

Fecal immunochemical test (FIT) stool test for colon cancer for Participants (male or female) aged ≥45 years and ≤75 years, if not performed within the 
past 12 months; or a colonoscopy (in lieu of an FIT stool test) if not performed within the past 5 years. If the test results are negative for colon cancer, the 
Participant will be allowed to enter the study. Participants aged ≥76 years will not be required to undergo colon cancer screening.

Low-dose chest computed tomography (CT) scan for lung cancer for current or previous smokers (male or female) who:
o
Are ≥ 50 years of age, are currently smoking, have a ≥ 30 pack-year history of smoking, and have not had a CT scan performed within the past 
12 months
o
Are ≥ 50 years of age, quit smoking but have smoked within the past 15 years, and have a ≥30 pack-year history.
If the test results are negative for lung cancer, the Participant will be allowed to enter the study.

Prostate-specific antigen (PSA) test for prostate cancer, if not performed within the past 12 months, for male Participants who are African-American aged 
≥45 years or other races aged ≥50 years. If the test results are negative for prostate cancer, the Participant will be allowed to enter the study.
8.
Retinal Fundoscopy will be performed by an ophthalmologist or optometrist at Screening, up to 45 days before the Day 90 Visit (pre-dose), and up to 30 days
before the Day 180 Visit (and, if possible, upon Early Termination if the Participant discontinues after the Day 90 Visit). If the retinal fundoscopy results at 
Screening are deemed insufficient to determine eligibility, fluorescein angiography may need to be performed. Results of the fundoscopy examinations at Days 
90 and 180 compared to results at Screening will be assessed by theInvestigator.
9.
12-Lead Electrocardiogram (ECG) will be performed at Screening, pre-dose on Day 90, and on Day 180. Any clinically significant findings at Screening will 
recorded as part of medical history. Clinically significant abnormalities are to be recorded as adverse events, except at Screening. The ECG recording and 
interpretation will be printed out and stored with the Participant’s records.

 
 
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10. Ultrasound of the right and left gastrocnemius muscles of the calf will be used to measure the depth to the muscles and width of the muscles at Screening in 
preparation for the IM injections of the study drug.
11. Serum Chemistry, Hematology, and Lipid Profile: These laboratory assessments will be evaluated at Screening to establish eligibility and baseline
measurements for comparison with assessments on Days 0, 90, and 180.

Chemistry includes sodium, potassium, chloride, bicarbonate, calcium, inorganic phosphate, magnesium, glucose, amylase, lipase, creatine kinase, 
lactate dehydrogenase, and
o
Kidney function tests (blood urea nitrogen, creatinine)
o
Liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, gamma-glutamyl transpeptidase 
[GGT], total bilirubin, total protein, and albumin)
o
Cystatin C (at Screening to calculate eGFR)

Hematology includes platelet count, hemoglobin, hematocrit, white blood cell count, and neutrophil count

Lipid Profile includes total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides
12. Estimated Glomerular Filtration Rate (eGFR) will be calculated only at Screening using the chronic kidney disease epidemiology collaboration (CKD-EPI)
formula based on Cystatin C levels.
13. Urine Pregnancy Test: Women of childbearing potential must have negative urine pregnancy tests at Screening, on Day 0, Day 90, and Day 180/ET.
14. Urine Drug Analysis includes amphetamines (methamphetamine), barbiturates, benzodiazepines, buprenorphine, cannabinoid (THC), cocaine, oxycodone,
methadone, opiates, phencyclidine (PCP), tricyclics (TCA), and ethyl alcohol. Cannabinoid detection is not an exclusion criterion but may be used in 
exploratory analyses. The urine drug analyses will be conducted at Screening, pre-dose on Days 0, 14, 90, and 104 and on Days 28, 60, 150, and Day 180. An 
ethyl alcohol saliva analysis will be used at Screening. Drug analyses will be performed by the central laboratory at all other time points.
15. HbA1c levels will be measured at Screening, on Day 90, and on Day 180.
16. Viral Screening is to be conducted at Screening and includes tests for human immunodeficiency virus (HIV), human T cell lymphotropic virus (HTLV) I/II 
antibody with reflex confirmatory assay, hepatitis B virus (HBV: IgM HBcAb, HBsAb, HBsAg, and a quantitative HBV if needed clinically), and anti-hepatitis 
C virus (HCV) antibodies and a positive qualitative PCR if needed clinically. Testing will be performed at a local laboratory. All tests for HIV, HTLV, HBV, 
and HCV must be completed and negative prior to randomization.
17. Hospital Anxiety and Depression Scale (HADS) will be completed at Screening.
18-19.
Concomitant Medications and Procedures: Record all medications or vaccines, including over-the-counter or prescription medicines, vitamins, herbal 
supplements and procedures that the Participant was receiving during 30 days prior to completion of the informed consent process, pre-dose on Days 0, 14, 90, 
and 104, and on Days 28, 60, 150, and 180/ET. For each medication, treatment, or procedure the following information will be collected: medication trade or 
generic name or type of procedure, indication, start date, stop date or ongoing, dose, units, frequency, and route.
20. Adjudication: The Adjudication Committee, composed of the Sponsor Medical Director, Medical Monitor, and Clinical Operations personnel, reviews the 
relevant clinical information of each Participant on a timely basis to ensure strict adherence to the Inclusion/Exclusion Criteria. The Committee either confirms 
the eligibility for randomization of an individual Participant or confers with the Investigator regarding the status of a Participant as a screen failure
21. Randomization: Completion of Screening activities, randomization, and first Study Injections (Treatment Cycle 1, Day 0) will occur on the same day (Day 0).
22. Study Injections – IM injections of Engensis or Placebo to the right and left gastrocnemius muscles will administered during the First Treatment Cycle (1st and 
2nd Study Injections on Days 0 and 14) and the Second Treatment Cycle (3rd and 4th Study Injections on Days 90 and 104). The Investigator or designee must 
follow up with a telephone call to the Participant within 2 to 3 days after Study Injections to ask the Participant about any reactions at any injection sites.

 
 
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23. Accurate Pain Reporting (APR): The Accurate Pain Reporting training will be conducted at Screening, pre-dose on Day 0, Day 14, Day 90, and Day 104, and 
on Days 28, 60, 150, and 180/ET.
Placebo Response Reduction (PRR): The Placebo Response Reduction training will be conducted at Screening, pre-dose on Day 0, Day 14, Day 90, and Day 
104, and on Days 28, 60, 150, and 180/ET.
24. Brief Pain Inventory (BPI-DPN) – Full Questionnaire: will be administered through the eDiary daily starting 7 days prior to the Day 0 (note: this starts after
adjudication), and for 7 days prior to the Day 90 and Day 180 Visits. If the eDiary contains fewer than 5 daily entries over the 7 days prior to Day 0 and 
Day 180, the Visit must be rescheduled (up to 3 days later) so that the Participant can record 5 daily entries over the 7 days.
25. Brief Pain Inventory (BPI) – Partial Questionnaire (questions 3, 5, and 9a from the full questionnaire) will be completed on the eDiary every day that the full 
BPI is not conducted, after randomization on Day 0 up to the Day 180 Visit.
26. Quality of Life (SF-36, EQ-5D) Questionnaires will be administered pre-dose on Days 0 and 90, and on Day 180/ET. The study coordinator will check the 
questionnaires for completeness. Any omissions or ambiguous answers will be clarified by the Participant prior to leaving the clinic.
27. Patient Global Impression of Change (PGIC) will be administered pre-dose on Day 90 and on Day 180/ET.
28. Adverse Events (AEs) and Treatment-Emergent Adverse Events (TEAEs): AEs will be recorded after informed consent until the first injections on Day 0. 
After the start of the 1st Injections on Day 0 through Day 180, AEs will be recorded as treatment-emergent adverse events (TEAEs). Adverse events that are 
serious (SAEs) occurring after randomization and throughout the study will be recorded. SAEs occurring after the completion of the consent process and before 
the 1st Injections on Day 0 should be recorded and reported only if associated with a protocol-specified procedure. All SAEs occurring after the time of the 1st 
Injections through the last Study Visit on Day 180 should be recorded and reported to the Sponsor within 24 hours of awareness of the SAE by the Site.
29. Adverse Events of Special Interest (AESIs): All AESIs will be continuously monitored throughout the study. Injection Site Reactions must be initially 
assessed immediately after all injections at an Injection Visit, followed up by the Investigator or designee with a documented telephone call to the Participant
within 2 to 3 days after Study Injections to ask the Participant about any reactions at any injection sites, and if any, the worst reaction will be recorded as a 
TEAE. Severe (Grade 3) and potentially life-threatening (Grade 4) Injection Site Reactions will be considered an AESI.
30. Cytokine Levels will be measured in blood samples collected pre- and post-dose (after 2 hours ± 1 hour post last injection) on Days 0 and 14, post-dose on 
Day 90, and pre- and post-dose on Day 104 for levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interferon gamma (IFN-γ), and 
interleukins IL-6, IL-4, IL-10, and IL-12p70 analyzed at a central laboratory.
31. Anti-Hepatocyte Growth Factor (HGF) Antibodies: Blood samples will be collected pre-dose on Days 0 and 90, and on Days 60, 150, and 180/ET for 
detection of anti-HGFantibodies.
32. Michigan Neuropathy Screening Instrument (MNSI) will be administered at Screening to determine the baseline Physical Assessment score and assess 
eligibility, and pre-dose on Day 90 and on Day 180/ET for assessing disease progression during the study.
33. Bedside Sensory Testing (BST) will be administered on Day 0 at any time prior to dosing to provide information that may be of value in training the 
Participants on how to more accurately report their pain, and then pre-dose on Day 90, and on Day 180/ET to provide additional information that will allow 
exploratory analysis of BST sensoryprofiles.

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As in all prior/ongoing studies, Engensis will be delivered as a solution containing 0.5 mg/mL of 
VM202. Participants will be treated with an overall final dose of 32 mg Engensis or Placebo, 
dosages well within those supported by the body of pharmacology and toxicology safety studies 
of Engensis.
Background
2.2.1. Pathophysiology of Diabetic Peripheral Neuropathy
Diabetic peripheral neuropathy (DPN) is a bilateral, particularly debilitating complication of 
diabetes characterized by pain that is burning, lancinating, tingling, or shooting (electric 
shock-like), occurring with paresthesia, and is typically worse at night. 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. Diabetic peripheral neuropathy accounts for significant morbidity by predisposing 
the foot to ulceration and lower extremity amputation.
Diabetic peripheral neuropathy manifests as three broad categories: sensory, motor, and 
autonomic, with the most prevalent form being somatic or sensorimotor neuropathy. Symptoms 
(e.g., burning, tingling, stabbing, or pins-and-needles) often exhibit a distal symmetric pattern, 
beginning at the base of the toes and ascending proximally up the lower leg as the disease 
progresses. 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.
The sequence of physiological events that result in DPN is poorly understood. The pathogenesis 
of diabetic neuropathy likely involves the interplay of hyperglycemia, ischemia, and oxidative 
stress. Figure 1 portrays the relationship of hyperglycemia to oxidative stress, metabolic 
alterations, vascular dysfunction, and neural damage.

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Oxidative Stress. Glucose can cause significant oxidative stress and damage when present in 
excess. Under physiological conditions, aerobic respiration is associated with the formation of a 
small number of free radicals or 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.2,3 The flood of excess 
glucose into endothelial cells is shunted into alternate metabolic pathways (e.g., polyol pathway, 
glycosylation, hexosamine pathway, the diacylglycerol activation of protein kinase C [PKC]). 
These pathways, particularly PKC, produce significantly larger amounts of ROS than aerobic 
respiration, overwhelming compensatory antioxidant mechanisms.4,5,6,7,8,9,10,11 The resulting 
hyperglycemic oxidative stress contributes to endothelial dysfunction by inhibiting endothelial 
nitric oxide production and by initiating and promoting the deposition of modified lipids in the 
subendothelium. These factors accelerate atherosclerotic macrovascular disease and are 
associated with the development of apoptosis in neurons and supporting glial cells.12
Vascular Damage. Nerve 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.
2.2.2. Current Treatment Options
Currently no approved drugs or interventional strategies are 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.
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. The consequences of DPN can be ameliorated by the 
education of patients and their care providers as to foot care, proper footwear and of 
hyposensitive areas and pressure points, all to prevent the occurrence of ulcers and to lower the 
risk of infection of soft tissue and bone.13
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.
Four drugs have been approved by the Food and Drug Administration (FDA) specifically for the 
treatment of the symptoms of DPN: Nucynta ER (tapentadol), an opioid medication; Cymbalta 
(duloxetine), a serotonin and norepinephrine reuptake inhibitor;  Lyrica (pregabalin), an
anticonvulsant drug; and Qutenza (capsaicin), a transdermal patch. All are prescribed for the 
management of pain associated with DPN.
See the IB for presentation of guidelines issued by international organizations for the use of
agents to treat DPN.
Another treatment option is α-lipoic acid, a naturally occurring antioxidant compound found in 
spinach and broccoli. α-Lipoic acid was recently studied in a multicenter, placebo-controlled 

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study of Participants with type 2 diabetes and symptomatic neuropathy. One hundred eighty-one
(181) Participants were given daily oral doses of 600, 1200, or 1800 mg of α-lipoic acid or 
placebo. After 5 weeks, neuropathic symptoms improved in those Participants who received 
α-lipoic acid. The 600-mg dose appeared to provide the optimum risk-to-benefit ratio.14
There are also invasive treatment options. One option is surgical decompression of the 
lower-extremity peripheral nerves in patients with DPN but this is still considered an 
experimental intervention (see IB for details). Pancreatic transplantation in patients with diabetes 
can stabilize neuropathy and, in some instances, improve motor, sensory, and autonomic 
function.
Other treatments include off-label use of several drugs and devices. Drugs commonlyprescribed 
to manage pain symptoms include tricyclic antidepressants (TCAs), selective serotonin reuptake 
inhibitors (SSRIs), and serotonin–norepinephrine reuptake inhibitors (SNRIs). Other treatment 
strategies such as acupuncture, transcutaneous electrical nerve stimulation (TENS), capsaicin 
patches and creams, topical anesthetics, and isosorbide dinitrate (ISDN) spray may also be used. 
Each of these can alleviate some of the pain symptoms. None demonstrate any ability to improve 
the underlying neuropathy.
2.2.3. Unmet Clinical Need
Diabetic peripheral neuropathy is a serious complication of diabetes mellitus (DM), with painful 
DPN being a frequent manifestation of neuropathy. Tight glycemic control and treatment of 
cardiovascular risk factors are effective preventive measures, but DPN remains the most 
common complication of DM, affecting 60% to 70% of diabetics. Progressive DPN may result in 
loss of function in affected legs, infection, and amputation.
Current treatments provide symptomatic relief of the pain associated with DPN. A clear unmet 
medical need exists for treatments that address the underlying pathology of DPN and prevent the 
progressive destruction and loss of function associated with this disease.
2.2.4. Hepatocyte Growth Factor for the Treatment of Diabetic Neuropathy
Hepatocyte growth factor (HGF) is a multifunctional protein with highly potent angiogenic and 
neurotrophic properties produced by various cell types of mesenchymal origin such as 
fibroblasts, macrophages, and stromal cells.15,16,17,18,19 Its biological function is mediated by its 
receptor c-Met, which is a member of the receptor tyrosine kinase family. In the peripheral 
nervous system and its associated tissues, c-Met is expressed in sensory neurons, Schwann cells, 
endothelial cells, and smooth muscle cells among others,20,21 which all play important roles in the 
functions of the peripheral nerve and its regeneration after pathological insults. Indeed, HGF has 
been reported to act on sensory and motor neurons to enhance their survivability and neurite 
outgrowth, and also produces a neuroprotective effect in injured sensory neurons.22,23,24,25,26
Local application of exogenous HGF has been shown to promote the growth of sympathetic 
neurons,27,28,29,30,31,32 and to induce the formation of collateral vessels and increased blood flow 
both in rat diabetic and non-diabetic models.33
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 in rodent blood of less than 15 minutes.34 One approach to maintaining a 

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2.2.6. Nonclinical Data
Collectively, VM202 has been well tolerated in all nonclinical 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 per leg (0.11 mg/kg for a 70-kg person). No evidence of 
systemic toxicity has been seen in any study, and human HGF has not been detected in the sera 
of rats or rabbits following IM injection. No evidence of genomic integration, potential germ cell 
transmission, or immunostimulatory effects was found following IM administration of VM202 to 
animals. Refer to the IB for additional details.
2.2.7. Clinical Data
Engensis has been or is being evaluated in 10 clinical studies in the USA and/or Korea. These 
include two studies (Phases 1 and 2) in critical limb ischemia (CLI), one study in peripheral 
artery disease (Phase 2), one study in coronary artery disease (Phase 1), four studies (one 
Phase 1/2, one Phase 2, and one Phase 3 and one Phase 3 extension) in Participants with painful 
DPN, a study (Phase 1/2) in amyotrophic lateral sclerosis (ALS), and one (Phase 3) study in 
diabetic Participants with chronic nonhealing foot ulcers (NHU). Engensis was well tolerated, 
the most frequent reaction being pain at injection sites in 1 to 4% of Participants, which was 
similar to that observed in the Placebo groups. 
2.2.7.1.
Phase 1 and 2 Studies with Engensis
Phase 1 and 2 clinical studies of Engensis have been completed in patients with CLI, DPN, and
ALS. Efficacy has been demonstrated in each of the indications studied to date. In a Phase 1
study using Engensis as an adjunct therapy to coronary artery bypass grafting (CABG) in 
Participants with ischemic heart disease (IHD), Engensis showed an improvement in regional 
myocardial perfusion and wall thickness in the area injected with Engensis. In CLI Participants, 
significant improvements were seen in wound healing, skin perfusion, and pain reduction after 
administration of Engensis. Significant improvements in pain were detected in Participants with 
painful DPN treated with Engensis compared to placebo. In ALS Participants, significant 
improvement was seen using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale 
(ALSFRS-R). See the IB for more information.
2.2.7.2.
Phase 3 Study and Extension in Participants with Painful DPN
Helixmith conducted a Phase 3, double-blind, randomized, placebo-controlled, multicenter study 
(VMDN-003) designed to assess the safety and efficacy of Engensis in Participants with painful 
DPN. The study enrolled Participants with DPN with significant pain at study entry (VAS score 
≥4 cm). A total of 507 Participants were randomized (7 were removed due to ineligibility) in a 
2:1 ratio to a final dose of 32 mg Engensis or to Placebo. DPN was verified symptomatically 
using the MNSI, and the Brief Peripheral Neuropathy Screening (BPNS) was used to confirm 
bilateral involvement. See the IB for more information.

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
adenocarcinoma (categorized as possibly related to the study drug by the investigator 
and not related to the study drug by Helixmith)
2.3.2. Benefit Assessment
Diabetic peripheral neuropathy is one of the most-commonly encountered neuropathic pain 
syndromes and affects nearly half of diabetic patients. Through its effects on somatic or 
sensorimotor neurons, disabling consequences on function and quality of life predominate that 
include sleep disturbances, dependence on narcotic analgesics for pain, and trauma and infection 
from sensory impairment.
Engensis induces relatively rapid and prolonged production of HGF, which, through its multiple 
mechanisms of actions on microvascular and neural repair, has the potential to improve 
outcomes in diabetic patients, as suggested by preceding studies.
2.3.3. Overall Benefit/Risk Conclusions
The overall profile of potential benefits and apparent safety for Engensis provide sufficient 
support to justify the conduct of the present study in its aim to meet the unmet needs of DPN 
patients.

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Objectives
Endpoints

Changes in Michigan Neuropathy 
Screening Instrument (MNSI) assessments 
from Baseline to Day 90 and to Day 180
for Engensis compared to Placebo

Changes in the 36-Item Short Form Health 
Survey (SF-36) from Baseline to Day 90 
and to Day 180 for Engensis compared to 
Placebo

Changes in the EuroQol Health Utilities 
Index (EQ-5D) from Baseline to Day 90 
and to Day 180 for Engensis compared to 
Placebo

Changes in the means of the daily use of 
rescue medication from Day 0 to Day 90, 
from Day 0 to Day 180, and from Day 90 
to Day 180 for Engensis compared to 
Placebo

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4.
STUDY DESIGN
Overall Design
VMDN-003-2 is an adaptive, Phase 3, double-blind, randomized, placebo-controlled, multicenter
study designed to assess the efficacy and safety of Engensis (containing the active 
pharmaceutical ingredient VM202) in Participants with painful DPN as compared with Placebo. 
Following completion of the ICF process, Screening activities (within -52 to -7 days prior to 
Day 0), followed by an adjudication process will determine Participants who meet all-but-one
eligibility criteria. Completion of a 7-day diary prior to Day 0 completes the eligibility process 
for each Participant. Eligible Participants will be enrolled and randomly assigned in a 
double-blinded fashion and in a 1:1 ratio to either Engensis or Placebo.
Pain, quality of life, cytokine levels, and the presence of anti-HGF antibodies will be assessed 
during the study. 
All Participants will receive sixteen (16) 0.5-mL injections (0.25 mg) of Engensis or Placebo in 
each calf gastrocnemius muscle at each of the two Visits (Days 0 and 14; Day 14 is 13 to 15 days 
after the Day 0 Visit) during the first Treatment Cycle. During the second Treatment Cycle, 
Participants will receive sixteen (16) 0.5-mL IM injections of Engensis or Placebo in each calf 
gastrocnemius muscle on Days 90 and 104 (Day 104 is 13 to 15 days after the Day 90 Visit).
4.1.1. First Treatment Cycle
Prior to the First Treatment Cycle, in addition to vital signs, physical exam, drug tests, and 
medical history, the full BPI-DPN, BST, SF-36, and EQ-5D will be administered, and blood will 
be collected to obtain baseline values of selected cytokines, anti-HGF antibodies, and for safety 
laboratory assessments (see SoA, Section 1.3). A urine pregnancy test will also be conducted on 
women of childbearing potential.
Participants will receive Engensis or Placebo by IM injections in the gastrocnemius muscle on 
both legs on Day 0 and Day 14 as shown in Table 2.
Table 2
Injection and Dosing Schedule - First Treatment Cycle: Days 0 and 14
First Treatment Cycle 1: Day 0
First Treatment Cycle 1: Day 14
Total 
per Treatment Cycle
Gastrocnemius
Right
Left
Right
Left
Number of Injections (Engensisa or Placebo)
1 injection = 0.5 mL
16 injections
16 injections
16 injections
16 injections
64 injections
Engensis (0.5 mg/mL) Dose per Gastrocnemius Muscle
4 mg
4 mg
4 mg
4 mg
8 mg
8 mg
16 mg
a Engensis concentration is 0.5 mg/mL, therefore each injection of Engensis contains 0.25 mg (per 0.5 mL).
All Participants will receive sixteen (16) 0.5-mL injections of Engensis or Placebo in the
gastrocnemius muscle of each leg at each of the two Visits during the First Treatment Cycle.

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Each gastrocnemius muscle will receive a total of 8 mL each Treatment Cycle day. At 
2 hours (± 1 hour) after injection on Day 0 and Day 14, vital signs and blood draws for cytokine 
levels will be performed and adverse events will be assessed according to the SoA in Section 1.3.
4.1.2. Second Treatment Cycle
Prior to the first injection of the second Treatment Cycle, in addition to vital signs, physical 
exam, drug tests, and medical history, the full BPI-DPN, SF-36, EQ-5D, MNSI, BST, and PGIC
will be administered, and blood will be collected to obtain baseline values of selected cytokines, 
anti-HGF antibodies, and for safety laboratory assessments (see SoA in Section 1.3). A urine 
pregnancy test will also be conducted on women of childbearing potential.
Participants will receive Engensis or Placebo by IM injections in the gastrocnemius muscle of 
both legs on Day 90 and Day 104 (13 to 15 days after the Day 90 Visit) as shown in Table 3.
Table 3
Injection and Dosing Schedule – Second Treatment Cycle: Days 90 and 104
Second Treatment Cycle 2: Day 90
Second Treatment Cycle 2: Day 104
Total 
per Treatment Cycle
Gastrocnemius
Right
Left
Right
Left
Number of Injections (Engensisa or Placebo)
1 injection = 0.5 mL
16 injections
16 injections
16 injections
16 injections
64 injections
Engensis (0.5 mg/mL) Dose per Gastrocnemius Muscle
4 mg
4 mg
4 mg
4 mg
8 mg
8 mg
16 mg
a Engensis concentration is 0.5 mg/mL, therefore each injection of Engensis contains 0.25 mg (per 0.5 mL)
All Participants will receive sixteen (16) 0.5-mL injections of Engensis or Placebo in the
gastrocnemius muscle of each leg at each of the two Visits during the Second Treatment Cycle. 
Each gastrocnemius muscle will receive a total of 8 mL each Treatment Cycle day. At 
2 hours (± 1 hour) after injection on Day 90 and Day 104, vital signs and blood draws for 
cytokine levels will be performed and adverse events will be assessed according to the SoA in 
Section 1.3.
Scientific Rationale for Study Design
VMDN-003-2 is designed as a well-controlled Phase 3 study, as it is a double-blind, randomized, 
placebo-controlled, and multicenter study that is sufficiently sized in numbers of Participants to 
evaluate the potential ability of Engensis to reduce neuropathic pain and disability in Participants 
with painful DPN. 
Collection of efficacy data will be conducted via e-Diaries, which will be used to remind 
Participants to record their efficacy data daily and in real time.

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Participant Input into Design
Participant input into the design of this study was not collected, as the same methods were used 
in previous studies with Engensis and did not lead to unacceptable numbers of Participants 
discontinuing the studies. In addition, the methods used to assess pain reduction (BPI-DPN) and 
patient clinical benefit of therapy (PGIC) have been validated and are the tools recommended by 
the regulatory authorities to assess efficacy (pain reduction) and response (clinical benefit) in 
patients with painful DPN.
Justification for Dose
As in all prior studies, Engensis will be delivered as a solution of 0.5 mg/mL VM202. 
Participants will be treated with Engensis to result in an overall final dose of 32 mg Engensis (or 
Placebo) during the study, delivered by IM injections to the gastrocnemius muscles of both legs; 
this dosage is well within those supported by the body of pharmacology and toxicology safety 
studies of Engensis. Safety studies in rabbit, rat, and mouse models demonstrate that doses more 
than 15 times the clinical dose (32 mg) to be used in this study resulted in no toxicities.
The Phase 2 DPN study (VMDN-002) in which a single Treatment Cycle was administered on 
Days 0 and 14 showed significant stable reductions in pain in many Participants in the clinical 
study, but the responder analysis showed that not all Participants achieved maximum possible 
levels of pain relief and justified adding a second set of treatment with Engensis. In the 3-month 
extension (VMDN-003b) of the Phase 3 DPN study in which Engensis had been administered in 
two Treatment Cycles (at Days 0 and 14, and again at Days 90 and 104), the efficacy endpoint of 
pain reduction at 1 year (or approximately 260 days after the final injections) was met, 
supporting the selection of the same dosing regimen for this study.
End of Study Definition
The end of the study is defined as the date on which the last Participant in the study completes 
the Day 180 Visit or is discontinued.
Study Completion
The study will be considered complete upon Sponsor approval of the clinical study report.
Completed Participants
A Participant is considered to have completed the study if the Participant completes the Day 180 
Visit and at least 5 days of the most recent 7 days with electronic diary (eDiary) entries prior to 
the Day 180 Visit.

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5.
STUDY POPULATION
Inclusion Criteria
1.
Male or female Participants age ≥18 years at time of completion of the informed 
consent process
2.
Type 1 or 2 diabetes mellitus (DM) and on current Standards of Medical Care in 
Diabetes – 2020 optimal guideline-directed medical therapy in Participants (including 
vaccine recommendations if possible), AND without unstable diabetes or significant 
medical problems, such as progressive end-organ disease, within 3 months of or during 
Screening, in the judgment of the Investigator
3.
Glycosylated hemoglobin A1c (HbA1c) of ≤10.0% using the first assessment collected 
during Screening
4.
Documented diagnosis of bilateral painful DPN in both lower extremities at least 
6 months prior to Screening
5.
An ADPS ≥4 (standard deviation ≥0.3 and ≤1.5) that is completed during the 7 days 
prior to randomization (Day 0)
6.
The physical examination component of the Michigan Neuropathy Screening 
Instrument (MNSI) score of ≥2.5
7.
If on medication for painful DPN (other than gabapentin or pregabalin), must be on a 
stable dose defined as < 50% change in total dose over 3 months prior to completion of 
informed consent
8.
Male Participants and their female partners must agree to use double-barrier 
contraception during the study or provide proof of postmenopausal state (minimum 
1 year) or surgical sterility
9.
Male Participants must not donate sperm during the study
10.
Female Participants must be nonpregnant, nonlactating, and either postmenopausal for 
at least 1 year, or surgically sterile for at least 3 months, or agree to use double-barrier 
contraception from 28 days prior to randomization and/or their last confirmed 
menstrual period prior to study randomization (whichever is longer) until the end of the 
study
11.
Capable and willing to comply with the requirements and restrictions of the protocol 
and informed consent form
12.
Able to complete all screening activities within 52 days of signing the informed consent 
form
Exclusion Criteria
1.
Other sources of pain that would prevent accurate assessment of DPN pain (e.g., 
thoracic and/or lumbar root proximal neuropathy, mononeuritis multiplex)

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2.
Peripheral neuropathy caused by a condition other than diabetes: e.g., anatomic (sciatic 
nerve compression), systemic (monoclonal gammopathy), metabolic (thyroid disease),
and toxic (alcohol use) neuropathies
3.
Has taken gabapentin or pregabalin during 30 days before completion of informed 
consent process or will take at any time during the study
4.
Progressive or degenerative neurological disorder, such as amyotrophic lateral sclerosis 
(ALS), Alzheimer’s disease, Parkinson’s disease, vascular dementia, multiple sclerosis, 
or other neurological disorders determined by the Investigator to preclude participation
5.
Symptomatic peripheral artery disease (PAD) or PAD requiring revascularization 
and/or that may interfere with the conduct of the study
6.
Vasculitis, such as from Buerger’s or other diseases
7.
Systolic blood pressure >180 mm Hg on tolerable doses of standard antihypertensive 
medications at Screening determined by the Investigator to preclude participation
8.
Hyperlipidemia or dyslipidemia not being treated with an optimal treatment regimen 
that follows the Standards of Care for hyperlipidemic/dyslipidemic patients with DM
9.
Class 3 or 4 heart failure
10.
Symptomatic bradycardia or untreated high degree atrioventricular block
11.
Stroke or cerebrovascular accident or myocardial infarction within 3 months before 
Screening
12.
eGFR < 30 mL/min/1.73 m2 using the chronic kidney disease epidemiology 
collaboration (CKD-EPI) formula based on Cystatin C levels
13.
Progressive renal dysfunction, defined as a decrease in eGFR to chronic kidney disease 
(CKD) Stage 1, 2, or 3 in the past 6 months before Screening
14.
Ophthalmologic conditions pertinent to signs or symptoms of proliferative diabetic 
retinopathy (PDR) or other ocular conditions that preclude standard ophthalmologic 
examination
15.
Myopathy (e.g., Duchenne or Becker muscular dystrophy, polymyositis)
16.
Any prior or planned lower extremity amputation (excluding toe amputations) due to 
diabetic complications or prior lower leg injury (e.g., scarring, muscle atrophy) in the 
calf area (gastrocnemius) that would significantly reduce the surface area of the skin or 
amount of intact skeletal muscle required for the 16 treatment injections of Engensis
17.
Active infection requiring antimicrobial agent(s) (chronic infection or severe active 
infection that may compromise the Participant’s well-being or participation in the 
study, in the Investigator’s judgment)
18.
Chronic inflammatory or autoimmune disease (e.g., Crohn’s disease, rheumatoid 
arthritis)
19.
Immunosuppression due to underlying disease (e.g., rheumatoid arthritis, systemic 
lupus erythematosus) or to currently receiving immunosuppressive drugs, (e.g., 
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20.
Participants requiring chronic oral or injectable steroids and unwilling to refrain from 
taking these drugs for the duration of the study
21.
Participants with a family medical history of 2 or more first-degree relatives (parent, 
sibling, child) diagnosed to have the same type of cancer – breast cancer, cervical 
cancer, colon cancer, endometrial cancer, lung cancer, or prostate cancer; or with a 
family medical history of Lynch Syndrome (hereditary non-polyposis colorectal cancer) 
in any first-degree relative; or who show positive results during cancer screening
22.
Positive human immunodeficiency virus (HIV) or human T-cell lymphotropic virus 
(HTLV) I/II test at Screening
23.
Participants with cancer who have not been cancer-free for ≥5 years with the following 
exceptions (not excluded): Participants with in-situ basal cell or squamous cell 
carcinoma
24.
Participants with a prior history of stem cell transplant for cancer no matter how long 
they have been cancer-free
25.
Active acute or chronic hepatitis B
26.
Active hepatitis C
27.
Clinically significant laboratory values or current medical conditions during Screening
that, in the judgment of the Investigator, should be exclusionary
28.
Hospital Anxiety and Depression Scale (HADS) score of ≥15 on either subscale
29.
History of drug abuse (the habitual taking of addictive or illegal drugs) in the past 
3 months and positive for Drugs of Abuse, with the exception of cannabis, during 
Screening
30.
Participants unwilling to discontinue their use of the following during Screening at least 
7 days before starting eDiary entries and not use any of the following during the study:

skeletal muscle relaxants

opioids

transcutaneous electrical nerve stimulation (TENS)

acupuncture

benzodiazepines (other than stable bedtime dose)

injectable or oral steroids
31.
Participants not on a stable dose and not willing to remain on a stable dose during the 
study for the following drugs:

antidepressants

antiepileptics

duloxetine

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32.
Participants currently using the following medications and unwilling to discontinue 
topical use on the lower legs and feet and throughout the study:

capsaicin

anesthetic creams (except during Study Injections)

anesthetic patches

ISDN spray
33.
Use of an investigational drug or treatment in past 30 days or previous participation in a 
clinical study with Engensis
34.
Body mass index (BMI) ≥42 kg/m2
35.
Recent treatment for COVID-19 with ongoing sequelae
Number of Participants
The target sample size is a minimum of 152 Participants with a maximum sample size of
250 Participants. Participants will be randomized in a 1:1 ratio. Based upon the results of the 
adaptive design interim analysis, which will include at least 76 completed or discontinued 
Participants, the number of Participants randomized may be increased to a maximum of 
250 Participants. The adaptive design provides for re-estimation of the sample size after 50% of 
Participants have completed their 6-month assessments or have discontinued. The total enrolled 
number of Participants may be increased to a maximum of 250 Participants if the results are 
promising (conditional power > 39.6%). The adaptive design process is described in the 
Statistical Analysis Plan (SAP).
Enrollment, Randomization, and Treatment Assignment
5.4.1. Enrollment Adjudication Process
All screening information (except the 7-day eDiary to be completed during Day -7 to Day 0) for 
each Participant prior to randomization will be sent to an Adjudication Committee (Figure 3). 
The Adjudication Committee is composed of the Sponsor Medical Director, Medical Monitor, 
and Clinical Operations personnel. The Adjudication Committee reviews the relevant clinical 
information of each Participant on a timely basis to ensure strict adherence to the 
Inclusion/Exclusion Criteria. The Committee either confirms the eligibility for randomization of 
an individual Participant or confers with the Investigator regarding the status of a Participant as a 
screen failure.

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Once a Participant is deemed to meet all Inclusion/Exclusion Criteria, blinded randomization 
will be conducted via an Interactive Web Response System (IWRS) in a 1:1 ratio to receive 
either Engensis or Placebo. The unblinded Pharmacist or delegated staff will prepare the 
Engensis or Placebo injections for that Participant prior to First Injections by the Investigator or 
qualified designee on Day 0.
Participant Identification
To maintain confidentiality, the name of the Participant should not be recorded on any study 
document other than the informed consent form. All Participants who sign the informed consent 
form will be assigned a unique identifier in the following format: XX-YYY where XX is the 
2-digit Site number and YYY is the 3-digit sequential ID number starting with 001 for the first 
Participant consented at that Site. For example, the first Participant consented at Site 11 will be 
assigned 11-001. ID numbers for screen failures will not be reused. If a screen failure is later 
reconsented for rescreening, a new ID number will be assigned.
Screen Failures
A consented Participant who does not meet all eligibility criteria will immediately cease further 
study-related testing; the cessation will be communicated to the Sponsor or designee within 
24 hours.
A minimal amount of screen failure information is required to ensure transparent reporting of 
screen failures to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes eligibility criteria, demographic data, screen failure details, and other pertinent 
materials.
Rescreening
Participants who provided informed consent but failed to meet all eligibility criteria may be 
rescreened with Sponsor written permission via the adjudication process. 
The following Screening assessments, if completed during the first Screening and found to meet 
eligibility criteria, may not need to be repeated when the Participant returns for rescreening:

Viral screening if performed within 3 months of signing the new informed consent

Retinal fundoscopy if performed within 30 days of signing the new informed consent
All other Screening assessments will need to be repeated.
Lifestyle Considerations
5.8.1. Meals and Dietary Restrictions
There are no meal or dietary restrictions for this study.

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5.8.2. Caffeine, Alcohol, and Tobacco
There are no caffeine, tobacco, or alcohol restrictions for this study. Tobacco use for current 
smokers [pack-year history = (packs smoked per day) x (years as a smoker)] will be recorded at 
Screening.
5.8.3. Supplements
There are no restrictions on herbal medicines or dietary supplements or changes in their use 
during the study. The use of any supplements during the study will be recorded on the 
Participant’s medical record and the electronic case report form (eCRF) as concomitant 
medications.
5.8.4. Activity
There are no restrictions on activity. Participants should be advised to continue their normal 
activity level during the study.

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6.
STUDY INTERVENTION
Study Intervention(s) Administered
Refer to the Injection Guideline for administration of Engensis or Placebo.
6.1.1. Engensis
Engensis contains the active pharmaceutical ingredient VM202, a plasmid DNA containing a 
novel genomic cDNA hybrid human HGF coding sequence, HGF-X7, that expresses two 
isoforms of HGF, HGF728 and HGF723. The plasmid has 7,377 base pairs with a human 
cytomegalovirus (HCMV) enhancer / promoter, a growth hormone polyadenylation terminator 
sequence, ColEl originator, and the kanamycin resistance gene on a pCK backbone.
The components of Engensis are provided in Table 4.
Table 4
Components of Engensis
Component
Function
Composition
VM202
Active pharmaceutical ingredient
2.5 mg
Sucrose
Suspension medium
55 mg (1.1%)a
Sodium Chloride
Suspension medium
45 mg (0.9%)a
Sterile Water for Injection
Suspension medium
5 mL
a Concentration after reconstitution in 5 mL water for injection.
6.1.2. Placebo
Placebo will be sterile Engensis vehicle. The components of Engensis vehicle are provided in 
Table 5. Engensis excipients are supplied in a sterile glass vial in liquid form. Each vial is only to 
be used for one Participant. Visually, Placebo is indistinguishable from reconstituted Engensis. 
The Participant, Investigator, and study nurse will not be able to distinguish Placebo from 
Engensis.
Table 5
Components of the Placebo
Component
Function
Composition
Sucrose
Suspension medium
55 mg (1.1%)
Sodium Chloride
Suspension medium
45 mg (0.9%)
Sterile Water for Injection
Suspension medium
5 mL

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6.1.3. Summary of Study Intervention Characteristics
Study Arm
Engensis
Placebo
Study Drug
Engensis
Placebo
Type
Biologic
N/A
Formulation
Lyophilized product to be 
reconstituted
Injectable liquid
Amount of Active Drug
2.5 mg Engensis per vial
N/A
Dosage Level per Treatment Cycle
Total of 16 mg per Treatment 
Cycle, with each cycle composed of 
2 days of 16 injections each to the 
right and left gastrocnemius 
muscles, spaced 2 weeks apart
Each Treatment Cycle composed of 
2 days of 16 injections each to the 
right and left gastrocnemius 
muscles, spaced 2 weeks apart
Route of Administration
IM injection
IM injection
Use
Experimental
Placebo
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and Labeling
Engensis will be provided in a vial. 
Each vial will be labeled per 
country requirement.
Placebo will be provided in a vial. 
Each vial will be labeled per 
country requirement.
Former Names
VM202
N/A
Abbreviations: IM = intramuscular; N/A = not applicable
Preparation/Handling/Storage/Accountability
6.2.1. Engensis Preparation
Engensis is supplied in a sterile glass vial containing lyophilized drug product with 2.5 mg of 
Engensis. Engensis will be reconstituted by the unblinded Pharmacist or delegated staff with 
5 mL of sterile non-bacteriostatic water for injection (WFI) for a final Engensis concentration of 
0.5 mg/mL (see Injection Guidelines). Each reconstituted vial is to be used for only one
Participant.
6.2.2. Storage of Engensis and Placebo
The unblinded Pharmacy staff is responsible for receiving and storing study drug according to 
the pharmacy manual.
Engensis and Placebo must be stored in a refrigerator at temperatures between 2°C and 8°C. 

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Reconstituted Engensis must be used within 12 hours. Engensis should never be frozen. Further 
information regarding study drug administration can be found in the Injection Guidelines.
A temperature log for the investigational drug product and Placebo storage refrigerator unit must 
be maintained, and the refrigerator unit temperature must be recorded on a daily basis from 
receipt until final reconciliation and return of the investigational drug product by the monitor or 
designee. Temperature monitoring will be the responsibility of the Investigator or the assigned 
designee(s).
In the case of temperature excursions, products should be placed in quarantine and not dispensed,
and the Investigator or the assigned designee(s) should contact the unblinded clinical research 
associate (CRA) as soon as possible to receive further instructions.
6.2.3. Product Accountability
In accordance with federal regulations (21 CFR 312.62), Investigators are required to keep 
accurate records showing final disposition of all investigational drugs.
Engensis is to be used only in accordance with this protocol and under supervision of the 
Pharmacist or delegated staff. A tear-off label will be provided with Engensis and Placebo,
which should be applied to the Participant’s drug accountability form by the unblinded 
Pharmacist or delegated staff when study medication is dispensed. The Pharmacist will maintain 
an accurate record of the receipt of Engensis and Placebo, including the date received. 
Specifically, the Pharmacist or assigned designee will confirm that all study drug supplies are 
received intact and in the correct amounts per the shipping form. In addition, an accurate study 
drug disposition record will be kept, specifying the date, time, and amount dispensed, to whom it 
was dispensed (Participant-by-Participant accounting), and the accounts of any drug accidentally
or intentionally destroyed. This inventory record must be available for inspection by the 
unblinded clinical research associate (CRA) at any time. Copies of this record will be provided to 
the Sponsor by the Pharmacist or delegated staff at the conclusion of the study.
After the study is completed, the Pharmacist or delegated staff must account for all study drug
used, unused, partially used, returned, and destroyed. All investigational product, Engensis and 
Placebo, including used, partially used, unused, and damaged product, will be returned to the 
Sponsor by the site after reconciliation by the unblinded CRA. Study medication from the Site 
will be returned to the Sponsor as directed in writing by the Sponsor for reconciliation.
Measures to Minimize Bias 
6.3.1. Randomization
Participants are to be randomized on Day 0. Randomization will be conducted via an IWRS in a 
1:1 ratio for Participants to receive either Engensis or Placebo.
6.3.2. Stratification
Participants will be stratified between the Engensis and Placebo groups according to their 
baseline ADPSs of < 7 and ≥ 7. The ADPS for the baseline determination will be considered 
missing if fewer than 5 of 7 days of the ADPS entries are provided. Participants will not be 

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randomized if the baseline ADPS has fewer than 5 days of the ADPS entries.
6.3.3. Blinding
Participants, Investigators, Site staff, CRO staff, and Sponsor staff will be blinded to treatment
assignments except for the designated unblinded Clinical Research Associate (CRA), Sponsor 
Clinical Supplies Manager, the unblinded Medical Monitor, and the Site’s unblinded Pharmacist
or delegated staff.
The unblinded pharmacy staff are responsible for receiving, storing, preparing, and dispensing 
study drug per the Pharmacy Manual. An Investigator and the designated unblinded Medical 
Monitor(s) may be unblinded to the treatment assignment for a Participant with an SAE when the 
treatment decision requires knowledge of the treatment assignment.
To avoid potential bias, Investigators and study staff are expected to refrain from sharing safety 
and treatment outcomes with other participating Sites.
The DSMB, independent of the Sponsor, may review individual unblinded Participant narratives
in the case of an SAE or multiple SAEs for which the DSMB Chair requests unblinding, but will 
not have access to unblinded tables and listings unless requested by the DSMB Chair when 
assessing a potential safety signal. While the study is ongoing and prior to database lock, the 
datasets will remain blinded with no preliminary summary of the study by the individual 
treatment arms except when requested by the DSMB Chair.
6.3.4. Maintenance of the Blind
Once the Participant has been adjudicated and deemed eligible for potential randomization, the 
drug depot will prepare and ship both Engensis and Placebo vials to the Site pharmacy. The 
pharmacy will keep both Engensis and Placebo vials and the dose preparation worksheet in a 
secure location with access limited to unblinded pharmacy personnel responsible for preparing 
the syringes with assigned study treatment. The Investigator or designee will randomize the 
Participant using the IWRS system on Day 0 after confirming eligibility criteria.
The unblinded Pharmacist or delegated staff will receive a notification from the IWRS system 
indicating into which arm the participant has been randomized.  The Pharmacist or delegated 
staff will prepare Engensis or Placebo per the Pharmacy Manual.
Blinding will be achieved by having study drug syringes prepared by the pharmacy staff and 
ensuring that the study drug vials are never left in a location where they could be seen by blinded 
study staff (e.g., study coordinator, study nurse, Investigator). The Engensis and Placebo vials
are readily distinguishable from each other, even from a distance. However, because
reconstituted Engensis is indistinguishable from Placebo, syringes containing Engensis are 
indistinguishable from syringes containing Placebo.
The pharmacy staff and select individuals such as the unblinded CRA will be unblinded to the 
treatment assignments. The Participant and study personnel, including study coordinators, study 
nurses, laboratory technicians, Investigators, and blinded CRAs, will remain blinded until all 
data has been entered into the database and the database is locked.

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IN CASE OF EMERGENCY (i.e., SERIOUS ADVERSE EVENT [SAE]) AND ONLY WHEN 
THIS INFORMATION INFLUENCES THE PARTICIPANT'S MEDICAL MANAGEMENT, 
the Investigator may contact the designated unblinded Medical Monitor to request unblinding of 
the treatment assignment. The date and reason for unblinding will be documented in the 
electronic data capture (EDC) system.
Study Intervention Compliance
All Site personnel involved with the receipt, storage, preparation, administration, and destruction 
of study drug are required to document their understanding of the Study Drug Injection 
Guidelines. Refer to the Injection Guidelines.
All study drug will be administered under the supervision of the Investigator.
Compliance with study drug administration instructions will be assessed through the review of 
accountability and preparation logs as well as the reconciliation of used and unused vials, vials 
destroyed, and vials returned to the Sponsor.
Concomitant Therapy
All concomitant therapies should be captured in the Concomitant Therapy section of the eCRF.
6.5.1. Rescue Medicine
The only allowed rescue medication is acetaminophen. On Day 0, the Site will dispense 
extra-strength acetaminophen (500 mg) provided by the Sponsor. The Participant will be 
instructed to take up to 2 caplets every 6 hours as needed for DPN pain for a maximum of 
6 caplets (3 grams) / day. The study-issued acetaminophen is only to be used for DPN pain, and 
the Participant is not to use any other source of acetaminophen for DPN pain. The Participant
may use up to 1 gram per day of a source of acetaminophen other than the study-issued 
acetaminophen for conditions other than DPN pain. The Participant will be provided with an 
eDiary to record their pain level (NRS = 0-10 scale) before use, the date and time of use, and the 
amount of acetaminophen used. The Participant will be asked to return the eDiary and the unused 
rescue medication at each Visit. At each Visit, the Site will reconcile how many caplets were 
used, as documented in the eDiary, with how many caplets remain in the bottle(s). New bottle(s) 
of acetaminophen will then be dispensed by the Site to the Participant.
Dose Interruption
No intentional modifications of the number or concentration of doses will be permitted. An 
unintentional interruption of the number of injections (32 per Study Injection Visit) is only 
allowed if the participant experiences an AE related to study drug administration or other 
health-related events (e.g., illness) during the study, or if the full set of injections cannot be 
prepared. If the full set of study injections cannot be administered during the normal Study 
Injection Visit, the Participant should be scheduled to receive the remaining injections within 
48 hours. If this is not possible, then the remainder of the injections for that visit will not be 
administered.

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Prohibited and Restricted Medications and Procedures
Prohibited medications and procedures are listed in Section 10.4, Appendix 4.
6.7.1. Medications That May Interfere with Engensis Bioactivity
Certain steroids (except inhaled, ocular, or intra-articular steroids) may interfere with the 
bioactivity of Engensis and are therefore prohibited from use during the study. Participants must 
agree to not take any of these drugs for the duration of the study. A list of the prohibited 
medications in this category can be found in Section 10.4, Appendix 4.
6.7.2. Medications and Procedures That May Interfere with Assessment of Pain
Participants may participate in the study if they are willing to discontinue use of the following 
therapies 7 days prior to starting the 7-Day BPI-DPN eDiary. Participants must refrain from use 
of these therapies for the duration of the study:

skeletal muscle relaxants

opioids

benzodiazepines (except for stable bedtime dose)

injectable steroids

capsaicin applied to the lower legs or feet

local anesthetic creams and patches applied to the lower legs or feet (except local/topical 
anesthetic cream applied immediately prior to study drug injections

ISDN spray applied to the lower legs or feet

transcutaneous electrical nerve stimulation (TENS), acupuncture
A list of prohibited medications and procedures in this category can be found in Section 10.4.
If not using a stable dose of duloxetine (Cymbalta), any antidepressants (e.g., amitriptyline and 
venlafaxine), or any other antiepileptics (e.g., valproic acid, carbamazepine, and vigabatrin) 
during Screening, Participants must agree to not start these drugs during the study. Potential 
Participants on these medications on the day of informed consent must maintain a stable dose 
during the study. Participants may not use pregabalin (Lyrica) or gabapentin (Neurontin) at any 
time during the study.
Prior and Concomitant Medications, Treatments, and Procedures
Medications and treatments taken within 30 days prior to Day 0 will be recorded on the 
Medication and History eCRF at the Day 0 Visit. Any medication or vaccine, including 
over-the-counter or prescription medicines, vitamins, herbal supplements, and topical anesthetics 
for post-injection pain and procedures that the Participant is receiving at the time of enrollment 
or receives during the study must be recorded on the Concomitant Medications or Concomitant 
Procedures eCRF. 

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For each medication or treatment, the following information will be collected:

Medication trade or generic name, or procedure

Indication for which the medication/procedure was given

Dose/strength, route, and frequency of administration

Date started and date stopped (or continuation at study exit)

Reason for use
The Medical Monitor will be contacted if there are any questions regarding concomitant or prior
therapy. Acetaminophen is the only rescue medication allowed in this study. Up to 3 grams per 
day will be allowed. Use of rescue medication will be recorded each day in the eDiary.

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7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION
Discontinuation of Study Intervention
In rare instances, it may be necessary to discontinue study drug for a Participant. If study drug is 
discontinued, the Participant will remain in the study to be evaluated for safety if the Participant
agrees to continue participating in the study. See Section 1.3 (SoA) for any further assessments 
that need to be completed.
Participant Discontinuation/Withdrawal/Early Termination from the Study
Any Participant may voluntarily discontinue the study at any time without prejudice. The 
Investigator may discontinue a Participant from the study at any time if, in the Investigator’s 
judgment, the Participant’s health or safety would be compromised by remaining in the study.
Specific reasons for study discontinuation include the following:

Participant’s decision

Investigator’s decision

Adverse event

Insufficient compliance with study requirements

Lost to follow-up

Other
The specific reasons for Participant discontinuation will be recorded.
The following assessments will be performed, if possible, for Participants who discontinue prior 
to the Day 180 Visit, at the Early Termination Visit (ET; see Section 1.3, SoA).

APR and PRR

Full BPI-DPN

MNSI

BST

PGIC

SF-36 and EQ-5D

Complete physical examination

Vital signs, weight

Retinal fundoscopy

Serum chemistry, lipid profile, and hematology

ECG

Urine pregnancy test

Urine drug analysis

HbA1c

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
Concomitant medications / procedures

Adverse events

Anti-HGF antibodies
Lost to Follow-up
A Participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled Visits and is unable to be contacted by the Site by Day 180 (+7 days).
The following actions must be taken if a Participant fails to return to the clinic for a required 
Study Visit:

The Site must attempt to contact the Participant and reschedule the missed Visit as soon 
as possible. The Site must counsel the Participant on the importance of maintaining the 
assigned Visit schedule and ascertain whether the Participant wishes to and/or should 
continue in the study.

If no response is obtained from the Participant, the Investigator is encouraged to contact 
one of the Participant’s relatives or his/her general practitioner.

Before a Participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the Participant, including at least three telephone calls 
and, finally, a certified letter to the Participant’s last known mailing address. These 
contact attempts should be documented in the source records.

Should the Participant continue to be unreachable, the Participant will be considered lost 
to follow-up.

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8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in Section 1.3 (SoA).
Protocol waivers or exemptions are not allowed. Adherence to the protocol requirements, 
including those specified in the SoA, is essential.
Screening Activities
8.1.1. Screening Days -52 to -7
Prior to Screening, Participants will give informed consent and then be initially screened using 
the symptoms portion of the MNSI. Only Participants with a MNSI physical assessment score of 
≥ 2.5 will be allowed to proceed with the full screening procedures.
If the MNSI criteria are met, the rest of Screening will proceed. Prior to randomization, 
Participant eligibility will be assessed as follows:

Evaluation of eligibility criteria

Medical history

Concomitant medications and procedures

Vital signs

Complete physical exam, including height, weight, waist circumference, and BMI

ECG

Cancer history and cancer screening tests where applicable

Smoking status (current or never smoker; for smokers, the pack-year history or number of 
packs/day and number of years smoking will be recorded)

Retinal fundoscopy

Ultrasound of right and left gastrocnemius muscles

Serum chemistry, hematology, and lipid profile

HbA1c

eGFR

Urine pregnancy test (for women of childbearing potential only)

Urine drug analysis

Viral screening – HIV, Anti-Human T-Cell Lymphotropic Virus (HTLV) I/II antibody 
with reflex confirmatory assay, Hepatitis B core antibody (IgM HBcAb), antibody to 
Hepatitis B antigen (HBsAb), Hepatitis B surface antigen (HBsAg) in addition to a 
quantitative HBV viral load if needed clinically, and Hepatitis C antibodies (Anti-HCV)
and a positive qualitative PCR to assess HCV viral load

Hospital Anxiety and Depression Scale (HADS)

Accurate Pain Reporting (APR)

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
Placebo Response Reduction (PRR)
8.1.1.1.
Cancer Screening Tests
All Participants in this study must undergo screening for multiple types of cancer according to 
current guidelines. Some diagnostic tests and procedures performed prior to completion of 
informed consent and that are documented in the Participant’s medical history may be acceptable 
where noted. 
Note that Participants with a first-degree relative (mother/father, sister/brother, daughter/son) 
with a diagnosis of Lynch Syndrome (hereditary non-polyposis colorectal cancer [HNPCC]) or 
Participants who have 2 or more first-degree relatives (parent, sibling, child) diagnosed with 
the same type of cancer – breast cancer, cervical cancer, colorectal cancer, endometrial cancer, 
lung cancer, or prostate cancer – are not to undergo cancer screening, as these Participants will 
be excluded from the study.
Cancer screening tests for those without a first-degree relative or with one first-degree 
relative with a family history of the indicated cancer include the following (note that past history 
refers to years before Screening):

Mammogram for breast cancer for female Participants aged 45 to 54 years, if not 
performed within the past 12 months; or if not performed within the past 24 months for 
female Participants aged ≥ 55 years. If the mammogram results are negative for cancer, 
the Participant will be allowed to enter the study.

Primary HPV test for cervical cancer for female Participants aged 25 to 65 years, if not 
performed within the past 5 years; if primary HPV test is not available, an HPV test in 
combination with cytology (PAP) if not performed within the past 5 years; or cytology 
alone if not performed within the past 3 years.35 If the test results are negative for 
cervical cancer, the Participant will be allowed to enter the study.

FIT stool test for colon cancer for Participants (male or female) aged ≥45 years and 
≤75 years, if not performed within the past 12 months; or a colonoscopy (in lieu of an 
FIT stool test) if not performed within the past 5 years.36,37,38,39 If the test results are 
negative for colon cancer, the Participant will be allowed to enter the study. Participants 
aged ≥76 years will not be required to undergo colon cancer screening.

Low-dose chest CT scan for lung cancer40,41,42,43 for current or previous smokers (male 
or female) who:
o
Are ≥ 50 years of age, are currently smoking, have a ≥ 30 pack-year history of 
smoking, and have not had a CT scan performed within the past 12 months
o
Are ≥ 50 years of age, quit smoking but have smoked within the past 15 years, and 
have a ≥30 pack-year history
If the low-dose chest CT scan test results are negative for lung cancer, the Participant will 
be allowed to enter the study.

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
PSA test for prostate cancer, if not performed within the past 12 months, for male 
Participants who are African-American aged ≥45 years or other races aged ≥50 years.44
If the test results are negative for prostate cancer, the Participant will be allowed to enter 
the study.
See Section 8.4.2 (Medical History) for information and references for familial risk for cancer 
and Section 8.5.4 (Adverse Events of Special Interest) for information and references for 
increased risk of cancer with obesity and in type 2 diabetes patients.
8.1.1.2.
Hospital Anxiety and Depression Scale
The HADS questionnaire will be completed by Participants at Screening through use of an 
eDiary. There are two separate scales for depression or anxiety and the exclusionary cutoff of 
≥15 applies to either subscale. The Investigator should ensure that the Participant is provided 
with instructions and is trained to use the eDiary and to complete the assessment tool properly 
before data collection begins at the Screening Visit. The HADS questionnaire is presented in 
Section 10.6, Appendix 6.
8.1.2. Screening Days (-7 to 0)
Following adjudication based on screening activities completed by Day -7, Participants will 
complete a 7-day diary that includes the Brief Pain Inventory for Diabetic Painful Neuropathy
(BPI-DPN) prior to Day 0 as a final eligibility assessment prior to randomization on Day 0 (see 
Section 8.3.1).
Participant Training
8.2.1. Accurate Pain Reporting
The Accurate Pain Reporting (APR) training instructs Participants how to report pain scores 
accurately and reliably, and on the proper use of pain scales, with the aim of increasing the 
reporting accuracy of Participant pain. Participants will receive training at Screening, pre-dose 
on Days 0, 14, 90, and 104, and on Days 28, 60, 150, and 180/ET.
8.2.2. Placebo Response Reduction
The Placebo Response Reduction (PRR) training teaches the Participant about the appropriate 
expectations of personal benefit while participating in a clinical trial. The purpose is to provide 
Participants with truthful information that will neutralize the typically excessive expectations 
that drive high placebo responses in clinical studies. Participants will receive training at 
Screening, pre-dose on Days 0, 14, 90, and 104, and on Days 28, 60, 150, and 180/ET.
Efficacy Assessment and Procedures
8.3.1. Brief Pain Inventory for Diabetic Painful Neuropathy
The Brief Pain Inventory for Diabetic Painful Neuropathy (BPI-DPN) assessment tool 
(Section 10.7, Appendix 7) will be administered through use of an eDiary. The Investigator 

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should ensure that the Participant is provided with instructions and is trained to use the eDiary 
and to complete the assessment tool properly before data collection begins. The BPI-DPN will be 
conducted using the full BPI-DPN questionnaire and/or the partial BPI-DPN questionnaire.
Scores obtained from the full BPI-DPN for 7 days prior to the Day 0, Day 90, and Day 180/ET 
Visits will be used to determine ADPSs. The ADPS is the mean of at least 5 daily pain scores 
recorded in the eDiary. If the eDiary contains fewer than 5 daily entries over the 7 days prior to 
the Day 0 and Day 180 Visits, the Visit must be rescheduled so that the Participant can record 
5 daily entries over the 7 days prior to the rescheduled Visit. The scores from the 7 days prior to 
Day 0 and the 7 days prior to Day 180 will be used in the primary endpoint.
Participants will use the eDiary to rate their Average Daily Pain and Worst Daily Pain on a daily 
basis from Days 0 to 180 to allow an assessment of onset, peak, and duration of pain relief in the 
active treatment group versus Placebo.
8.3.2. Quality of Life/Participant Reported Outcome Measures
8.3.2.1.
Patient Global Impression of Change
The Participant’s impression of change after treatment will be measured with the Patient Global 
Impression of Change (PGIC) questionnaire through use of an eDiary. The Investigator should 
ensure that the Participant is provided with instructions and is trained to use the eDiary and to 
complete the assessment tool properly before data collection begins (Section 10.8, Appendix 8). 
This questionnaire measures the Participant’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. The test will be 
self-administered during the Day 90 and Day 180/ET Visits.
Upon completion of the questionnaire, the study coordinator will check the questionnaire for 
completeness. Any omissions or ambiguous answers will be clarified by the Participant prior to 
leaving the clinic.
8.3.2.2.
Short Form Health Survey
The 36-item Short Form Health Survey (SF-36; Section 10.9, Appendix 9) will be administered 
through use of an eDiary. The Investigator should ensure that the Participant is provided with 
instructions and is trained to use the eDiary and to complete the assessment tool properly before 
data collection begins to measure the Participant’s perception of their overall health status 
pre-dose on Days 0 and 90 and on Day 180/ET. This 36-question survey measures the 
Participant’s perception of vitality, physical functioning, bodily pain, general health perceptions, 
physical role functioning, emotional role functioning, social role functioning, and mental health.
Upon completion of the questionnaire, the study coordinator will check the questionnaire for 
completeness. Any omissions or ambiguous answers will be clarified by the Participant prior to 
leaving the clinic.

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8.3.2.3.
EuroQol Health Utilities Index
The EuroQol Health Utilities Index (EQ-5D) instrument (Section 10.10, Appendix 10) will also 
be administered through use of an eDiary. The Investigator should ensure that the Participant is 
provided with instructions and is trained to use the eDiary and to complete the assessment tool 
properly before data collection begins to measure the Participant’s perception of their overall 
health status pre-dose on Days 0 and 90 and on Day 180/ET. The instrument has two parts – the 
descriptive system that measures mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression; and the visual analog scale that records the Participant’s self-rated health.
Upon completion of the questionnaire, the study coordinator will check the questionnaire for 
completeness. Any omissions or ambiguous answers will be clarified by the Participant prior to 
leaving the clinic.
8.3.3. Bedside Sensory Testing
Sensory tests will be performed at 3 predefined locations: dorsum of the foot, mid-shin, and 
mid-thigh, except low threshold mechanoreceptive function, which will be conducted at the 
bottom of the foot at any time prior to dosing on Day 0 and Day 90. The BST should also be 
done on day 180. The Investigator should ensure that the Participant is seated comfortably before 
data collection begins. 
The Bedside Sensory Testing is presented in Section 10.11, Appendix 11.
8.3.4. Michigan Neuropathy Screening Instrument
The Michigan Neuropathy Screening Instrument (MNSI) (Section 10.12, Appendix 12) will be 
administered through use of an eDiary (for the Participant) or an electronic tablet (for the Site) 
during Screening in order to confirm the diagnosis of DPN, based on the cutoff ≥ 2.5,45,46 and on 
Day 90 and the Day 180/ET Visit to track disease progression. The Investigator should ensure 
that the Participant is provided with instructions and is trained to use the eDiary and to complete 
the assessment tool properly before data collection begins. The MNSI comprises a Participant
questionnaire (15 questions) and a physical evaluation that includes a foot inspection, vibration 
sensation testing, muscle stretch reflexes, and monofilament testing.
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 Participant prior 
to leaving the clinic. The Participant will be required to electronically sign and date the 
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Safety Assessments
8.4.1. Physical Examinations
Complete physical examinations (PEs) will be performed at Screening, pre-dose on Days 0, 14, 
90, and 104, and on Days 28, 60, 150, and 180/ET; and at the last Visit if the Participant
discontinues prior to Day 180. The complete PE will include the following: an examination of 
the skin/integumentary systems, general appearance, head, neck (including thyroid), eyes, ears, 
nose, throat, lymph nodes, chest (lungs), heart, abdomen, musculoskeletal system, neurological 
system, and any additional assessments needed to establish baseline status or evaluate symptoms 
or AEs. Height, BMI, and waist circumference will be recorded only during Screening. Any 
physical examination abnormalities considered to be clinically significant (CS) should be added 
to AEs using medically appropriate terminology.
8.4.2. Medical History and Familial History of Cancer
A detailed description of the Participant’s current disease status, past medical conditions 
(including cancer), and medication and treatment history will be recorded at the Screening Visit.
The medical history (including treatment history) will include a detailed assessment of past 
diabetes history including DPN, events, interventions, and procedures. Other potential causes of 
peripheral neuropathy will be documented (e.g., alcohol consumption, hypothyroidism, collagen 
vascular diseases, vasculitis, or B-12 or folate deficiency).
All medication history within 30 days before randomization will also be collected at Screening.
Any untoward medical events that occur from the time of signing of informed consent and 
during Screening (prior to study drug administration) will be captured as new medical problems 
and added to the medical history. A change in medical status or medical history from time of 
signing of informed consent up to immediately prior to taking the first dose of study drug is also 
to be added to the medical history.
The Investigator or qualified medical personnel who routinely perform these evaluations in 
patients with DPN will conduct the examination, determine findings, and assess any 
abnormalities as to clinical significance.
Cancer history will be collected for the 5 years prior to Screening. In addition, familial history of 
cancer will also be recorded at Screening. Familial risks for cancer have been identified for 
breast,47 colon,48,49,50 endometrial,51 lung,52 and prostate53,54 cancer. In addition, if the Participant
has Lynch Syndrome, a hereditary non-polyposis colorectal cancer, this information will be 
recorded at Screening.55
Elevated risks of cancer for type 2 diabetes or obesity are detailed in Section 8.5.4, Adverse 
Events of Special Interest.
8.4.3. 12-Lead Electrocardiograms
12-Lead electrocardiograms (ECGs) will be performed during Screening, pre-dose on Day 90, 
and on Day 180. Any clinically significant abnormalities are to be recorded. The ECG recording 
will be printed, and the Investigator or delegated staff will initial and date the printout to indicate 

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their review of the findings. The trace and the interpretation will then be stored with the 
Participant’s records.
8.4.4. Ultrasound of Right and Left Lower Legs
A posterior-to-anterior (P-A) ultrasound of the right and left lower extremities will be performed 
at Screening to assess the surface area and depth of skin, subcutaneous tissue, and fat covering 
the gastrocnemius muscles of each leg and the location of other anatomical components that 
might interfere with the Engensis Injections. 

The surface area of the gastrocnemius muscle available for placement of the 
16 injections of Engensis (which must be injected into skeletal muscle to be effective) 
will be calculated by multiplying the length (medial and lateral condyles of the femur to 
the top of the Achilles tendon/gastrocnemius aponeurosis) and the width (widest section 
that includes the medial and lateral heads of the gastrocnemius muscle) identified by 
ultrasound.

The depth of the skin and subcutaneous tissue to the surface of the gastrocnemius 
muscle as well as the thickness of the gastrocnemius measured by ultrasound will be 
used to determine the length of needle that will need to be used for accurate injection of 
Engensis into the skeletal muscle tissue (to a depth of at least 1 cm into the muscle).

The location(s) of the Achilles tendon/gastrocnemius aponeurosis and other sites of 
fibrous tissue or connective tissue within the medial and lateral heads of the 
gastrocnemius muscle of each leg will be identified by ultrasound. Engensis must not be 
injected into connective tissue, fibrous tissue, or tendons as HGF cannot be expressed 
from the plasmid in these tissues.
8.4.5. Vital Signs
Vital signs will be measured at Screening, pre- and post-dose at Study Injection Visits during 
Treatment Cycle 1 (Days 0 and 14) and Treatment Cycle 2 (Days 90 and 104), and at all other 
Study Visits. Weight will be collected pre-dose at Study Injection Visits. After resting in the 
seated position for 5 minutes, vital signs measured will include temperature, sitting blood 
pressure, heart rate, respiratory rate, and oxygen saturation on room air. The method of 
temperature measurement should be according to the Site’s policy and should be consistently 
applied.
8.4.6. Clinical Laboratory Assessments
See Section 1.3 (SoA) for the timing and frequency.
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study. The laboratory reports must be filed with 
the source documents. Clinically significant abnormal laboratory findings are those that are not 
associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the Participant’s condition.
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laboratory manual and the SoA.
8.4.6.1.
Local and Central Laboratory Assessments
The following laboratory assessments for safety and establishing eligibility will be performed at 
local laboratories during Screening as noted in the SoA. Everything from Day 0 to 180 will be 
performed by the central laboratory.
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study. The laboratory reports must be filed with 
the source documents and uploaded into the EDC. Clinically significant abnormal laboratory 
findings are those that are not associated with the underlying disease, unless judged by the
Investigator to be more severe than expected for the Participant’s condition.
All protocol-required laboratory assessments must be performed in accordance with the 
laboratory manual and the SoA.
8.4.6.1.1. Hematology

White blood cell count

Neutrophil (including calculated absolute neutrophil count)

Hemoglobin

Hematocrit

Platelet count
8.4.6.1.2. Kidney Function Tests

Blood urea nitrogen (BUN)

Creatinine

Estimated glomerular filtration rate (eGFR, calculated using the chronic kidney disease 
epidemiology collaboration [CKD-EPI] formula based on Cystatin C levels)
8.4.6.1.3. Liver Function Tests

Aspartate aminotransferase (AST)

Alanine aminotransferase (ALT)

Alkaline phosphatase

Gamma-glutamyl transpeptidase (GGT)

Total bilirubin

Total protein

Albumin
8.4.6.1.4. Clinical Chemistry

Electrolytes (sodium, potassium, chloride, bicarbonate, calcium, inorganic phosphate, 
magnesium)

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
Glucose (random collection, i.e., not necessarily fasting)

Amylase

Lipase

Lactate dehydrogenase

Creatine kinase

HbA1c

Cystatin C (for calculation of eGFR)
8.4.6.1.5. Lipid Profile

Total cholesterol

High-density lipoprotein cholesterol (HDL-C)

Low-density lipoprotein cholesterol (LDL-C)

Triglycerides
8.4.6.1.6. Additional Tests

Urine pregnancy test

Urine drug analysis
8.4.6.1.7. Viral Screening

HIV

HTLV I/II antibody with reflex confirmatory assay

HBcAb (IgM)

HBsAb

HBsAg

HBV viral load (if needed clinically)

Anti-HCV antibodies and a positive qualitative PCR to assess HCV viral load
8.4.6.2.
Central Laboratory Analytical Testing

Anti-HGF antibodies

Cytokines
8.4.7. Retinal Fundoscopy
Proliferative diabetic 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 during Screening for eligibility 
and repeated at Day 90 and Day 180/Early Termination. Retinal fundoscopy must be performed 

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by an ophthalmologist or optometrist within 52 days prior to Day 0 and within 45 days of Day 
90, and within 30 days of Day 180. The same ophthalmology practice should be used for all 
measurements of individual participation. In cases where fundoscopy alone is deemed 
insufficient to determine eligibility, fluorescein angiography may be performed during 
Screening.
Adverse Events and Serious Adverse Events
The definitions of AEs, TEAEs, and SAEs can be found in Section 10.2, Appendix 2.
8.5.1. Time Period and Frequency for Collecting AE, TEAE, SAE, and TESAE
Information
Medical occurrences that begin before the start of study intervention and not related to required 
study procedures, but after obtaining informed consent will be recorded on the Medical 
History/Current Medical Conditions section of the case report form (CRF) and not as AEs.
All medical occurrences will be considered AEs/SAEs if identified during the screening period 
and are related to study-required procedures or interventions and will be collected starting after 
completion of the informed consent process to Day 0 prior to randomization. 
All TEAEs and treatment-emergent SAEs (TESAEs) will be collected after study drug 
administration on Day 0 through Day 180 (see definition of TEAE, Section 10.2).
All SAEs, including TESAEs, will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as indicated in 
Section 10.2.5, Appendix 2. The Investigator will submit any updated SAE/TESAE data to the 
Sponsor within 24 hours of its availability.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a Participant has been discharged from the study, and he/she considers the event to be possibly, 
probably, or definitely related to the study intervention or study participation, the Investigator
must promptly notify the Sponsor.
8.5.2. Method of Reporting AEs, TEAEs, SAEs, TESAEs, and AESIs
The method of recording, evaluating, and assessing causality of AEs, SAEs, TEAEs, TESAEs,
and AESIs and the procedures for completing and transmitting SAE reports are provided in 
Section 10.2, Appendix 2.
Care will be taken not to introduce bias when identifying AEs/TEAEs and/or SAEs/TESAEs. 
Open-ended and non-leading verbal questioning of the Participant is the preferred method to 
inquire about AE occurrences.
8.5.3. SAE Reporting to the Sponsor or Designee
All SAEs/TESAEs should be reported to the Sponsor or designee within 24 hours of knowledge 
of the SAE/TESAE occurring.

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8.5.4. Adverse Events of Special Interest
Categories of AESIs
There are four main categories of AESIs: 1) those considered to be related to the angiogenesis 
potential of Engensis, 2) other medical problems in this patient population, 3) severe (Grade 3) 
and potentially life-threatening (Grade 4) Injection Site Reactions, and 4) COVID-19 infections 
occurring after randomization of the participants. The Sponsor is responsible for deciding which 
events are deemed as AESIs
8.5.4.1.
AESIs Related to Angiogenesis 
Atherosclerosis
Hyperplasia of the vasa vasorum in the early stages of atherosclerosis is independent of 
angiogenesis, but the intimal neovascularization that follows the hyperplasia of the vasa vasorum 
is angiogenesis-dependent.56 Angiogenesis increases oxygen and nutrients to the artery wall and 
supports initial plaque growth. Once the atherosclerotic plaque develops, intimal angiogenesis is 
thought to contribute to characteristics of an unstable plaque, plaque hemorrhage, and plaque 
rupture. Therefore, diagnoses suggestive of recent coronary artery disease since Baseline will be 
evaluated as AESIs.
Proliferative diabetic retinopathy
Neovascularization is an advanced stage of diabetic retinopathy that is due to relentless abnormal 
fibrovascular proliferation.57 Because the angiogenic potential of Engensis may promote the 
development of or stimulate abnormal fibrovascular proliferation in the retina, new fundoscopic 
changes or symptoms of proliferative diabetic retinopathy that occur after Baseline are 
considered AESIs. 
Cancer
Angiogenesis plays an important role in the proliferation and metastatic spread of cancer as these 
processes are dependent on an adequate supply of oxygen and nutrients and removal of waste 
products.58 All types of cancer reported after randomization will be deemed to be AESIs.
Diabetes mellitus and obesity (BMI ≥30) each increases the risk of several types of cancer.59,60 In 
type 2 DM, there is a 2- to 3-fold increased risk for pancreatic cancer, a 2-fold increased risk for 
hepatobiliary and endometrial cancers, a 50% increased incidence of colorectal cancer, and a 
20% increased risk for breast cancer.61 Obese postmenopausal women have an increased risk of 
breast cancer,62 and obesity is associated with a modestly increased risk of colorectal cancer,63,64
pancreatic cancer,65 and prostate cancer.66
Because the medical problems of type 2 DM and obesity (BMI ≥30) increase the risks of several 
types of cancers, cancer screening tests have been implemented to exclude obese diabetic 
patients with even higher than expected risks of developing cancer based on medical history or 
cancer screening tests, or who have various types of subclinical cancer. 
8.5.4.2.
AESIs Related to Other Medical Problems
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that should be considered AESIs. These medical problems are listed below by type of medical 
problem.
Infections and infestations; Skin and Subcutaneous disorders 
Because patients with diabetic peripheral neuropathy are at an increased risk to develop skin 
lesions (e.g., blisters, ulcers) and various lower limb infectious complications (e.g., cellulitis, 
osteomyelitis) that may be associated with systemic infections (e.g., bacteremia, sepsis, or septic 
shock), all of these types of medical problems that occur after Randomization (Day 0) will be 
considered AESIs. In addition, any amputations involving the lower extremity, development of 
Charcot foot, or other similar complications will also be considered AESIs.
Peripheral Arterial Disease
An overlap of DPN and peripheral arterial disease (PAD) apparently exists in type 2 diabetic 
patients.67 Because Participants with DPN may develop signs or symptoms of PAD after 
randomization in the VMDN-003-2 trial, detailed evaluations of Participants considered to have 
PAD will be considered AESIs. 
Diabetic Neuropathies 
Because Participants in this study may develop other types of peripheral diabetic neuropathies 
while in the study, the following events will be considered to be AESIs in Participants with 
DPN: diabetic mononeuropathy, diabetic mononeuropathy multiplex, and diabetic 
polyradiculopathy. The occurrence of these other types of peripheral neuropathies in a 
Participant with DPN may indicate a more severe form of diabetic peripheral neuropathy. 
Because Participants in this study may develop various manifestations of autonomic neuropathy 
(typically involves the gastrointestinal, genitourinary tract, cardiovascular systems) after 
randomization, the clinical manifestations of diabetic autonomic neuropathy will be considered 
to be AESIs. 
Glycemic Control
Hypoglycemia, hyperglycemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia 
are to be listed as AESIs based on the Common Terminology Criteria for Adverse Events 
(CTCAE) grading if they are Grades 3 or 4.
Metabolic complications of DM (such as diabetic ketoacidosis [DKA], hyperglycemic 
hyperosmolar non-ketotic coma, lactic acidosis, metabolic acidosis [overlaps with DKA]) are to 
be listed as AESIs.
8.5.4.3.
Injection Site Reactions
Immediately following completion of injections of Engensis or Placebo at each Study Injection 
Visit (on Days 0, 14, 90, and 104), the Investigator or designee must evaluate all injection sites 
for any reactions and record the findings on the Injection Site Reaction (ISR) CRF. Within 2 to 
3 days after each Study Injection Visit, a documented telephone call will be placed from the 
clinical site to the Participant to ask if there are any Injection Site Reactions (across all injection 
sites on both calves), and if any ISRs occurred, the worst reaction across all injection sites is to 
be reported as a TEAE and will be considered an AESI if severe (Grade 3) or potentially life-
threatening (Grade 4). Grading of severity of ISRs is presented in Section 10.3, Appendix 3.

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For an ISR to qualify as an AESI, the severity of the ISR should be Grade 3 or 4 according to the 
grading presented in Table 6. Injection Site Reactions that are observed by the PI or reported by 
the participant within 2 to 3 days after Study Injections on Days 0, 14, 90, and 104. The PI 
should conduct an unscheduled visit, if warranted, to assess the ISR. The ISRs that remain 
unresolved after 2 to 3 days will continue to be assessed at subsequent Visits as ongoing AEs 
until resolved.
8.5.4.4.
COVID-19 Infections
A diagnosis of a COVID-19 infection occurring in participants after randomization will be 
recorded as an AESI and their disposition during the trial following the diagnosis of the 
COVID-19 infection will be tracked.
8.5.5. Follow-up of AEs/TEAEs, SAEs/TESAEs, and AESIs
After the initial AE/TEAE/SAE/TESAE report, the Investigator is required to proactively follow 
each Participant at subsequent Visits/contacts. All SAEs and AESIs (see Section 8.5.4) will be 
followed until resolution, stabilization, the event is otherwise explained, or the Participant is lost 
to follow-up (as defined in Section 7.3).
8.5.6. Regulatory Reporting Requirements for SAEs/TESAEs
Prompt notification by the Investigator to the Sponsor of an SAE/TESAE is essential to ensure
that legal obligations and ethical responsibilities towards the safety of Participants and the safety 
of a study drug under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The Sponsor
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRBs), and Investigators.
For all studies, Investigator Safety Reports must be prepared for suspected unexpected serious 
adverse reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary.
An Investigator who receives an Investigator Safety Report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then 
notify the IRB if appropriate according to local requirements.
8.5.6.1.
Sponsor’s Responsibility
All AEs and SAEs will be reported on an annual basis to FDA in accordance with the IND 
regulation (21 CFR 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 and unexpected study-drug-related or suspected adverse reactions will be reportedto 
FDA and to all participating Investigators as an IND Safety Report within 15 calendar days of 

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the event after the Sponsor determines that the suspected adverse reaction qualifies for reporting 
(21 CFR 312.32). Any unexpected fatal or life-threatening, study-drug-related, or suspected 
adverse reaction 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 Engensis administration or in the overall conduct of the study.
8.5.7. Pregnancy and Contraception
8.5.7.1.
Pregnancy Test (Women of Childbearing Potential Only) and Contraception
Female Participants must be nonpregnant, nonlactating, and either postmenopausal for at least 
1 year, or surgically sterile for at least 3 months, or agree to use double-barrier contraception 
from 28 days prior to randomization and/or their last confirmed menstrual period prior to study 
randomization (whichever is longer) until 2 months after study completion. Male Participants 
must also agree to use double-barrier contraception from randomization until 2 months after 
study completion. 
Double-barrier female contraception may include, but is not limited to, intrauterine device with 
spermicide, female condom with spermicide, diaphragm with spermicide, cervical cap with 
spermicide.
For women of childbearing potential, a urine beta human chorionic gonadotropin (β-HCG) test 
will be performed during Screening and before randomization (Day 0); results of the test must be 
negative. The β-HCG test will also be performed at Day 180 or the last Study Visit to evaluate 
whether the Participant is pregnant.
The rhythm method and contraception by a partner are not considered acceptable methods of 
contraception.
8.5.7.2.
Pregnancy
The Investigator will collect pregnancy information on any female Participant who becomes 
pregnant while participating in this study. The initial information will be submitted to the 
Sponsor within 24 hours of learning of a Participant’s pregnancy.
Further dosing will be discontinued for any female Participant who becomes pregnant during the 
study.
The Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the Participant and the neonate, and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. A 
spontaneous abortion (occurring at < 22 weeks gestational age) or stillbirth (occurring at
> 22 weeks gestational age) is always considered to be an SAE and will be reported as such. 
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are also considered SAEs and will be reported.
Any post-study pregnancy-related SAE considered possibly, probably, or definitely related to the 
study drug by the Investigator will be reported to the Sponsor. While the Investigator is not 
obligated to actively seek this information in former study Participants, he or she may learn of an 
SAE through voluntary reporting.
The Investigator will record a narrative description of the course of each pregnancy and its 
outcome.
8.5.8. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs
Except for signs and symptoms of diabetic peripheral neuropathy (i.e., numbness, pain, tingling 
or burning sensation, cramps, and increased sensitivity to touch), all disease-related events or 
disease-related outcomes qualify as AEs or SAEs.
Immunogenicity Assessments
Pre-dose and post-dose (after 2 hours ± 1 hour post last injection) blood samples will be 
collected on Days 0 and 14, post-dose on Day 90, and pre-dose and post-dose samples will be 
collected on Day 104 for measurement of levels of TNF-α, IL-1β, IFN- γ, IL-6, IL-4, IL-10, and 
IL-12p70. 
A blood sample will be collected pre-dose on Days 0 and 90, and on Days 60, 150, and 180 for 
detection of anti-HGF antibodies.

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9.
STATISTICAL CONSIDERATIONS
Detailed statistical methods are described in the Statistical Analysis Plan (SAP).
Sample Size Determination
The sample size for the primary efficacy endpoint is calculated based on the hypothesis for the 
primary efficacy endpoints.
The primary efficacy endpoint is the change in the mean ADPS recorded at the Day 0 and 
Day 180 Visits obtained from 5 to 7 daily entries in the BPI-DPN eDiary prior to those Visits.
The statistical hypothesis for the primary efficacy endpoint (Hypothesis I) is:
H0: μt = μp versus Ha: μt ≠ μp, (I)
where µt and µp are the mean pain change from Baseline to 6-month follow-up for the Engensis 
and Placebo groups, respectively. A negative mean value means a reduction in the pain score, 
and a positive mean value means an increase in the pain score. The statistical power is 80%.
Details on the assumptions for sample size determination are described in the Statistical Analysis 
Plan.
Populations for Analyses
9.2.1. Intent-To-Treat Population
This subset includes all Participants who are randomized (Participants). All Baseline
characteristics will be summarized based on intent-to-treat (ITT). Participants 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.
9.2.2. Safety Population
The safety analysis population will contain all Participants who receive at least one Study 
Injection.
9.2.3. Modified Intent-to-Treat Population
The modified ITT (mITT) population includes all Participants who meet the following:

Underwent (any) injections

Correctly completed at least 5 out of 7 days of the BPI-DPN eDiary at Baseline and the 
6-month follow-up
Participants 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.

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9.2.4. Per Protocol (PP) Population
The Per Protocol population is a subset of mITT. It includes all mITT Participants who meet all 
the following criteria:

The Participant met major protocol eligibility criteria determined by Clinical Data 
Review Committee (CDRC) prior to database lock and breaking the randomization codes.

The Participant received all injections based on the randomized treatments and had a 
Day 180 Visit, including a 7-day ADPS.
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 Participant.
The PP population will be used in the sensitivity analyses for the primary and secondary efficacy 
endpoints.
Statistical Analyses
The Statistical Analysis Plan will be finalized prior to database lock and will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned endpoints and the statistical analyses.
9.3.1. Primary Endpoint(s)
As described in Section 3, the primary efficacy endpoint is:
Change in the means of the ADPSs from the BPI-DPN from the7 days prior to the Day 0 Visit to 
the 7 days prior to the Day 180 Visit for Engensis compared to Placebo in the ITT population
9.3.2. Secondary Endpoints
The secondary efficacy endpoints include the following:

Change in the means of the Worst Pain Scores from the BPI-DPN from the 7 days prior 
to the Day 0 Visit to the 7 days prior to the Day 180 Visit for Engensis compared to 
Placebo

Proportion of Responders (≥ 50% reduction in the means of ADPSs from the BPI-DPN) 
from the 7 days prior to the Day 0 Visit to the 7 days prior to the Day 180 Visit for 
Engensis compared to Placebo
Safety endpoints include:

Incidence of TEAEs and TESAEs for Engensis compared to Placebo

Incidence of injection site reactions for Engensis compared to Placebo

Incidence of clinically significant laboratory values for Engensis compared to Placebo

Change from Baseline in the cytokine profile through post-dose on Day 104 for Engensis 
compared to Placebo

Presence of anti-HGF antibodies following Engensis administration compared to Placebo

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9.3.3. Exploratory Efficacy Endpoints
The exploratory efficacy endpoints include the following:

Patient Global Impression of Change (PGIC) on Day 90 and on Day 180 for Engensis 
compared to Placebo

Proportion of Responders (based on ≥50% reduction in the means of ADPS from the 
BPI-DPN) from the 7 days prior to Day 180 who were Responders on Day 104 (final 
injection visit) for Engensis compared to Placebo

Changes in the Bedside Sensory Testing (BST) from Baseline to Day 90 and to Day 180
for Engensis compared to Placebo

Proportion of Responders (≥20, 30, 40, 60 and 70% reduction in the means of ADPSs
from the BPI-DPN) from the 7 days prior to the Day 0 Visit to the 7 days prior to the
Day 90 Visit and the 7 days prior to the Day 180 Visit for Engensis compared to Placebo

Changes in the means of the Average Daily Pain Scores (ADPSs) from the BPI-DPN 
from the 7 days prior to the Day 0 Visit to the 7 days prior to the Day 90 Visit for 
Engensis compared to Placebo

Changes in the severity scores (Worst Pain, Least Pain, Average Pain, and Pain Right 
Now) from the full BPI-DPN from the 7 days prior to the Day 0 Visit to the 7 days prior 
to the Day 90 Visit and the 7 days prior to the Day 180 Visit for Engensis compared to 
Placebo

Changes in Michigan Neuropathy Screening Instrument (MNSI) assessments from 
Baseline to Day 90 and to Day 180 for Engensis compared to Placebo

Changes in Quality of Life in the SF-36 from Baseline to Day 90 and Day 180 for 
Engensis compared to Placebo

Changes in Quality of Life in the EQ-5D from Baseline to Day 90 and to Day 180 for 
Engensis compared to Placebo

Changes in the means of the daily use of rescue medication from Day 0 to Day 90, from 
Day 0 to Day 180, and from Day 90 to Day 180 for Engensis compared to Placebo
9.3.4. Safety Analyses
Safety analyses in this study will evaluate the safety profile of Engensis as compared to Placebo. 
No formal statistical testing will be conducted for the safety analyses. All Participants in the 
safety subset will be included in these analyses. Participants will be grouped by treatment 
received. All summaries will be derived based on available data. No imputation will be 
performed for missing values. All safety analyses will be made on the Safety Population.
9.3.5. Interim Analysis
An interim analysis will be conducted after approximately 50% of Participants in the target 
sample size (i.e., 76 Participants) have completed the primary efficacy endpoint at Day 180 or 
have withdrawn prematurely. The conditional power will be calculated and used to support a 

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decision regarding the following three options:

Continue enrolling participants to the prespecified target sample size

Continue enrolling participants to a sample size of ___ 

Stop enrolling participants based on futility (CP<39.6%)
The Statistical Analysis Plan will describe the planned interim analysis in greater detail.

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
10.1.1.1.
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 ensuring that an IRB compliant with the requirements 
set forth in 21 CFR 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 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 prior to release of study supplies.
Health authority regulations require that all advertisements for Participant recruitment be 
approved by an IRB prior to implementation. The complete text and format must be submitted to 
the Sponsor for approval prior to IRB submission.
The Investigator is responsible for notifying the IRB of any SAEs as required by the IRB. A 
copy of the notification must be forwarded to the Sponsor or its designee.
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.
10.1.1.2.
Informed Consent Process
The Investigator has the responsibility to inform each Participant, prior to the Screening
evaluation, of the purpose of this clinical study, including possible risks and benefits, and 
document the informed consent process in the Participant’s chart. An informed consent form 
(ICF) containing the required elements of informed consent must be generated by the 
Investigator. After approval by the Sponsor, the ICF must be submitted to and approved by an 
IRB. Prior to entry into the study or initiation of any study-related procedures, the Participant
must read, sign, and date the ICF. The person executing the consent must also sign and date the 
IRB-approved ICF. One original ICF is to be retained by the Study Site, and a copy is to be 
given to the Participant. The informed consent process must be documented in the Participant’s 
source/medical record.
The ICF must be written in a language in which the Participant is fluent. If a foreign language 
translation is required, a statement of certification of the translation must be issued. Regulations 
require that foreign language ICFs be submitted to the IRB for approval. The Investigator must 
forward a copy of the ICF, the certified foreign language translation, and an IRB approval letter 
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The Investigator will explain the study purpose, procedures, and Participant’s responsibilities to 
the Participant. The Participant’s willingness and ability to meet the follow-up requirements will 
be determined and written informed consent will be obtained. The Participant will sign and date 
the ICF. The Investigator or a qualified designee will also sign and date the ICF. The original 
ICF will be retained with the Participant’s records; a copy will be provided to the Participant.
If the ICF is amended during the study, the Investigator or a qualified designee must follow all 
applicable regulatory requirements pertaining to approval of the amended ICF by the IRB. For 
each new version of the ICF, the IRB will be consulted to determine if Participants who have not 
completed the study must be re-consented to the new ICF.
10.1.1.3.
Obligations of the Sponsor and the Investigator
The Sponsor will select Investigators on the basis of multiple criteria that include their expertise 
in the area of DPN, their Site personnel’s experience in conducting investigational clinical 
studies, their prospects for recruiting Participants to the study, and the proficiency with which 
he/she responds to the requirements of the Sponsor.
The Sponsor and Investigator must comply with all applicable regulations. In addition, the 
Investigator must follow local and institutional requirements pertaining, but not limited, to 
investigational product, clinical research, informed consent including the use and disclosure of 
the Participants’ protected health information (PHI), and IRB regulations. The Sponsor will 
notify the Investigator of protocol and amendment approvals by regulatory authorities when 
applicable.
The Investigator and clinical research coordinator will be available to respond to reasonable 
requests and audit queries made by the authorized regulatory agency representatives. The 
Investigator and clinical research coordinator will provide the Sponsor with advance written 
notification if they plan to relocate to another institution.
Except where the Investigator’s signature is specifically required, the term “Investigator” asused 
in this protocol and protocol-related documents is understood to refer to the Principal
Investigator (PI) or appropriate Study Site personnel whom the PI designates to perform a certain 
duty. This delegation of authority needs to be documented appropriately and signed by the PI. 
The PI is ultimately responsible for the conduct of all aspects of the clinical study.
Sub-investigators or other appropriate Study Site personnel (e.g., listed on the Form FDA 1572) 
are eligible to sign for the PI on laboratory reports and may be designated to verify and 
electronically sign eCRFs.
10.1.2. Financial Disclosure
10.1.2.1.
Conflict of Interest Policy
The independence of the study from any actual or perceived influence is critical. Therefore, any 
actual conflict of interest or financial interest of persons who have a role in the design, conduct, 
analysis, publication, or any aspect of this study should be disclosed. Furthermore, persons who 
have a perceived conflict of interest or financial interest will be required to have such conflicts 
managed in a way that is appropriate to their participation in the design and conduct of this 

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study.
10.1.2.2.
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
10.1.3. Participant Selection and Informed Consent Process
The Investigator will screen Participants who meet the eligibility criteria. The Investigator will 
not exercise selectivity, so that bias is prevented. All Participants must sign an ICF that has been 
approved both by the Sponsor and by the reviewing IEC/IRB. The informed consent should be in 
accordance with the current revision of the Declaration of Helsinki as well as current ICH and 
Good Clinical Practice (GCP) guidelines.
Prior to randomization, Participants will receive a comprehensive explanation of the proposed 
treatment including the nature and risks of the study, alternate therapies, any known AEs, the 
investigational status of the product, and the other elements that are part of obtaining proper 
informed consent. Potential Participants will also receive a detailed explanation of the proposed 
use and disclosure of their protected health information, including specifically any saved blood 
samples. Potential Participants will be allowed sufficient time to consider participation in the 
study after having the nature and risks of the study explained to them. The ICF must not include 
any exculpatory statements. The ICF and any separate Health Insurance Portability and 
Accountability Act (HIPAA) authorization form, if applicable, should be reviewed and approved 
by the Sponsor prior to IRB/IEC submission.
The Sponsor will provide to the Investigator, in writing, any new information that significantly 
bears on the Participants’ risk in receiving the study drug. This new information will be 
communicated by the Investigator to Participants in accordance with IRB/IEC requirements. The 
ICF will be updated, and Participants will be re-consented, if necessary.
Site staff may conduct standard-of-care procedures and employ recruitment efforts prior to 
Participant consent; however, before any protocol-specified procedures are performed to 
determine protocol eligibility, an ICF must be signed. Participants will be given a copy of all 
consent forms that they sign.
By signing the ICF, the Participant agrees to complete all evaluations required by the study 
unless the Participant withdraws voluntarily or is terminated from the study for any reason.
10.1.4. Data Protection and Confidentiality
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. At the end of 
the study, a clinical study report will be written by the Sponsor.

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10.1.4.1.
Confidentiality
Participant confidentiality and privacy are strictly held in trust by the Investigators, their staff, 
and the Sponsor. This confidentiality is extended to cover testing of biological samples in 
addition to the clinical information relating to Participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the Sponsor.
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical companies supplying study product may inspect all 
documents and records required to be maintained by the Investigator including, but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for Participants. The 
Clinical Study Site will permit access to such records.
The Participant’s contact information will be securely stored at each Clinical Site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB/IEC, applicable regulatory agencies, 
institutional policies, and/or Sponsor requirements.
Participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored by the Sponsor or their designee. This will not include the 
Participant’s contact or identifying information. Rather, individual Participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by Clinical Sites and by research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived.
10.1.4.2.
Data Protection
In accordance with GCP and with the national data protection laws, all information concerning 
the Participants 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 
developed or acquired in connection with the study is 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 the Sponsor in writing. Such consent will 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.
Potential Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the Participant who will be required to give consent for their data to be used as 
described in the ICF.
Potential Participants must be informed that their medical records may be examined by Clinical 

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Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities.
10.1.5. Committee Structure
10.1.5.1.
Data Safety Monitoring Board
An independent Data Safety Monitoring Board (DSMB) has been chartered for this study to 
review all safety data during the study and safeguard the interests of the Participants. The 
objectives of the DSMB meetings are to review the safety outcomes of the study and provide 
guidance to the Sponsor regarding the safety of Engensis. The DSMB will meet periodically and 
review a limited set of unblinded tables and/or listings, including all reported AEs/TEAEs, 
SAEs/TESAEs, and AESIs. The data analyses for the DSMB meetings will be directly provided 
to the DSMB members; no data will be released to the Sponsor and blinded designees. No 
adjustment will be made for multiple testing due to the DSMB data review.
The DSMB will consist of two physicians with expertise in clinical studies and one statistician.
Members of the DSMB will be independent of study conduct and free of conflict of interest, or 
measures should be in place to minimize perceived conflicts of interest. An independent 
biostatistician will be available for consultation.
The DSMB will operate under the rules of the charter, which have been reviewed at 
organizational meetings of the DSMB. Each data element that the DSMB requires to assess the 
safety of Engensis will be agreed upon prior to study start. Routine DSMB meetings will be 
regularly scheduled per the DSMB Chair to review safety and 12-week pooled all-cause 
mortality data, including unblinded Participant narratives. The DSMB Chair may request 
additional unblinded information at any time to further understand a safety trend. Ad hoc DSMB 
meetings can be convened at any time at the discretion of the DSMB Chair or the Sponsor. 
However, the DSMB Chair may not share any unblinded information with the Sponsor unless it 
is deemed necessary for the Sponsor to address a potential safety concern. The DSMB will 
provide recommendations to the Sponsor in accordance with the DSMB Charter.
10.1.5.2.
Institutional Biosafety Committee
The Sites at which this study 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 or Synthetic Nucleic Acid Molecules (April 2019), promulgated by the 
NIH Office of Science Policy (OSP).
The Investigator will be responsible for petitioning the IBC and obtaining approval prior to 
enrolling any Participant 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 the OSP.

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10.1.6. Data Quality Assurance
10.1.6.1.
Clinical Monitoring
The Sponsor or designee will visit (in person or remotely, according to FDA Guidance on 
Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic, March 2020, 
updated 27 Jan 2021) the Clinical Site for monitoring. The Sponsor’s clinical monitor shall 
ensure that the Investigator understands the investigational status of the product, all protocol 
requirements, and his/her regulatory responsibilities as an Investigator. The clinical monitors will 
visit (in person or remotely) Clinical Sites at appropriate intervals to ensure compliance with the 
protocol and to verify the accuracy, completeness, and correctness of data reported and 
accountability of Engensis supplies.
The clinical monitor shall be available for consultation by the Investigator and serves as a liaison 
between the Clinical Site and the Sponsor. The clinical monitor or other authorized 
representatives of the Sponsor may inspect all data, documents, and records required to be 
maintained by the Investigator including, but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for Participants. The Clinical Site will permit access to such 
records. The Investigator will obtain, as part of the informed consent process, HIPAA-compliant 
authorization from Participants to use and disclose the requisite and relevant PHI and permission 
for authorized representatives of the Sponsor, or regulatory authorities including the FDA, to 
review, in confidence, any records identifying Participants in the clinical study.
10.1.6.2.
Access to Study Documents and Study Monitoring
The Sponsor or its designee will 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 Participant 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 that study Participants 
begin to be enrolled to ensure that Participants are being properly selected and that study data are 
being correctly recorded.
During the study, the clinical monitor will visit (in person or remotely) the study facilities 
regularly and use telephone and written communications on an ongoing basis to maintain current 
knowledge of the study. During periodic visits to the Clinical Site (in person or remotely), the 
monitor will review the source documents 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. Source documents must contain all data entered in the EDC system. All data generated 
during this study and the source documents from which they originated are subject to inspection 
by the Sponsor or its representatives, and the FDA and other regulatory agencies.
Upon completion of the study, the clinical monitor will conduct a final visit (closeout) to the 
Site. The objectives of this visit are to confirm 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.

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10.1.6.3.
Quality Assurance and Quality Control
Each Clinical Site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation, and completion.
Quality control (QC) procedures will be implemented beginning with the data entry system, and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the sites for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical study is conducted, data are generated, and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements [e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices 
(GMP)].
The Clinical Site will provide direct access to all study-related source data documents and 
reports for the purpose of monitoring and auditing by the Sponsor, and inspection by local and 
regulatory authorities.
The Pharmacist must ensure that Engensis and Placebo are stored as specified in the protocol and 
Pharmacy Manual. The Pharmacist must maintain accurate records of the receipt of all Engensis 
and Placebo supplies and details of the dispensing and administration as specified in the 
Pharmacy Manual. The Engensis and Placebo must be administered only at the institution 
specified on the Form FDA 1572 for the Site.
The study will be conducted in accordance with the principles of GCPs: 21 CFR 50, 21 CFR 54, 
21 CFR 56, and 21 CFR 312, Subpart D; the 2016 ICH Guideline on Good Clinical Practice 
(ICH E6(R2)); and HIPAA.
The Investigator at the Clinical Site must sign the Investigator Statement ofAgreement.
10.1.6.4.
Data Quality Assurance
The Sponsor’s employees and/or their contracted representatives use 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 
GCP 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 ICFs, source documents, 
medical records, and 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.
All Participant data relating to the study will be recorded on an electronic CRF (eCRF) unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

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The Investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents.
The Sponsor is responsible for the data management of this study including quality checking of 
the data.
The Sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized Site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of Participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
10.1.6.5.
Data Collection and Management Responsibilities
Data collection is the responsibility of the clinical study staff under the supervision of the 
Investigator. During the study, the Investigator will maintain complete and accurate 
documentation for the study.
All eCRF data will be entered into a validated database compliant with 21 CFR Part 11. 
Laboratory data will be either manually entered or imported to the clinical database 
electronically. All data entry, verification, and validation will be performed in accordance with 
the current SOPs of the Sponsor or its designee. The database will be authorized for lock once no 
data queries are outstanding, all study data are considered clean, and all defined procedures are 
completed.
The Clinical Site will be provided with eCRFs and ePRO/eCOA devices in which to record all 
the protocol-specified data for each Participant. Entries made in the eCRF must be verifiable 
against source documents, or in certain circumstances as directed by the Sponsor, entries will 
have been directly entered into the eCRF; in such cases, the entry in the eCRF will be considered 
as the source data. Data reported in the eCRF that are derived from source documents should be 
consistent with the source documents or the discrepancies should be explained. The Investigator 
will be responsible for reviewing all data and eCRF entries and will sign and date the designated 
pages in each Participant’s eCRF, verifying that the information is true and correct. Queries 
generated by Data Management will be sent to the Clinical Site for resolution. The Investigator is 
responsible for the review and approval of all responses to eCRF queries.
10.1.6.6.
Protocol Deviations
The Investigator will not deviate from this protocol for any reason without prior written approval 
by the Medical Monitor on behalf of the Sponsor except in the case of a medical emergency 
when the change is necessary to eliminate an apparent and immediate hazard to the Participant. 
In the event of such an emergency, the Investigator will notify the Medical Monitor immediately 
by phone, notify the IRB, and confirm with the Medical Monitor in writing within 5 working 
days of the change being implemented.
Protocol deviations will be tracked through the EDC.

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10.1.6.7.
Source Documents
As defined in the ICH Guidelines for Good Clinical Practice E6(R2), Section 1.52, source 
documents may include: original documents, data, and records (e.g., hospital records, clinical 
and office charts, laboratory notes, memoranda, Participant’s diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x rays, Participant files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical study).
Source documents provide evidence for the existence of the Participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s Site.
The Investigator may need to request previous medical records or transfer records, depending on 
the study. Current medical records must also be available.
10.1.7. Data Management
All Participant data will be entered into a password-protected validated EDC system by 
authorized Site personnel according to the CRO’s SOPs.
Data discrepancies identified via programmed edit checks, manual data review or discovered 
during data monitoring will be addressed and resolved. An audit trail in the EDC system will list 
all changes made to the data, with a date/time stamp and user initials. Upon database lock, 
occurring after data are declared clean and eCRFs have been approved by the Investigator, the 
CRO will provide SAS datasets to the Sponsor and designated Statistician for data analysis via 
secure data transfer specified in the Study Data Management Plan.
10.1.8. Recordkeeping and Retention
Data generated for the study should be stored in a limited-access file area and be accessible only 
to representatives of the Clinical Site, the Sponsor and its representatives, and FDA/relevant 
health authorities/regulatory agencies. All reports and communications relating to Participants
will identify Participants only by Participant identification number. Complete Participant
identification will be kept by the Investigator. This information will be treated with strict 
adherence to professional standards of confidentiality.
The Investigator must in reasonable time, upon request from any properly authorized officer or 
employee of the FDA/relevant health authority/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/regulatory agency, the Investigator will contact the Sponsor immediately. The 
Investigator will also grant the Sponsor’s 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:

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
A completed and signed Form FDA 1572. If, during the study, any changes occur that are 
not reflected on the current 1572, a new 1572 must be completed and returned to the 
Sponsor or its designee for submission to the FDA

Current signed curricula vitae (within 2 years prior to study initiation) and current 
medical licenses for the Investigator and all co-Investigators listed on the 1572

A copy of the original approval by the IRB for conducting the study. Renewals, with 
continuance of the study, must be submitted at yearly intervals or as required by IRB 
policy.

A copy of the IRB-approved ICF

The IRB member list and/or DHHS General Assurance Number (if the IRB hasan 
Assurance number)

A copy of the original approval by the IBC for conducting the study, if applicable. 
Renewals, with continuance of the study, must be submitted at yearly intervals or as 
required by IBC policy.

Signed Financial Disclosure Forms 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 Investigator

The signature page of the IB signed and dated by the Investigator
In addition to the documents listed above, the Clinical Site will also retain the following items:

Certifications and laboratory reference ranges for all local laboratories used for this study

A copy of delegation of authority log

All original ICFs with required signatures

All IRB correspondence (e.g., informed consent [including any approved revisions], 
protocol, AE, advertisements, newsletters)

All IBC correspondence

A copy of the Study Monitoring Log

Clinical and nonclinical supply shipment forms

Copies of all pertinent correspondence pertaining to the study (except budget issues) 
between the Sponsor and the Site

Copies of all SAE reports submitted to the Sponsor

Copies of all Investigator Safety Reports submitted to the Site by the Sponsor

Copies of approved package labelling, if applicable

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10.1.9. Study and Site Start and Closure
The study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification documenting the reason for study suspension or 
termination will be provided by the Sponsor to Investigators and regulatory authorities. If the
study is prematurely terminated or suspended, the Investigator will promptly inform Participants
and the IRB and will provide the reasons for the termination or suspension. Participants will be 
contacted, as applicable, and be informed of changes to Study Visit schedules.
The Sponsor reserves the right to discontinue the study for any safety, ethical, or administrative 
reason at any time.
The Sponsor or designee reserves the right to close a Clinical Site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion.
The Investigator may initiate Clinical Site closure at any time, provided reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a Clinical Site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines

Inadequate recruitment of Participants by the Investigator

Discontinuation of further study drug development
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, IRBs, the regulatory authorities, and any CROs used in the study of the reason for 
termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator will promptly inform the Participants and should ensure appropriate Participant
therapy and/or follow-up.
10.1.10.
Publication Policy
The study will be conducted in accordance with the publication and data sharing policies and 
regulations as defined in the agreement between the Sponsor and the institution. In addition, this 
study will be registered at www.ClinicalTrials.gov and in any other protocol registries required 
by the regions in which the study is conducted, and the results from this study will become 
publicly 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.
10.1.11.
Insurance
Matters relating to insurance for this study are to be defined in the agreement between the 
Sponsor and the institution.

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Appendix 3.
Grading of Injection Site Reactions
A global assessment across all injection sites on each leg is to be performed following each 
treatment. The injection site reaction with the most severe pain/tenderness, 
erythema/itching/urticaria, and bruising/swelling/bleeding on each leg is to be used for reporting
injection site reaction grades (mild, moderate, severe, or life-threatening) following each 
treatment. Severe (Grade 3) and potentially life-threatening (Grade 4) Injection Site Reactions 
will be AESIs. Two sources were used for compiling the following grading guidelines for 
Injection Site Reactions (Table 6):  
1. FDA Guidance: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials, September 2007. 
2. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) 
v5.0, Nov. 27, 2017.
Table 6
Injection Site Reaction Grading
Reaction at 
Injection 
Sitea
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially 
Life-Threatening 
(Grade 4)
Pain, 
tenderness
Mild discomfort to 
touch, with or 
without warmth, 
erythema, itching
Does not interfere 
with daily activity
No or local treatment
Symptoms with or 
without swelling 
and/or phlebitis
Interferes with daily 
activity
Use of non-narcotic 
pain reliever
Symptoms with or 
without swelling or 
phlebitis or mild 
infection
Precludes daily 
activity
Use of narcotic pain 
reliever and/or oral 
antibiotics
Symptoms with
severe infection or 
tissue injury or 
ulceration
Requires advanced 
medical and/or 
surgical care, 
including IV 
medications
Erythema, 
itching, 
urticaria
Mild, localized 
itching, erythema or 
urticaria.
Does not interfere 
with activity
Use of topical 
treatment
Symptoms with skin 
changes beyond local 
injection site(s)
Interferes with 
movement and daily 
activity
Use of NSAIDs and/or 
antihistamines
Symptoms with 
widespread skin 
changes
Interferes with daily 
activity
Use of oral steroids or 
immunosuppressives
Bronchospasm, 
anaphylactoid, or 
anaphylactic 
reaction
Requires advanced 
medical care, 
including IV 
medication
Bruising, 
swelling, 
bleeding
Mild, localized 
swelling, ecchymosis 
or hematoma
Does not interfere 
with activity
No treatment
Moderate ecchymosis 
or hematoma
Interferes with daily 
activity
Requires leg elevation, 
conservative treatment
Extensive 
ecchymoses, large 
hematoma
Precludes activity
Requires minimally 
invasive drainage
Hypotension, life-
threatening 
consequences
Requires 
transfusion, urgent 
intervention
a Injection Site Reactions are a category of AEs and should be recorded as AEs using these grading guidelines.

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Appendix 4.
Prohibited Medications and Procedures
Table 7
Prohibited Medications – Steroids
Drug
Example of Common 
Name(s)
Maximum Dose Allowed 
During Study
Steroids
Injected or oral 
corticosteroidsa
prednisone,
betamethasone,
dexamethasone, 
cortisone, 
hydrocortisone, 
triamcinolone
None
Topical corticosteroids on 
the lower legs or feet
prednisone, 
betamethasone, 
dexamethasone, 
cortisone, 
hydrocortisone, 
triamcinolone
None on the lower legs or 
feetb
a Inhaled, ocular, and intra-articular steroids are allowed.
b Topical corticosteroid use is allowed on body surfaces other than the lower legs and feet.
Table 8
Prohibited Medications and Procedures – Opioids and Other Therapies
Drug or Procedure
Maximum Dose Allowed During Study
Acupuncture
None
Anesthetic creams (for use only during injections) and 
patches, including capsaicin, on lower legs and feet
None
Benzodiazepines
None, except for stable bedtime dose
Gabapentin, pregabalin
None
Isosorbide dinitrate spray on lower legs and feet
None
Opioids (e.g., morphine, oxycodone, tramadol, 
methadone, fentanyl)
None, except after trauma or surgery
Skeletal muscle relaxants (e.g., cyclobenzaprine, 
metaxalone, chlorzoxazone)
None
Transcutaneous electrical nerve stimulation
None

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Appendix 5.
Abbreviations and Definitions
10.5.1. Abbreviations
Abbreviation
Definition
ADPS
Average Daily Pain Score
AE
adverse event
AESI
adverse event of special interest
ALS
amyotrophic lateral sclerosis
ALT
alanine transaminase (SGPT)
Anti-HCV Ab
hepatitis C antibodies
APR
Accurate Pain Reporting
AST
aspartate transaminase (SGOT)
β-HCG
Beta human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
BPI-DPN
Brief Pain Inventory for Diabetic Peripheral Neuropathy
BPNS
Brief Peripheral Neuropathy Screening
BUN
blood urea nitrogen
BST
Bedside Sensory Testing
CABG
coronary artery bypass grafting
cDNA
complementary DNA
CDRC
Clinical Data Review Committee
CFR
Code of Federal Regulations
CKD-EPI
chronic kidney disease epidemiology collaboration 
CLI
critical limb ischemia
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRO
clinical research organization
CS
clinically significant
CT
Computed Tomography
DIP
distal interphalangeal
DKA
diabetic ketoacidosis
DM
diabetes mellitus
DMC
Data Monitoring Committee

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Abbreviation
Definition
DNA
deoxyribonucleic acid
DPN
diabetic peripheral neuropathy
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture system
eDiary
electronic diary
eGFR
estimated glomerular filtration rate
EQ-5D
EuroQol Health Utilities Index
FIT
Fecal Immunochemical Test
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
GLP
Good Laboratory Practice
HADS
Hospital Anxiety and Depression Scale
HbA1c
Hemoglobin A1c
HBV
hepatitis B virus
HBcAb
hepatitis B core antibody (IgG and IgM)
HBsAb
antibody to hepatitis B surface antigen
HBsAg
hepatitis B surface antigen
HCMV
human cytomegalovirus
HCV
hepatitis C virus
HDL-C
high-density lipoprotein cholesterol
HEENT
head, eyes, ears, nose, and throat
Hgb
Hemoglobin
HGF
hepatocyte growth factor
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HPV
primary human papillomavirus
HTLV
human T cell lymphotropic virus
IB
Investigator’s Brochure
IBC
Institutional Biosafety Committee
ICF
informed consent form

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Abbreviation
Definition
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IFN-γ
interferon gamma
IgG
immunoglobulin G
IgM
immunoglobulin M
IHD
ischemic heart disease
IL-1β
interleukin-1beta
IM
Intramuscular
IND
Investigational New Drug application
IRB
Institutional Review Board
ISDN
isosorbide dinitrate
ISR
injection site reaction
ITT
intent-to-treat
IUD
intrauterine device
IWRS
Interactive Web Response System
LDL-C
low-density lipoprotein cholesterol
mITT
modified intent-to-treat
MNSI
Michigan Neuropathy Screening Instrument
NCS
not clinically significant
NDA
New Drug Application
NHU
nonhealing foot ulcer
NIH
National Institutes of Health
NRS
Numerical Rating Scale
OSP
Office of Science Policy
P-A
posterior to anterior
Pap
Papanicolaou
PAD
peripheral arterial disease
PCR
polymerase chain reaction
PCP
Phencyclidine
PDR
proliferative diabetic retinopathy
PE
physical examination
PGIC
Patient Global Impression of Change
PHI
protected health information
PI
Principal Investigator

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Abbreviation
Definition
PKC
Protein kinase C
PP
per protocol
PRO
Pro re nata (“as the situation demands”)
PRR
Placebo Response Reduction
PSA
Prostate Specific Antigen
QC
quality control
QoL
Quality of Life
ROS
reactive oxygen species
SAE
serious adverse event
SAP
statistical analysis plan
SF-36
36-Item Short Form Health Survey
SoA
Schedule of Activities
SOP
standard operating procedure
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
TCA
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TENS
transcutaneous electrical nerve stimulation
THC
Cannabinoid
TNF-α
tumor necrosis factor alpha
VAS
Visual Analog Scale
VEGF
vascular endothelial growth factor
WFI
water for injection

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10.5.2. Definitions
Active Infection
Chronic infection or severe active infection that may compromise the 
Participant’s well-being or participation in the study, in the Investigator’s 
judgment
Allowed Opioid Use
When Participants require opioids for non-DPN post-trauma pain or pain after 
surgery that was unanticipated during Screening, short-acting formulations 
are to be used, enabling a more rapid washout and reduced effect on DPN-
related pain
Average Daily Pain Score
(ADPS)
The mean of at least 5 daily pain scores recorded for Question 5 of the 
BPI-DPN (Section 10.7) in eDiary during the 7 days prior to the Visits on 
Day 0, Day 90, and Day 180
Worst Daily Pain Score
The mean of at least 5 worst daily pain scores recorded for Question 3 of the 
BPI-DPN (Section 10.7) in eDiary during the 7 days prior to the Visits on Day 
0, Day 90, and Day 180
Day 14, etc.
Day 14 (for example) refers specifically to the actual day of the Visit
designated as the Day 14 Visit, and not to the 14th day of the study for a 
Participant.
Drug Abuse
The habitual taking of addictive or illegal drugs
Drugs of Abuse
Amphetamines, barbiturates, benzodiazepines, buprenorphine, cocaine, 
fentanyl, meperidine, methadone, opiates, oxycodone, oxymorphone, 
phencyclidine, tramadol
EMLA Cream
A mixture of lidocaine 2.5% and prilocaine 2.5%
First-degree relative
Parent, sibling, or child
Highly Effective Contraception 
Method
See Section 8.5.7
Injection Site Reaction
An AE located in close proximity to the injection sites on the calves and first 
observed within 48 hours following Study Injections
Investigator
The PI or appropriate Study Site personnel whom the PI designates to perform 
a certain duty
Lower Leg
The part of the leg between the knee joint and the ankle joint. Does not 
include the foot.
Medical Monitor
The Responsible Medical Officer or designee
Participant
An individual who has signed informed consent to be entered into the study
Placebo
Placebo comprises 45 mg sodium chloride and 55 mg sucrose in 5 mL of 
water for injection. Engensis vials contain the same excipients.
Primary HPV Test
A Primary HPV test is an HPV test that is done by itself for screening. The 
US Food and Drug Administration has approved certain tests to be primary 
HPV tests. This is the recommended test by the ACS; however, it is not 
always available.

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Safety Analysis Population
All Participants who receive a Study Injection
Site
A clinical research facility participating in the VMDN-003-2 study
Sponsor
Helixmith Co., Ltd. and its representatives contracted to provide services for 
study conduct
Stable Dosing Regimen
≤50% change in total daily dose relative to dosing at baseline of 
any medication
Stage 4 or 5 Kidney Disease
eGFR < 30 mL/min/1.73 m2
Study Drug
Engensis or Placebo
Study Injection
Injection of Engensis or Placebo
Treatment Cycle
Two sets of Study Injections 14 days apart comprising a single dose
Unstable Diabetes
Elevations and/or depressions in blood sugar causing episodes of diabetic 
ketoacidosis (DKA) and/or hypoglycemia

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Participant’s Initials: _______
Date: _______

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Appendix 9. Short Form Health Survey (SF-36) Example
Short Form 36 (SF-36) Quality of Life Scale

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Administering Bedside Sensory Testing (BST)
Administration. An Investigator should administer BST at Baseline (Day 0) and Days 90 and 
180 Visits. All sensory tests are being performed at 3 predefined locations: dorsum of the foot, 
mid-shin, and mid-thigh, except low threshold mechanoreceptive function, which will be 
conducted at the bottom of the foot only.
The Participant should be seated comfortably during all five procedures of the BST.
Procedure 1: Neuropen Test. The Neuropen test allows assessment of the extent of damage of
the low threshold mechanoreceptive small fibers.
Method of Administration. Application of the von Frey filament (10 g) to ten random locations 
on the bottom of the foot
Summary Score. Frequency count of von Frey stimuli detected (range 0-10; 0 = none detected; 
10 = all detected) for bottom of the foot; then reverse score frequency count to align with 
interpretation of other sensory tests.
Procedure 2: Foam Brush Test. Allodynia, a phenomenon in which exposure to a non-painful 
stimulus is perceived as painful, is associated with small fiber neuropathy. The foam brush test 
allows for assessment of Dynamic Mechanical Allodynia.
Method of Administration. Stroke each anatomical location with brush making plus shape.
Summary Score. Single 0-10 NRS pain intensity rating for each anatomical location
Procedure 3: Safety Pin Test. Hyperalgesia, a phenomenon in which exposure to a painful 
stimulus is perceived as more painful than it should be, is associated with small fiber neuropathy. 
The safety pin test allows for the assessment of punctate hyperalgesia.
Method of administration. Tap safety pin five times within each anatomical location
Summary Score. Average of five 0-10 NRS pain intensity ratings in each anatomical location
Procedure 4: Von Frey Filament Test. Temporal Summation is a phenomenon in which 
exposure to the application of consecutive repeated stimuli is perceived as more painful than 
exposure to a single stimulus. The Von Frey filament test allows for quantification of Temporal 
Summation.
Method of Administration. Apply von Frey filament five times in rapid succession within each 
anatomical location
Summary Score. Delta between first and last 0-10 NRS pain intensity rating in each anatomical 
location
Procedure 5: Tuning Fork Test. Allodynia, a phenomenon in which exposure to a non-painful 
stimulus is perceived as painful, is associated with small fiber neuropathy. The tuning fork test 
allows for assessment of Cold Allodynia.
Method of Administration. Apply tuning fork for 10 seconds at each anatomical location.
Summary Score. Single 0-10 NRS pain intensity rating for each anatomical location

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How to Use the Michigan Neuropathy Screening Instrument
History. The history questionnaire is self-administered by the Participant. 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 
Participant version.
Upon completion of the questionnaire, the study coordinator will check the questionnaire for 
completeness. Note, the Participant will be asked 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. Participants, 
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 Participant can 
at the great toe (e.g., examiner’s DIP joint of the first finger versus Participant’s toe). If the 
examiner feels vibration for 10 or more seconds on his or her finger, then vibration is considered 
decreased. A study should be given when the tuning fork is not vibrating to be certain that the 
Participant 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 Participant 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 Participant 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 Participant’s foot be 
supported (i.e., allow the sole of the foot to rest on a flat, warm surface). The 10-gram filament 
should initially be pre-stressed (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 Participant, 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 

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correct responses indicate reduced sensation, and no correct answers translates into absent 
sensation.

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Section # and Name
Description of Change(s)
Brief Rationale
Removed direct bilirubin, indirect 
bilirubin, and globulin (also in 
Section 8.4.6.1.3 Liver Function 
Tests)
Total bilirubin results sufficient; 
globulin testing no longer available 
in most sites
Added text “to calculate eGFR” to 
Cystatin C testing (also in Section 
8.4.6.1.4 Clinical Chemistry)
Define use for Cystatin C results
Trace and interpretation will be 
signed by Investigator or delegated 
staff following review of findings 
and stored in Participant’s records 
(also in Section 8.4.3.12 Lead 
Electrocardiogram)
Clarification of need for signatures 
to indicate review; interpretation of 
ECG results to be collected
Methaqualone and propoxyphene 
removed from urine drug analysis 
testing
Drugs are no longer available in the 
US
Specified saliva analysis for ethyl 
alcohol testing at site during 
Screening. Noted that drug analysis 
will be performed by central 
laboratory at other time points.
Kit provided to sites for drug testing 
uses saliva analysis for ethyl alcohol. 
Clarify that central laboratory will 
conduct all other drug testing.
HTLV I/II antibody with reflex 
confirmatory assay, quantitative 
HBV viral load assay, and positive 
qualitative PCR for HCV added 
(also in Section 8.1, Screening and 
Section 8.4.6.1.7 Viral Screening).
Add further specifics for viral 
screening as clarification for sites
Add language for follow-up 
telephone call after injections to 
study injection footnote
Reiterate that injection site reactions 
must be checked 2 to 3 days after 
injection
Administration of BST on Day 0 to 
follow randomization (also in 
Section 8.3.3 Bedside Sensory 
Testing)
Clarification of test timing on Day 0
2.2.7 Clinical Data
Removed statement about no 
systemic effects
Correction

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Section # and Name
Description of Change(s)
Brief Rationale
2.3.1 Risk Assessment
Under Angiogenesis and promotion 
of tumor growth (cancer), added 
hyperplasia of vasa vasorum and 
exclusion of Participants with 
cerebrovascular accident or 
myocardial infarction
Provide additional risk information
4.1.1 First Treatment 
Cycle
Vital signs, physical exam, drug 
tests, medical history, BST, 
pregnancy test added to list
Provide complete list of assessments 
during First Treatment Cycle
4.1.2 Second Treatment 
Cycle
Vital signs, physical exam, drug 
tests, medical history, BST, MNSI, 
pregnancy test added
Provide complete list of assessments 
during Second Treatment Cycle
5.1 Inclusion Criteria
Inclusion Criterion #2 – Added 
“such as” before progressive end-
organ disease
Clarify that progressive end-organ 
disease is an example of significant 
medical problems
Inclusion Criterion #12 – Added to 
ensure potential Participant can 
complete all screening activities 
within 45 days
Potential Participant needs to be 
rescreened if screening activities 
cannot be completed within 45-day 
window
5.2 Exclusion Criteria
Exclusion Criterion #3 – Modified 
language around timing of 
gabapentin and pregabalin use
Clarification
Exclusion Criterion #7 –
Hypertension definition modified to 
systolic blood pressure > 180 mmHg 
on tolerable doses of standard 
antihypertensive medications
Review of literature supports 
definition of hypertension of systolic 
blood pressure > 180 mmHg on 
antihypertensive medication
Exclusion Criterion #16 – Added 
language to remove toe amputations 
as exclusion
Allow potential Participants with toe 
amputations on study
Exclusion Criterion #23 – Restored 
exclusion for Participants who have 
not been cancer-free for ≥5 years; 
restored in-situ basal cell, squamous 
cell cancers as excluded
Ensure that potential Participants 
with higher likelihood of cancer are 
excluded
Exclusion Criterion #25 generalized
Exclude any active acute or chronic 
hepatitis B
Exclusion Criterion #26 generalized
Exclude any active hepatitis C

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Section # and Name
Description of Change(s)
Brief Rationale
Exclusion Criterion #27 – added “or 
current medical conditions” to 
reasons that Investigator can exclude 
potential Participants
Allow Investigator to exclude 
potential Participant based on 
current medical conditions 
Exclusion Criterion #29 – Cannabis 
use removed as exclusion
Cannabis use not exclusionary
Exclusion Criterion #31 – Modified 
language regarding stable dose 
requirement
Simplify explanation of stable dose
Exclusion Criterion #33 – Changed 
use of investigational drug or 
treatment exclusion from 6 months 
to 30 days
Effects from most drugs gone after 
30 days
Exclusion Criterion #35 – Added 
exclusion of potential Participants 
who were recently treated for 
COVID-19 and have ongoing 
sequelae
Exclude potential Participants who 
might have complications from 
recent COVID-19 infection
6.2.2 Storage of Engensis 
and Placebo
Added that products should be 
placed in quarantine in cases of 
temperature excursion
Ensure quarantining of product not 
maintained at correct temperature
6.2.3 Product 
Accountability
Added that all investigational 
product is to be returned to the 
Sponsor after reconciliation
Ensure that sites know to return all 
drug to sponsor
6.3.3 Blinding
Exceptions to remaining blinded 
were added for unblinded Medical 
Monitor, Site’s unblinded 
Pharmacist or delegated staff
Clarification of unblinded personnel
6.5 Concomitant Therapy, 
10.3 Care of Patients with 
Diabetes Mellitus and 
Conditions Associated 
with DPN Management
Removed Appendix 3; added that all 
concomitant therapies to be captured 
on eCRF
Description of Standard of Care for 
DPN not needed in protocol 
(information available from medical 
organizations); add method for 
recording concomitant therapies
6.5.1 Rescue Medication
Reorganized description of 
acetaminophen use as rescue 
medication
Clarification

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Section # and Name
Description of Change(s)
Brief Rationale
6.6 Dose Interruption
Added language in case full set of 
injections cannot be prepared
Add circumstance for which 
unintentional interruptions of 
Engensis injections would be 
allowed
6.7.2 Medications and 
Procedures That May 
Interfere with Assessment 
of Pain
“If not using a stable dose” added to 
duloxetine
Clarification and consistency
8.1 Screening (Days -52
to -7)
Added weight, waist circumference 
to physical exam
Make consistent with Schedule of 
Activities
Added “where applicable” to Cancer 
Screening Tests
Clarification to add screening tests 
for cancer only as applicable to 
potential Participant
Urine drug analysis added
Make consistent with Schedule of 
Activities
8.4.2 Medical History and 
Familial History of Cancer
“Including DPN” added to past 
diabetes history
Ensure that DPN history captured by 
site
8.4.6.1 Local and Central 
Laboratory Assessments
Rearranged text regarding local lab 
testing
Ensure that local labs used for 
Screening tests only
8.4.7 Retinal Fundoscopy
Added allowance for fundoscopy 
within 30 days prior to Day 180
Allow flexibility of retinal 
fundoscopy timing for Day 180
8.5.1 Time Period and 
Frequency for Collecting 
AE, SAE, TEAE, and 
TESAE Information
Added that medical events before 
study start are to be recorded as 
medical history; TESAEs added; 
timing for collection of adverse 
event reporting reorganized
Provide clearer definition of 
terminology based on timing of 
events
8.5.2 Method of Reporting 
AEs, SAEs, TEAEs, and 
TESAEs
Corrected section title, text; added 
AESIs, TESAEs
Correction, consistency with other 
parts of protocol
8.5.4 Adverse Events of 
Special Interest; 8.5.4.4 
COVID-19 Infections
Added COVID-19 infections that 
occur after randomization to list of 
AESIs
Capture COVID-19 infections as an 
AESI in the safety database
8.5.4.3 Injection Site 
Reactions
Timing of first observation and 
grading, together with close 
proximity to injection site of ISR 
added for consideration of ISR as 
AE; timing for follow-up for 
unresolved ISRs added
Additional information for ISRs to 
qualify as AEs; length of follow-up 
required for unresolved ISRs

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Section # and Name
Description of Change(s)
Brief Rationale
8.5.7.1 Pregnancy Test
Need for male Participants to use 
double-barrier contraception during 
study added
Ensure that male Participants 
practice double-barrier contraception 
as well
9.1 Sample Size 
Determination; 9.3.1 
Primary Endpoint(s)
“Mean” added to ADPS for 
statistical analysis for primary 
efficacy endpoint
Clarification that mean ADPS will 
be used
9.3.2 Secondary 
Endpoints, 9.3.3 
Exploratory Efficacy 
Endpoints
Rearranged and updated
Match endpoint list with Section 3 
Objectives and Endpoints 
10.1.5.1 Data Safety 
Monitoring Board
Added TEAEs, SAEs, TESAEs, and 
AESIs to list of items being 
reviewed by DSMB
DSMB to review all safety data
Changed from 6- to 12-week pooled 
data
Longer period for pooled data is 
appropriate for timing of enrollment 
and Participant visits during study
Narratives rather than Participant 
profiles will be provided to DSMB 
(also in Section 6.3.3 Blinding)
Clarification
10.1.6.2 Access to Study 
Documents and Study 
Monitoring
Removed designation of CRO for 
study monitoring
Study monitoring being conducted 
by Sponsor
10.2.1 Definition of AE
Reworded AE definition
Clarification
10.4 Prohibited 
Medications and 
Procedures
Table 9 – Added gabapentin, 
pregabalin
Both medications not allowed on 
trial
10.5.2 Definitions 
Injection Site Reaction – Changed 
from 24 to 48 hours
Correction; consistency with earlier 
text
Primary HPV test definition added
Clarification of what constitutes 
primary HPV test
Propoxyphene removed from list of 
Drugs of Abuse
Propoxyphene no longer available in 
the US
Uncontrolled hypertension deleted
Definition no longer needed
10.9 Appendix 9. Short 
Form Health Survey (SF-
36)
Added “Example” to the title
Appendix content may not be an 
exact replica of the actual survey 
used

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11.
REFERENCES

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1 Figueroa-Romero C, Sadidi M, Feldman EL. Mechanisms of disease. The oxidative stress theory of diabetic 
neuropathy. Rev Endocr Metab Disord. 2008;9(4):301-14.
2 Kumagai AK. Glucose transport in brain and retina: implications in the management and complications of 
diabetes. Diabetes Metab Res Rev. 1999;15(4):261-73.
3 Tien T, Barrette KF, Chronopoulos A, Roy S. Effects of high glucose-induced Cx43 downregulation on occludin 
and ZO-1 expression and tight junction barrier function in retinal endothelial cells. Invest Ophthalmol Vis Sci. 
2013;54(10):6518-25.
4 Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813-20.
5 de M Bandeira S, da Fonseca LJS, da S Guedes G, Rabelo LA, Goulart MOF, Vasconcelos SML. Oxidative stress 
as an underlying contributor in the development of chronic complications in diabetes mellitus. Int J Mol Sci. 
2013;14:3265-84.
6 Yanagida K, Maejima Y, Santoso P, et al. Hexosamine pathway but not interstitial changes mediates glucotoxicity 
in pancreatic β-cells as assessed by cytosolic Ca2+ response to glucose. Aging. 2014;6(3):207-14.
7 Tang WH, Martin KA, Hwa J. Aldose reductase, oxidative stress, and diabetic mellitus. Front Pharmacol. 
2012;3:87.
8 Vedantham S, Ananthakrishnan R, Schmidt AM, Ramasamy R. Aldose reductase, oxidative stress and diabetic 
cardiovascular complications. Cardiovasc Hematol Agents Med Chem. 2012;10(3):234-40.
9 Gray SP, Di Marco E, Okabe J, et al. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated 
atherosclerosis. Circulation. 2013;127(18):1888-902.
10 Naudi A, Jove M, Ayala V, et al. Cellular dysfunction in diabetes as maladaptive response to mitochondrial 
oxidative stress. Exp Diabetes Res. 2012;2012:696215.
11 Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional 
significance and therapeutic opportunities. Antioxid Redox Signal. 2010;12(4):537-77.
12 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(9):2178-83.
13 Farber DC, Farber JS. Office-based screening, prevention, and management of diabetic foot disorders. Prim Care. 
2007;34(4):873-85, vii-viii.
14 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(11):2365-70.
15 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(3):629-41.
16 Nakagami H, Kaneda Y, Ogihara T, Morishita R. Hepatocyte growth factor as potential cardiovascular therapy. 
Expert Rev Cardiovasc Ther. 2005;3(3):513-9.
17 Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J Biochem. 
1996;119(4):591-600.
18 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(6):1160-5.
19 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(3):273-84.
20 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(7):1403-7.
21 Jiang W, Hiscox S, Matsumoto K, Nakamura T. Hepatocyte growth factor/scatter factor, its molecular, cellular 
and clinical implications in cancer. Crit Rev Oncol Hematol. 1999;29(3):209-48.
22 Ebens A, Brose K, Leonardo ED, et al. Hepatocyte growth factor/scatter factor is an axonal chemoattractant and a 
neurotrophic factor for spinal motor neurons. Neuron. 1996;17(6):1157-1172.
23 Gascon E, Gaillard S, Malapert P, et al. Hepatocyte growth factor-Met signaling is required for Runx1 extinction 
and peptidergic differentiation in primary nociceptive neurons. J Neurosci. 2010;30(37):12414-23.
24 Maina F, Hilton MC, Andres R, Wyatt S, Klein R, Davies AM. Multiple roles for hepatocyte growth factor in 
sympathetic neuron development. Neuron. 1998:20(5):835-46.
25 Maina F, Hilton MC, Ponzetto C, Davies AM, Klein R. Met receptor signaling is required for sensory nerve 
development and HGF promotes axonal growth and survival of sensory neurons. Genes Dev. 
1997;11(24):3341-50.
26 Yang XM, Toma JG, Bamji SX, et al. Autocrine hepatocyte growth factor provides a local mechanism for 
promoting axonal growth. J Neurosci. 1998;18(20):8369-81.

Helixmith Co., Ltd.
CONFIDENTIAL
VMDN-003-2
Version 6.0
127
Final: 28 Jan 2022
27 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(2):431-45.
28 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.
29 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(6):779-81.
30 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;17(1):42-50.
31 Tönges 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. J Neurochem. 2011;117:892-903.
32 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 Ther. 2001;8:181-9.
33 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 USA. 1994;91:4357-61.
34 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(1):129-40.
35 Fontham ETH, Wolf AMD, Church TR, et al. Cervical cancer screening for individuals at average risk: 2020 
guideline update from the American Cancer Society. CA Cancer J Clin. 2020. doi:10.3322/caac.21628.
36 Brenner H, Chang-Claude J, Jansen L, et al. Reduced risk of colorectal cancer up to 10 years after screening, 
surveillance or diagnostic colonoscopy. Gastroenterology. 2014;146:709-17.
37 Doubeni CA, Corley DA, Quinn VP, et al. Effectiveness of screening colonoscopy in reducing the risk of death 
from right and left colon cancer: a large community-based study. Gut. 2018:67:291-8. doi: 10.1136/gutjnl-2016-
312712. Epub 2016 Oct 12.
38 Adler A, Geiger S, Keil A, et al. Improving compliance to colorectal cancer screening using blood and stool based 
tests in patients refusing screening colonoscopy in Germany. BMC Gastroenterol. 2014;14:183.
39 Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: recommendations for physicians and 
patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;153:307-23.
40 Toyoda T, Nakyama T, Kusunoki Y, Iso H, Suzuki T. Sensitivity and specificity of lung cancer screening using 
chest low-dose computed tomography. Brit J Cancer. 2008;98:1602-7.
41 Jemal A, Fedewa SA. Lung cancer screening with low-dose computed tomography in the United States—2010 to 
2015. JAMA Oncol. 2017;3(9):1278-81.
42 Dajac J, Kamdar J, Moats A, Nguyen B. To screen or not to screen: low dose computed tomography in 
comparison to chest radiography or usual care in reducing morbidity and mortality from lung cancer. Cureus. 
2016;8(4). e589. doi: 10.7759/cureus.589.
43 Huo J, Shen C, Volk RJ, et al. Use of CT and chest radiography for lung cancer screening before and after 
publication of screening guidelines: intended and unintended uptake. JAMA Intern Med. 2017;177(3):439-41.
44 US Preventative Services Task Force. Screening for prostate cancer. JAMA. 2018; 319(18):1901-13.
45 Herman WH, Pop-Busui R, Braffett BH, et al. Use of the Michigan Neuropathy Screening Instrument as a 
measure of distal symmetrical peripheral neuropathy in type 1 diabetes: results from the diabetes Control and 
Complications Trial/Epidemiology of Diabetes Interventions and Complications. Diabet Med. 2012;29(7):937-44.
46 Feldman EL, Stevens MJ, Thomas PK, et al. A practical two-step quantitative clinical and electrophysiological 
assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17(11):1281-89.
47 Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for 
BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-16.
48 Giovannucci E, Michaud D. The role of obesity and related metabolic disturbances in cancers of the colon, 
prostrate, and pancreas. Gastroenterology. 2007;132(6):2208-25.
49 Stocks T, Lukanova A, Johansson M, et al. Components of the metabolic syndrome and colorectal cancer risk; a 
prospective study. Int J Obes (Lond). 2008;32:304-14.
50 Weigl K, Tikk K, Hoffmeister M, et al. Prevalence of a first-degree relative with colorectal cancer and uptake of 
screening among persons 40 to 54 years old. Clin Gastroenterol Hepatol. 2019;S1542-3565(19)31384-9. doi: 
10.1016/j.cgh.2019.11.044. Online ahead of print.
51 Johnatty SE, Tan YY, Buchanan DD, et al. Family history of cancer predicts endometrial cancer risk 
independently of Lynch Syndrome: Implications for genetic counselling. Gynecol Oncol. 2017;147:381-7.
52 Bailey-Wilson JE, Amos CI, Pinney SM et al. A major lung cancer susceptibility locus maps to chromosome 
6q23–25. Am J Hum Genet. 2004;75:460-74.

Helixmith Co., Ltd.
CONFIDENTIAL
VMDN-003-2
Version 6.0
128
Final: 28 Jan 2022
53 Bratt O, Drevin L, Akre O, Garmo H, Stattin P. Family history and probability of prostate cancer, differentiated 
by risk category: a nationwide population-based study. J Natl Cancer Inst. 2016;108(10):djw110.
54 Bruner DW, Moore D, Parlanti A, et al. Relative risk of prostate cancer for men with affected relatives: systematic 
review and meta-analysis. Int J Cancer. 2003;107:797-803.
55 Cox VL, Bamashmos AAS, Foo WC, et al. Lynch syndrome: Genomics update and imaging review. 
RadioGraphics. 2018;38:483-99.
56 Patel A. Does the role of angiogenesis play a role in atherosclerosis and plaque instability? Anat Physiol. 
2014;4(3). doi:10.4172/2161-0940.1000147.
57 Simó R, Carrasco E, García-Ramírez M, Hernández C. Angiogenic and antiangiogenic factors in proliferative 
diabetic retinopathy. Curr Diabetes Rev. 2006;2(1):71-98.
58 Nishida T, Tsuji S, Tsujii M, et al. Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis. 
Am J Gastroenterol. 2006;101(1):70-5.
59 Kolb R, Sutterwalla FS, Zhang W. Obesity and cancer: inflammation bridges the two. Curr Opin Pharmacol. 
2016; 29:77–89. doi:10.1016/j.coph.2016.07.005.
60 Shlomai G, Neel B, LeRoith D, et al. Type 2 diabetes mellitus and cancer: The role of pharmacotherapy. J Clin 
Oncol. 2016;34(35):4261-9.
61 Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP. Type 2 diabetes and cancer: Umbrella review of 
meta-analyses of observational studies. BMJ. 2015;350:g7607.
62 Munsell MF, Sprague BL, Berry DA, Chisholm G, Trentham-Dietz A. Body mass index and breast cancer risk 
according to postmenopausal estrogen-progestin use and hormone receptor status. Epidemiol Rev. 
2014;36:114-36. 
63 Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to 
obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88. 
64 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a 
prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–38. 
65 Wiseman M. The second World Cancer Research Fund/American Institute for Cancer Research expert report. 
Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Proc Nutr Soc. 2008;6:253-6. 
66 Hu MB, Liu SH, Jiang HW, Bai PD, Ding Q. Obesity affects the biopsy-mediated detection of prostate cancer, 
particularly high-grade prostate cancer: a dose-response meta-analysis of 29,464 patients. PLoS One. 
2014;9(9):e106677.
67 Charles M, Ejskjaer N, Witte DR, Borch-Johnsen K, Lauritzen T, Sandbaek A. Prevalence of neuropathy and 
peripheral arterial disease and the impact of treatment in people with screen-detected type 2 diabetes: the 
ADDITION-Denmark study. Diabetes Care. 2011;34:2244-9.