A Phase IIB Pilot Study to Confirm the Feasibility and Tolerability of a Modified Dosage Regimen of AMG0001 in Subjects With Critical Limb Ischemia
Phase: PHASE2
Conditions: Critical Limb Ischemia, Vascular Diseases, Peripheral Arterial Disease
Sponsor: AnGes USA, Inc.

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AnGes, Inc                                            CONFIDENTIAL 
 
 
 
 
AMG0001 
Protocol AG-CLI-0209 
 
A PHASE IIB PILOT STUDY TO CONFIRM THE FEASIBILITY AND 
TOLERABILITY OF A MODIFIED DOSAGE REGIMEN OF AMG0001 IN 
SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
 
  
 
 
March 3, 2016 
 
 
 
Sponsor: AnGes, Inc. 
CONFIDENTIAL: The information submitted herein constitutes trade secrets and/or is 
confidential information which is the property of  AnGes Inc. as provided by 21 CFR §20.61. 
Do not disclose without prior written permission from Sponsor. 
 

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AnGes, Inc                                            CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
Protocol Number: 
AG-CLI-0209 
Title: 
A PHASE IIB PILOT STUDY TO CONFIRM THE FEASIBILITY AND 
TOLERABILITY OF A MODIFIED DOSAGE REGIMEN OF 
AMG0001 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA 
Protocol Version Date: 
03 March 2016 
Amendment Number: 
04 
 
 
By signing this cover page I attest that I have read and understand the contents of the original Clinical 
Protocol AG-CLI-0209 and any subsequent amendments. I agree to adhere to the design, conduct and 
reporting requirements of the study as stated in the clinical protocol and to my obligations to The 
Sponsor as described in the protocol and executed contracts between myself, my Institution and The 
Sponsor. 
Investigator's Signature:  
_____________________________________________ 
Investigator's Name:  
_____________________________________________ 
Institution:  
 
_____________________________________________ 
Date: (DD/MM/YYYY format)_____________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1. 
INTRODUCTION ......................................................................................................10 
1.1. 
Rationale for the Current Study, AG-CLI-0209 .........................................................10 
2. 
STUDY OBJECTIVES ..............................................................................................11 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Study Population .........................................................................................................12 
3.2. 
Inclusion criteria .........................................................................................................13 
3.3. 
Exclusion Criteria .......................................................................................................14 
3.4. 
Administration of Study Product ................................................................................15 
4. 
DESCRIPTION OF STUDY PROCEDURES ...........................................................16 
4.1. 
Informed Consent .......................................................................................................16 
4.2. 
Medical History ..........................................................................................................16 
4.3. 
Physical Examination .................................................................................................17 
4.4. 
Concomitant Medications ...........................................................................................17 
4.5. 
Electrocardiogram .......................................................................................................18 
4.6. 
Angiogram ..................................................................................................................18 
4.7. 
Peripheral Vascular Intervention History (or Update) ................................................18 
4.8. 
Hemodynamic Measurements ....................................................................................19 
4.9. 
Assessment of CLI and Ulcer Photography and Tracings ..........................................19 
4.10. 
Laboratory Tests .........................................................................................................20 
4.11. 
Ischemic Rest Pain Measurement ...............................................................................21 
4.12. 
Post-Dosing Procedures ..............................................................................................21 
4.13. 
Adverse Event Review ...............................................................................................21 
4.14. 
Retinopathy .................................................................................................................22 
5. 
OVERVIEW OF STUDY PROCEDURES ................................................................23 
5.1. 
Screening ....................................................................................................................26 
5.2. 
Confirmation of Subjects’ CLI Stability Pre-Dose .....................................................26 
5.3. 
Dosing Visit Study Procedures:  Day 0 ......................................................................27 
5.3.1. 
Pre-Dosing Procedures ...............................................................................................27 
5.3.2. 
Dosing Procedures:  Day 0 .........................................................................................27 
5.3.3. 
Post-Dosing Procedures:  Day 0 .................................................................................28 
5.4. 
PK Sampling Visit:  Days 4 ........................................................................................28 

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5.5. 
Dosing Visit Study Procedures:  Days 14 (± 2 days), 28 (± 2 days), and 42 (± 2 
days) ............................................................................................................................28 
5.6. 
Dosing Visit Study Procedures:  Month 3 (± 7 days) .................................................29 
5.6.1. 
Post-Dosing Procedures:  Month 3 (± 7 days) ............................................................30 
5.6.2. 
Dosing Visit Study Procedures:  Month 3+14 days (± 2 days), Month 3+28 days 
(± 2 days), and Month 3+42days (± 2 days) ...............................................................30 
5.7. 
Follow-Up Visit Study Procedures:  Month 6 (± 7 days) ...........................................31 
5.8. 
Dosing Visit Study Procedures:  Month 9 (± 7 days) .................................................31 
5.9. 
Dosing Visit Study Procedures:  Month 9+14 days (± 2 days), Month 9+28 days 
(± 2 days), and Month 9+42 days (± 2 days) ..............................................................32 
5.10. 
Dosing Visit Study Procedures:  Month 12 (± 7 days) ...............................................32 
5.11. 
PK Sampling Visit:  Month 12 + 4 Days ....................................................................33 
5.12. 
Dosing Visit Study Procedures:  Month 12+14 days (± 2 days), Month 12+28 days 
(± 2 days), and Month 12+42days (± 2 days) .............................................................33 
5.13. 
Follow-Up Visit Study Procedures:  Month 15 (± 7 days) .........................................33 
5.14. 
Follow-Up Visit Study Procedures:  Month 18 (± 7 days) .........................................33 
5.15. 
Assessments to Complete Prior to a Planned Intervention (Surgical 
Revascularization or Major Amputation) ...................................................................34 
5.16. 
Interim Telephone Contacts ........................................................................................34 
5.17. 
Unscheduled Visits .....................................................................................................34 
5.18. 
Ulcer Healing ..............................................................................................................35 
5.19. 
Diabetic control ..........................................................................................................35 
5.20. 
Documentation of Deaths ...........................................................................................35 
6. 
SCREEN FAILURES AND SUBJECT WITHDRAWALS ......................................35 
6.1. 
Withdrawals ................................................................................................................35 
6.2. 
Screen Failures ............................................................................................................36 
6.3. 
Study Suspension or Termination ...............................................................................36 
7. 
STUDY PRODUCT ...................................................................................................37 
7.1. 
Product Description ....................................................................................................37 
7.2. 
Packaging and Labeling ..............................................................................................37 
7.3. 
Storage ........................................................................................................................37 
7.4. 
Study Product Accountability .....................................................................................38 
8. 
SAFETY REPORTING ..............................................................................................39 

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8.1. 
Adverse Events and Serious Adverse Events .............................................................39 
8.1.1. 
Adverse Events Associated with Worsening CLI ......................................................39 
8.1.2. 
SAEs Associated with Worsening CLI.......................................................................40 
8.1.3. 
Deaths Following Worsening of CLI .........................................................................40 
8.1.4. 
Deaths .........................................................................................................................40 
8.2. 
Definitions ..................................................................................................................40 
8.2.1. 
Treatment-Emergent Adverse Events .........................................................................40 
8.2.2. 
Serious Adverse Event ................................................................................................41 
8.2.3. 
Expected Adverse Events ...........................................................................................41 
8.2.4. 
Intensity or Severity of Adverse Events .....................................................................42 
8.2.5. 
Relatedness of Adverse Event to an Intervention .......................................................42 
9. 
EVALUATIONS AND STATISTICAL METHODS ................................................43 
9.1. 
Evaluations .................................................................................................................43 
9.2. 
Statistical Methods ......................................................................................................43 
9.2.1. 
Disposition, Compliance, Demographic and Background Characteristics 
(Including Medical History) .......................................................................................43 
9.2.2. 
Statistical Analysis for Efficacy and Safety ...............................................................43 
9.2.3. 
Windows for time points ............................................................................................44 
10. 
SAFETY FOLLOW-UP PROGRAM ........................................................................45 
11. 
ADMINISTRATIVE PROCEDURES .......................................................................46 
11.1. 
Institutional Review Board/ Ethics Committee ..........................................................46 
11.2. 
Institutional Biosafety Committee (IBC) ....................................................................46 
12. 
CONFIDENTIALITY ................................................................................................47 
APPENDIX A. STUDY PRODUCT PREPARATION &ADMINISTRATION .......................48 
APPENDIX B. HEMODYNAMIC PROCEDURES .................................................................56 
APPENDIX C. RUTHERFORD CLASSIFICATION ...............................................................58 
APPENDIX D. WOUND CARE GUIDELINES .......................................................................59 
APPENDIX E. THE VISUAL ANALOG SCALE (VAS) PROCEDURES -MEASURING 
REST PAIN ................................................................................................................60 
APPENDIX F. POST 18-MONTH FOLLOW-UP QUESTIONNAIRE ....................................61 
APPENDIX G. PREGNANCY PREVENTION AND REPORTING ........................................63 
 
 

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LIST OF TABLES 
Table 1: 
Dosage Regimen for the AG-CLI-0209 Study ...........................................................11 
Table 2: 
List of Screening Procedures ......................................................................................23 
Table 3: 
Schedule of Study Procedures ....................................................................................24 
Table 4: 
Schedule of Sample Collection for the Serum HGF Protein & PCR for HGF 
Plasmid Assays ...........................................................................................................25 
 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABI 
Ankle Brachial Index 
AE 
Adverse Event 
AKA 
Above Knee Amputation 
ALT 
Alanine Aminotransferase  
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
ASO 
Arteriosclerosis Obliterans 
AST 
Aspartate Aminotransferase 
bFGF 
basic Fibroblast Growth Factor 
BKA 
Below Knee Amputation 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bp 
base pairs 
bpm 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations (U.S.) 
CI 
Confidence interval 
Cl 
Chloride 
CLI 
Critical Limb Ischemia 
cm 
Centimeter 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CRO  
Contract Research Organization 
CTA 
Computed tomography angiography 
CV 
Curriculum vitae 
CVD 
Cardiovascular Disease 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ELISA 
Enzyme Linked Immunosorbent Assay 
ESRD 
End Stage Renal Disease  
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FBG 
Fasting Blood Glucose 
FDA 
Food and Drug Administration 
FGF 
Fibroblast Growth Factor 
FSH 
Follicle-Stimulating Hormone 
HbA1c 
Glycated hemoglobin 
HBO 
Hyperbaric Oxygen 
HCC 
Hepatocellular Carcinoma 
HDL 
High Density Lipoprotein 
HGF 
Hepatocyte Growth Factor 
HR 
Hazard Ratio 
HUV 
Human Umbilical Vein  

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IBC 
Institutional Biosafety Committee 
IC 
Intermittent Claudication 
IM 
Intramuscular 
IRB 
Institutional Review Board 
ITT 
Intention To Treat 
IV 
Intravenous 
K 
Potassium 
kg 
Kilogram 
KM 
Kaplan Meier 
LDH 
Lactic Acid Dehydrogenase 
LDL 
Low Density Lipoprotein 
LLOQ 
Lower limit of quantification 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
mm 
Millimeter 
mg 
Milligram 
mmHg 
Millimeters of Mercury 
MRA 
Magnetic resonance angiogram 
Na 
Sodium 
NIH 
National Institutes of Health 
OBA 
Office of Biotechnology Activities (Division of the National Institutes of Health) 
PAD 
Peripheral Arterial Disease 
PAP 
Papanicolaou 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PSA 
Prostate-specific antigen 
PTA 
Percutaneous Transluminal Angioplasty 
PTFE 
Polytetrafluoroethylene 
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SFA 
Superficial Femoral Artery 
TAO 
Thrombo-angiitis Obliterans 
TBI 
Toe Brachial Index 
TcPO2 
Transcutaneous Oxygen Tension 
VAS 
Visual Analogue Scale 
VEGF 
Vascular Endothelial Growth Factor 
VSMC 
Vascular Smooth Muscle Cells 
WBC 
White Blood Cell 
 
 
 

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1. 
INTRODUCTION 
Peripheral artery disease (PAD) affecting the lower limbs results from the consequences of 
atherosclerosis. Critical limb ischemia (CLI) is the severest form of PAD and occurs when tissue 
viability is jeopardized at rest. The chief manifestations of CLI include ischemic pain at rest 
(Rutherford class 4, Fontaine class 3) and/or tissue loss (Fontaine class 4 or Rutherford class 5 
when tissue loss is minor and Rutherford class 6 when tissue loss is major) resulting in ischemic 
ulceration and gangrene. 
The management of CLI includes risk factor modification including the treatment of 
hyperlipidemia, hypertension, diabetes, and smoking.  In addition, analgesics (often opioids) are 
used for the relief of rest pain.  Meticulous foot care and local wound care are important to 
prevent or manage tissue loss.  Finally the majority of subjects are treated with antiplatelet 
therapy and a statin. The current management, in addition to the above, includes 
revascularization by surgery or by endovascular interventions. Up to 15% of subjects are 
unsuitable for either of these forms of revascularization procedures while others (~40%) are at 
high risk (poor candidates) for surgical revascularization. Even though revascularization 
procedures have improved survival and may delay the need for major amputation (amputation at 
or above the ankle), their effectiveness is often short-lived and surgery is associated with 
significant morbidity. 
Subjects unsuitable for revascularization are candidates for major amputation. This procedure is 
associated with considerable morbidity, a poor quality of life, and complications including, in 
some cases, death. 
Subjects with CLI have, overall, a poor prognosis with a 5-year mortality of 50%. Their quality 
of life is comparable to the quality of life of subjects with advanced cancer. No systemic drug 
treatment is available for the treatment of CLI. There is an urgent medical need for additional 
management options. 
1.1. 
Rationale for the Current Study, AG-CLI-0209 
In summary, the clinical data generated to date through AMG0001 early phase studies have 
shown efficacy of AMG0001 in improving tissue perfusion (increase in TcPO2), ulcer healing, 
rest pain relief, toe pressure and TBI improvement.  In addition, the safety data to date in the 
AMG0001 clinical program confirms that the product is well tolerated.  Based on these results, a 
phase 3 study AG-CLI-0206 was planned as a registration study and received SPA approval by 
the FDA. It will be undertaken in subjects with CLI who have no option for revascularization 
and also subjects who have poor option (high risk) for revascularization by surgery. The study 
will confirm the safety and efficacy of AMG0001. 
Prior to undertaking the phase 3 study, a pilot study to confirm the feasibility of the study-related 
activities in study 0206 and the tolerability of the dosage regimen will be undertaken in 8-10 
subjects. In this pilot study, subjects will receive 4 sets of injections of HGF plasmid two weeks 
apart starting at Day 0 and again at Month 3 (first cycle) and at Month 9 and  again at Month 12 
(second cycle), see table below. 

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Table 1: 
Dosage Regimen for the AG-CLI-0209 Study 
First Cycle 
Day 0, Day 14, Day 28, and Day 42 
(4 sets of injections, 2 weeks apart; each set is 4 mg subdivided into 8 
injections of 0.5 mg of HGF plasmid in 3 mL saline) 
 
Month 3, Month 3+14 days, Month 3+28 days, and Month 3+42 days 
(4 sets of injections, 2 weeks apart; each set is 4 mg subdivided into 8 
injections of 0.5 mg of HGF plasmid in 3 mL saline) 
Second Cycle 
Month 9, Month 9+14 days, Month 9+28 days, and Month 9+42days 
(4 sets of injections, 2 weeks apart; each set is 4 mg subdivided into 8 
injections of 0.5 mg of HGF plasmid in 3 mL saline or matching placebo) 
 
Month 12, Month 12+14 days, Month 12+28 days, and Month 12+42 
days 
(4 sets of injections, 2 weeks apart; each set is 4 mg subdivided into 8 
injections of 0.5 mg of HGF plasmid in 3 mL saline) 
Note: for the purposes of this study a month is defined as 30 days; days 14, 28 and 42 are calculated from either 
Day 0, Month 3, Month 9 or Month 12. 
2. 
STUDY OBJECTIVES 
The primary objectives of the clinical trial are: 
1. To confirm the feasibility of study-related activities and the tolerability of a modified 
dosage regimen of AMG0001 in CLI 
2. To evaluate the safety of AMG0001 
3. 
STUDY DESIGN 
This is a pilot study of AMG0001 (HGF plasmid) in approximately 8-10 CLI subjects.  Subjects 
eligible for the study are CLI subjects (due to atherosclerotic arterial disease of the lower limb) 
with no option for revascularization by surgical bypass or endovascular intervention, or have a 
poor option (high risk) for revascularization by surgical bypass but no option for an endovascular 
intervention (Type D lesions or worse using the TASC II classification).  Clinic visits will occur 
for screening, Days 0, 14, 28, 42, Month 3, Month 3+14 days, Month 3+28 days, Month 3+42 
days, Month 6, Month 9, Month 9+ 14 days, Month 9 + 28 days, Month 9 +42 days, Month 12, 
Month 12+14 days, Month 12+28 days, Month 12+42 days, Month 15, and Month 18. Safety 
follow-up data using a questionnaire will be obtained every 6 months for 1.5 years after the 18 
month study visit.  The total duration of the study will be up to 37 months.   All subjects will 
receive AMG0001 intramuscularly in the muscles of the diseased limb based on the location of 
disease.  
Note: for the purposes of this study a month is defined as 30 days; days 14, 28 and 42 are calculated from 
either Day 0, Month 3, Month 9 or Month 12.  
 

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3.1. 
Study Population 
Subjects (40-90 years old) with Chronic Critical Limb Ischemia who have: 
Severe ischemic pedal rest pain (nocturnal metatarsalgia, Rutherford 4) in the index lower limb 
with ankle and/or toe systolic pressures of less than 50 and 30 mmHg, respectively, classical 
features of rest pain and on opioids for pain relief. Classical features include pedal pain that is 
severe and typically occurs at night when the limb is no longer in a dependent position but in 
severe cases can be continuous. The pain is localized in the distal part of the foot. Partial relief 
may be obtained by the dependent position whereas cold and elevation of the lower limb 
aggravates the pain. Severe pain responds only to opioids. 
OR 
Ischemic ulcers /gangrene (Rutherford 5) in the affected lower limb with ischemic ulcer 
measurements <20 cm2 in area (<10 cm2 for ischemic ulcers at the heel) for the largest ischemic 
ulcer with or without rest pain, and ankle and/or toe pressures less than 70 and 50 mmHg, 
respectively. 
IN ADDITION, SUBJECTS WILL HAVE: 
No option for revascularization by endovascular intervention or bypass surgery (see definitions 
below). 
No option is defined as the inability to receive an endovascular intervention or surgical bypass 
procedure due to inflow, conduit or outflow reasons or due to a severe and irreversible co-
morbidity. 
OR 
Poor option (high risk) for revascularization by surgery (see definition below) but no option for 
revascularization by an endovascular procedure (Type D lesions or worse using the TASC II 
classification).1 
Definition for poor option (high risk) for revascularization surgery: 
Anatomic 
 Need for a tibial level synthetic or cryoperserved bypass  
 Need for use of great saphenous vein < 3mm in diameter for tibial level bypass based 
on venous duplex ultrasound 
 Need for use of spliced vein or single piece of non-great saphenous vein < 3mm in 
diameter, for tibial level bypass 
 Distal target unsuitable for bypass, e.g. < 2mm in diameter or circumferentially 
calcified  
                                                 
 
1Norgren, L., Hiatt, W.R., et al., Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC 
II),   Eur J. VascEndovascSurg, Vol 33, S1-S70; 2007. 

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 Open lower extremity wound that would preclude construction of bypass 
OR 
Medical 
 Subjects with severe cardiac, respiratory, or renal disease who are at increased risk of 
complications from surgery or anesthesia, e.g., significant heart disease (NYHA class 
III or IV), severe Chronic Obstructive Pulmonary Disease (COPD), or severe renal 
disease (creatinine clearance 30-45 mL/minute). 
 Subjects with ischemic rest pain (Rutherford Class 4) will be included if the rest pain 
is severe, requires opioids, has the classical descriptions, and the ankle and/or toe 
pressures are less than 50 mm Hg or 30 mm Hg, respectively. 
 All subjects with severe Rutherford 4 who enter the study should have rest pain that is 
stable for at least 2 weeks prior to entry into the study. All Rutherford 5 subjects 
should have stable wounds with no infection. 
 Subjects will have been on a statin (unless there is a contraindication) and an 
antiplatelet agent (unless there is a contraindication) for 2 weeks or more prior to Day 
0. 
3.2. 
Inclusion criteria 
Subjects must meet the following inclusion criteria in order to be enrolled into the study.   
1. Subjects with CLI (Severe Rutherford 4 and Rutherford 5) who have: 
 No option for revascularization by endovascular intervention or surgical bypass 
 
 
OR 
 Poor option (high risk) for revascularization by surgery and no option for an 
endovascular intervention (see Section 3.1 for full definition for appropriate 
inclusions). 
2. Subjects 40-90 years of either gender who have signed an informed consent form either 
directly or through a legally authorized representative. 
3. Subjects currently are taking a statin and an anti-platelet agent (e.g., clopidogrel, 
ticlopidine, aspirin, etc.) for 2 weeks or more prior to Day 0 as part of their standard of 
care, unless contraindicated. Subjects for whom these agents are contraindicated will 
have the reason for contraindication recorded in their case report form (CRF).  
4. Only women who are post-menopausal, who are surgically sterile, or who have 
documented primary ovarian insufficiency (premature ovarian failure) are eligible for 
inclusion (Please see Appendix G for further information). 
5. If a male subject is of reproductive potential, he must agree to use an accepted and 
effective (barrier) form of birth control starting with the first dose of study product and 
continue for 12 weeks from the last dose of study product.  This applies to both courses 
of treatment. 

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6. Subjects with a previous medical history of myocardial infarction and/or stroke should 
have adequate management of risk factors to prevent secondary occurrence.   (See 
Section 4.2 Medical History for guidelines on appropriate secondary prevention.) 
7. Subjects should have the ability to understand the requirements of the protocol and agree 
to return for the required study visits and assessments. 
The index leg will be the leg with the greater severity of CLI disease.  Entry requirements 
apply to the index leg.  The index leg may also be referred to as the treated leg or affected 
leg in the text of this protocol or other study documents.   If the subject has two legs that 
have the same Rutherford classification (severe Rutherford 4 or Rutherford 5) and are 
both eligible for treatment, the leg with greater disease severity (based on more extensive 
necrosis or more extensive/deeper ulceration(s), difference in ABI or TBI ≥ 0.1, and/or 
more extensive vascular disease based on the angiogram) will be chosen as the index leg.   If 
there is no clinical, hemodynamic or angiographic or other evidence to determine which leg 
has greater disease severity, the subject will be excluded from the study. 
3.3. 
Exclusion Criteria 
1. Subjects whose CLI status is unstable (spontaneous marked improvement or marked 
worsening during the screening period) or who have excessive tissue necrosis that is 
unlikely to benefit from medication, or those poor option subjects requiring immediate 
revascularization by surgery. Stability of the CLI status will be confirmed by the 
Principal Investigator prior to randomization and retrospectively reviewed by the entry 
committee. 
2. Subjects who may require a major amputation (amputation at or above the ankle) within 4 
weeks of Day 0 (± 4 weeks of Day 0). 
3. Subjects with ulcers with exposure of tendons, osteomyelitis or uncontrolled infection or 
with the largest ulcer that is greater than 20 cm2 in area (>10 cm2 area if on the heel). 
4. Subjects with purely neuropathic or venous ulcers. 
5. Subjects in Rutherford 6 class. 
6. Subjects who have had revascularization by surgery or angioplasty within 3 months, 
unless the procedure has failed based on the anatomy or the hemodynamic measurements. 
7. Subjects with a diagnosis of Buerger’s disease (Thrombo-angiitis Obliterans). 
8. Subjects currently receiving immunosuppressive, chemo or radiation therapy.  
9. Evidence or history of malignant neoplasm (clinical, laboratory or imaging) except for 
successfully excised basal cell or squamous cell carcinoma, or successfully excised early 
melanoma of the skin.  Subjects, who had successful tumor resection or radio-
chemotherapy of breast cancer more than 10 years prior to inclusion in the study, and 
with no recurrence, may be enrolled in the study. Subjects, who had successful tumor 
resection or radio-chemotherapy of all other tumor types and have been in remission for 
more than 5 years prior to inclusion in the study, and with no recurrence, may be enrolled 
in the study.  A dermatological exam will have ruled out any skin cancer. 

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10. Subjects who have proliferative retinopathy, or moderate or severe non-proliferative 
retinopathy, from any cause (ETDRS Score > 35), clinically significant macular oedema 
or previous panretinal photocoagulation therapy (Results from the Early Treatment 
Diabetic Retinopathy Study. Ophthalmology May 1991 Supplement 98: 823-833). 
11. Females of child-bearing potential are excluded.  This includes females who are either 
post-menopausal, surgically sterile (see Appendix G for further information of surgical 
sterility) or have documented primary ovarian insufficiency.   
12. Subjects with severe renal disease defined as significant renal dysfunction evidenced by 
an estimated creatinine clearance of <30 mL/minute (calculated using the Cockroft Gault 
formula), or receiving chronic hemodialysis therapy.  
13. A Stroke, TIA or MI within 3 months of entry into the study. 
14. Subjects with known liver disease (e.g., hepatitis B or C or cirrhosis of the liver). 
15. A subject with HIV, AIDS, or severe uncontrolled ulcerative colitis or Crohn’s disease. 
16. Subjects with a current, uncorrected history of alcohol or substance abuse.  
17. Subjects that have been administered rhPDGF (e.g, becaplermin) or other growth factors 
locally within one month of randomization.  
18. Subjects who have received another investigational drug within 30 days of randomization 
or have previously received any gene transfer therapy within 3 years of entering the 
study. 
Note: No waivers will be granted for subjects regarding Inclusion/Exclusion criteria. 
3.4. 
Administration of Study Product 
Study product will be administered to subjects who were confirmed eligible by the Principal 
Investigator (eligibility will be confirmed by an entry committee) and whose CLI is stable (see 
Exclusion Criteria Section 3.3, item #1).  
The study product will be administered by eight (8) intramuscular injections delivered to the 
index leg (see Section 3.2 Inclusion criteria for definition of index leg) at each dosing visit (see 
Table 1 Dosage Regimen above). For each of the 8 injections, 3 mL of AMG0001 will be 
injected in about 3 seconds.  The precise anatomical location for study product injections will be 
based on vascular anatomy.  The site will receive a detailed schema from the above entry 
committee indicating where the injection sites should occur.  Duplex scanning must be used 
during the injection procedure to further clarify the injection sites.   
Subjects will not be eligible to receive the subsequent doses of study product if a major 
amputation of the index leg has occurred.  If the subject has been revascularized in the index leg, 
the Investigator should ensure that the subsequent doses of study product are not administered 
less than 1 month post-revascularization.  
Analgesics may be administered prior to treatment injections.  Local anesthetics applied to the 
skin are recommended.  An anti-anxiety agent may be administered pre-dose to relieve any 
anxiety surrounding treatment procedures.  Administration of analgesics is at the discretion of 

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the Investigator, but cannot be given to the subject prior to VAS pain scale measurement or 
Quality of Life (VascuQol Questionnaire) measurements.  All analgesics given prior to injection 
should be accurately recorded on the appropriate Concomitant Medication CRF. 
4. 
DESCRIPTION OF STUDY PROCEDURES 
4.1. 
Informed Consent 
An Informed Consent template containing all the regulatory elements will be provided by the 
Sponsor to the site.  The site may modify this document as long as the text relating to the FDA 
and/or other agency regulations are retained.  A copy of the site’s proposed Informed Consent 
document(s) must be submitted to the Sponsor or designee for review and comment prior to 
submission to the reviewing Institutional Review Board/ Ethics Committee (IRB/EC).  The 
Informed Consent document must be approved by the IRB/EC and contain all elements required 
by FDA (21 CFR 50.25), ICH GCP, national, state, local and institutional regulations or 
requirements.  If updates to the Informed Consent are required during the trial, the site must 
obtain IRB/EC approval of the new Informed Consent version as per national, state, local and 
institutional regulations or requirements and all active subjects must be re-consented. 
It is the responsibility of the Investigator to provide each subject with full and adequate 
information using the IRB/EC approved Informed Consent document(s), including the objectives 
and procedures of the study, possible risks involved and alternative treatments, before inclusion 
in the study.  Each subject must voluntarily provide written Informed Consent (including 
disclosure for the use and disclosure of research-related health information if applicable).  The 
consent must be obtained prior to performing any study-related procedures that are not part of 
normal subject care.  A copy of the signed Informed Consent must be given to the subject and an 
original copy of the Informed Consent must stay with the subject records at the site. 
4.2. 
Medical History 
The Investigator or designee will obtain a general medical history of past and present illnesses as 
well as medications currently being taken to address current illnesses. The medical history will 
include alcohol consumption, tobacco use, substance abuse, diabetic status, and status of any 
concurrent diseases. History of current symptoms and their severity will be obtained and 
recorded. History of drug allergies/reactions will also be obtained.  See Section 4.7 Peripheral 
Vascular Intervention History (or Update) for medical history information collected at screening. 
Subjects that have had previous myocardial infarction must have appropriate secondary 
prevention previously established and adequately documented in their medical record.  Adequate 
secondary prevention includes: 
 Lifestyle modification including the cessation of smoking, control of hypertension, 
and appropriate diet for optimum BMI management 
 Aspirin therapy (72 mg to 162 mg every day) should be established unless 
contraindicated or the subject is receiving Plavix or a similar compound 

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 Treatment with statins for lipid abnormalities should be established unless 
contraindicated. (Note: Subjects will be receiving statins for PAD unless 
contraindicated.) 
 An ACE-Inhibitor should be considered in all subjects unless contraindicated.  As an 
alternative, subjects with Left-Ventricular Dysfunction maybe established on ARBs 
such as Valsartan. 
 Beta-Blockers are recommended unless contraindicated 
Subjects that have had a previous stroke should have appropriate secondary prevention 
previously established and adequately documented in their medical record. Adequate secondary 
prevention is defined as: 
 Lifestyle modification to include the cessation of smoking, reduction in alcohol 
consumption, optimum BMI management, and increased moderate-intensity physical 
activity.  
 Anti-hypertensive treatment is recommended, and treatment should be individualized 
according to the subject’s characteristics. 
 Subjects with diabetes should be under rigorous control of blood pressure and 
maintain blood glucose at near normal glucose levels.  ACE-Inhibitors and ARBs are 
recommended for subjects with hypertension and diabetes mellitus to reduce the 
progression of renal disease.   HbA1c should be targeted at < 7%. 
 Statins are generally recommended as an agent for lowering lipid levels unless 
contraindicated.  Subjects who have had an ischemic stroke or TIA, elevated 
cholesterol, co-morbid CAD or any evidence of atherosclerotic origin should be 
managed by NCEPIII guidelines. (Note: Subjects will be receiving statins for PAD 
unless contraindicated.) 
4.3. 
Physical Examination 
A complete general physical examination of the skin and major body systems (Eyes, Ears, Nose 
and Throat; Cardiovascular; Respiratory; Gastrointestinal; Musculoskeletal/Connective Tissue; 
Neurological; Endocrine/Metabolic; Hematopoietic/Lymphatic; Genitourinary) will be 
completed as part of the study procedures.  
Any suspicious lesion found on the skin during the physical examination at Screening should be 
evaluated by a Dermatologist.   
An abbreviated physical exam does not evaluate all systems, but those systems for which exams 
are deemed medically necessary based on symptoms (symptom-driven exam). 
4.4. 
Concomitant Medications 
Concomitant medication and the indication for its use must be clearly documented and recorded 
in the source documentation and CRF for each subject.  Any medications taken from the date 
informed consent is signed and onward should be documented in the CRF. 

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The use of analgesic medications during the study should be carefully recorded.  Investigators 
should refrain from making changes in the subject’s use of analgesic medications after the 
baseline visit, unless the subject’s medical condition warrants changes to their treatment. 
Changes in the use of analgesic medications after the baseline visit could confound the 
interpretation of endpoint assessments.   
Topical wound medications must be captured as concomitant medications in the CRFs. Wound 
care products such as Regranex® (rhPDGF), Apligraft®, Dermagraft®, Oasis®, as well as 
any other skin equivalents or topical growth factors are excluded for use during this trial.  
Hyperbaric oxygen (HBO) treatment is also excluded. 
All subjects should be on a statin and an anti-platelet agent (e.g., clopidogrel, ticlopidine, aspirin, 
etc.) as part of their standard of care, unless contraindicated. Subjects for which these agents are 
contraindicated must have the restriction reason recorded in their source documentation and 
CRF.  
4.5. 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed during the Screening Period to document 
clinically significant anomalies (if not done up to 6 months prior to Day 0). 
4.6. 
Angiogram 
An aorto-iliac angiogram will be performed and will be used to determine the suitability of the 
subject for enrollment into the study and to determine injection site locations. The angiogram 
may have been completed up to 3 months prior to the start of screening, as long as the subject’s 
clinical condition has not changed since the angiogram was performed or undergone a bypass or 
endovascular intervention within the previous 3 months. Acceptable forms of imaging for this 
trial also include Computerized Tomography Angiogram (CTA) and Magnetic Resonance 
Angiogram (MRA).  An angiogram will also be required to be performed prior to a proposed 
surgical revascularization or major amputation. 
4.7. 
Peripheral Vascular Intervention History (or Update) 
During Screening 
At Screening, the Investigator will perform a detailed assessment of all past peripheral vascular 
interventions (surgical bypass, an endovascular intervention or major/minor amputations). If the 
subject has never undergone a peripheral vascular intervention then the lack of these events will 
be documented as well. Information may include: date(s) of intervention, type(s) of intervention 
(e.g., PTA, surgical bypass, amputation, etc.), intervention site (e.g., iliac, femoro-popliteal, 
infrapopliteal, etc.), intervention side (right or left leg and index or non-index leg) conduit used 
(e.g., saphenous vein, polytetrafluoroethylene [PTFE], human umbilical vein [HUV], Dacron, 
etc.), and patency of most recent intervention prior to study start (including a description of the 
results from the most recent vascular imaging if available). Information concerning both major 
(defined as at or above the ankle) and minor (below the ankle) amputation should be collected.  
Specific information for each peripheral vascular procedure will be obtained and recorded on the 

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subjects’ source documentation and CRF to allow independent review of the subjects’ CLI status 
and suitability for entry into the study.  
During Treatment and Follow up Period 
During the study, detailed information must be documented in the subjects’ source 
documentation and CRF on the subject’s CLI status of the index leg including any treatment 
received for worsening CLI of the index leg, plan for major or minor amputations of the index 
leg, plan for revascularization procedures of the index leg, etc.  Detailed information on the 
subjects’ CLI status must be documented prior to planning a surgical revascularization or major 
amputation of the index leg.  Data relating to the reasons for performing a surgical 
revascularization or major amputation of the index leg will be reviewed.   
In no way will intervention that is deemed necessary be withheld for any subject. 
4.8. 
Hemodynamic Measurements 
The hemodynamic status of the affected lower limb will be evaluated to confirm the CLI 
diagnosis, and the subject’s suitability for inclusion into the study. The ankle and toe pressures 
will be measured using Doppler or a photoplethysmograph (PPG) and the ankle/brachial index 
(ABI) and toe/ brachial index (TBI) will be estimated in the index leg, measuring both the 
posterior tibial and dorsalis pedis arteries for the ABI.  The higher of the two readings will be 
used.  The methodology for obtaining these measurements is outlined in Appendix B. A Vascular 
Report must be included in the source documentation to support the hemodynamic data. 
During Screening hemodynamic measurements are required for both the index and non-
index leg. Otherwise, at all other time points during the study, hemodynamic 
measurements are only required for the index leg. 
If it is not possible to obtain the toe pressure because the big toe has been amputated, or is too 
deformed or necrotic to apply the cuff, then the second toe may be used. This should be noted in 
the source documentation and in the CRF.  
A vessel with no detectable Doppler signal (complete occlusion) will be recorded as having a 
zero pressure (“0 mmHg”). Calcification of the media is common in diabetic subjects, rendering 
the tibial and peroneal arteries non-compressible, which causes falsely elevated ABI (>1.30). If 
the measurement cannot be assessed due to calcification then the non-compressible status of 
these arteries should be noted in the source documentation and CRF and the toe pressure used to 
diagnose and assess CLI.  
4.9. 
Assessment of CLI and Ulcer Photography and Tracings 
For study entry, the subject must be evaluated for clinical evidence of CLI according to the 
definition of the study population for this protocol found in Section 3.1 Study Population.  
The Investigator must assign a baseline status to the subject’s peripheral vascular disease based 
on the status of the index leg using the Rutherford Classifications (see Appendix C). In case of 
Rutherford Category 4 and Rutherford Category 5, the Principal Investigator must make sure that 
the inclusion criteria for subjects with Rutherford Category 4 and Rutherford Category 5 are 

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strictly followed for the subjects to be eligible to enter the study. (See Section 3.1 Study 
Population) 
During the study, specific information on the subject’s CLI status will be documented on the 
CRF and in the source documentation including information on ulcers/gangrene, rest pain, 
debridement/wound care, infection treatment, hospitalizations, minor and major amputations, 
revascularization by surgical bypass, etc.   
In order to accurately assess ulcer size, the ulcer (s) must be cleaned and debrided to 
remove necrotic tissue, eschar, and callouses prior to photographs and ulcer tracings, as 
per the wound care guidelines (see Appendix D).   
During Screening, ulcer photography and tracings of the largest ulcer (with ulcer debridement 
occurring prior to photography and tracing) must be performed and used as one of the 
evaluations to be made to confirm CLI stability for entry into the study.  Ulcer photography at 
screening should include one photograph of the largest ulcer on the index leg and additional 
photographs of the index leg that capture the foot and lower leg to confirm the location of the 
largest ulcer, as well as all additional ulcers (and gangrene) and the overall status of the index leg 
at screening.    
Prior to dosing on Day 0, ulcer photography and tracing of the largest ulcer as at Screening (with 
ulcer debridement occurring prior to photography and tracing) will be completed again for 
establishing stability of the largest ulcer and of additional ulcers on the index leg prior to 
randomization.  Ulcer photographs and photographs of the index leg will be taken at each visit 
(Day 14 through Month 18) and prior to any planned intervention of the index leg (surgical 
revascularization or major amputation).  If the largest ulcer on the index leg heals during the 
study period, the ulcer must be re-evaluated 2 weeks after healing to confirm it has remained 
healed for a period of 2 weeks (this will require an additional visit to the site).  Ulcer healing will 
be confirmed later via photographs by the study entry committee.  Ulcer and leg photographs 
must continue to be taken throughout the study period, regardless of the healing of the largest 
ulcer. 
4.10. 
Laboratory Tests 
The following clinical laboratory tests will be performed: 
1. Hematology: including hemoglobin, hematocrit, RBC count, WBC count (total and 
differential) and platelet count. 
2. Urinalysis including protein, glucose, blood, ketones, bile, and microscopic examination. 
3. Blood chemistry: glucose (fasting), uric acid, total cholesterol, HDL, calculated LDL, 
triglycerides, aspartate transaminase (AST), alanine aminotransferase (ALT), calcium, 
phosphorus, total bilirubin, alkaline phosphatase, total protein, albumin, globulin, lactic 
acid dehydrogenase (LDH), serum creatinine, creatinine clearance (estimated using the 
Cockroft Gault formula), blood urea nitrogen (BUN), and electrolytes (Na+, K+, Cl-),). 
4. Serum HGF protein assay and PCR for HGF plasmid and  Anti HGF antibodies 
5. HbA1c in diabetic subjects 

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6. FSH and estradiol levels in women 55 years or less (screening only) 
7. Urine Pregnancy Test (screening only) 
See Section 5 for screening period procedures, Table 3 “Schedule of Study Procedures” and 
Table 4 “Schedule of Sample Collection for the Serum HGF protein & PCR for HGF Plasmid 
Assays” for details on what visits these laboratory samples should be collected.  Please see the 
Laboratory Procedure Manual for details regarding blood drawing, storage, processing, and 
transport.   
Diabetic status: To determine the subjects’ diabetic status at screening, all subjects will have 
their fasting blood glucose (FBG) measured. In subjects with known diabetes, supportive 
documentation will be required to confirm the diagnosis, e.g., evidence of raised blood glucose 
levels, treatment with insulin or oral anti-diabetic drugs. Diagnostic criteria for diabetes are in 
the table below. 
Diabetic Status Criteria 
If FBG  < 7.0 mmol/L (126 mg/dL) 
Non-diabetic 
If FBG  7.0 mmol/L (126 mg/dL), or previous diabetes 
diagnosis 
Diabetic 
4.11. 
Ischemic Rest Pain Measurement 
The severity of rest pain based on the average over the previous 7 days will be recorded using the 
10 cm visual analog scale (VAS) (see Appendix E).  The VAS score must be documented at all 
visits and prior to any planned intervention (revascularization or major amputation).  In order to 
assess rest pain adequately, the use of pain medication/opioids must be specifically documented 
in the CRF during the VAS evaluation period.  The subject should not be allowed to see his 
previous rest pain measurements nor should the score be revealed to him/her. 
4.12. 
Post-Dosing Procedures 
Blood samples will be obtained for measurement of serum HGF protein and HGF plasmid DNA 
four (4) hours after the injections are completed. These blood samples are required at certain 
dosing visits as per Table 4 “Schedule of Sample Collection for the Serum HGF protein & PCR 
for HGF Plasmid Assays”. 
All subjects should be observed and Adverse Events (AEs) recorded.  Subject will be discharged 
from the clinic when clinically stable. 
4.13. 
Adverse Event Review 
The Investigator should start documenting adverse events after the first dose of study product 
administration, during study product administration, post treatment and throughout the study 
period (Month 18 Visit). See Section 8.0 Adverse Events for details. 

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Events relating to the worsening of CLI that occur in the index limb such as increased rest pain, 
new ischemic ulceration or increase the size of the ulcer, gangrene, cellulitis or osteomyelitis, 
and redness that are related to the study disease and are symptoms/signs of progression of study 
disease will not be recorded as adverse events (unless the speed or extent of the symptoms/signs 
are unexpected based on the natural history or bear a strong temporal relationship to the study 
product).Data on the subject’s CLI status of the index limb will be recorded in detail on non-AE 
CRFs and is therefore not required to be documented as an AE or SAE. 
In cases which any of the worsening of CLI events that occur in the index limb such as increased 
rest pain, new ischemic ulceration or increase in the size of the ulcer, gangrene, cellulitis or 
osteomyelitis, and redness that are symptoms/signs of progression of critical limb ischemia, and 
that result in death, the event should be reported as an SAE. 
Systemic or metabolic complications that ensue subsequent to worsening CLI of the index leg 
should be reported as AEs or SAEs.   Systemic complications include events such as septicemia, 
pneumonia, multi-organ failure and events resulting in death.  These events should be captured 
on the AE or SAE section of the CRF. Metabolic complications include excessive increase in 
blood glucose or serum creatinine. Events that result in death should be reported as a SAE. 
Limb specific events that occur in the non-index limb such as increased ischemic rest pain, new 
ischemic ulceration or increase in the size of the ulcer, gangrene, minor or major amputations, 
will be recorded as an AE or SAE on the AE CRF.  
4.14. 
Retinopathy 
A retinal exam will be performed by an ophthalmologist as part of the screening procedures 
(performed up to 6 months prior to Day 0) to exclude proliferative retinopathy, severe non-
proliferative retinopathy from any cause (ETDRS retinopathy score > 35), clinically significant 
macular edema or previous pan retinal photocoagulation therapy.  The ETDRS retinopathy score 
will be recorded.  The exam will be repeated 0-14 days before the Month 12 and Month 18 visits.  
Subjects are not to receive study product at the Month 12 visit until the report has been reviewed. 

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5. 
OVERVIEW OF STUDY PROCEDURES 
Table 2: 
List of Screening Procedures 
Time: -30 days to Day -1 
Comments 
Subject Consent & Medical History 
  
Complete Physical Examination 
  
Peripheral Vascular Intervention History 
Submit to the Entry committee to confirm eligibility 
CLI Assessment 
Submit to the Entry committee to confirm eligibility 
Ulcer Tracings 
Photos and tracing of largest ulcer on the index leg 
only.  At least 2 photos should capture the largest 
ulcer and other picture(s) to capture the entire leg 
showing the location of the largest ulcer, all ulcers 
and status of the limb. Debridement should be 
performed prior to these evaluations. All photos and 
tracings must be submitted to the Entry committee to 
confirm eligibility. 
Ulcer Photography 
Retinopathy Examination 
Performed by an ophthalmologist up to 6 months 
prior to Day 0 
12-Lead ECG 
Up to 6 months prior to Day 0 
HbA1C and FBG 
  
Angiogram Assessment 
Submit to the Entry committee to confirm eligibility 
Hemodynamic Measurements 
Submit to the Entry committee to confirm eligibility 
VAS (pain scale) 
Submit to the Entry committee to confirm eligibility 
Urine Pregnancy (Females) 
Performed on all women under the age of 55 
(regardless of surgical sterility)   
FSH and Estradiol Serum Tests (see 
Appendix G) 
Performed on all women under the age of 55  
Hematology, Chemistry, CBC, 
Urinalysis 
  
Concomitant Medication Review 
  
 
The entry committee will be responsible for oversight of entry, confirming the stability of wound 
(post randomization) indicating the schema for injection sites and adjudicating on the 
justification for revascularization and major amputation. 
 
 

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Table 3: 
Schedule of Study Procedures 
 
 

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** For the purposes of this study a month is defined as 30 days. Days 14, 28 and 42 are calculated from either Day 0, Month 3, Month 
9 or Month 12. All (non-dosing) follow-up visits should be calculated based on Day 0/Baseline. 
 
Table 4: 
Schedule of Sample Collection for the Serum HGF Protein & PCR for HGF Plasmid Assays  
 
 
** The first 5 subjects who were randomized and received test medication will have blood samples drawn for PK 4 days following 
their Month 9 Visit.

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5.1. 
Screening 
Written informed consent must be obtained before the subject can begin any screening 
procedures that are not considered part of standard patient care.  Once written informed consent 
is obtained, the subject must be assigned a screening number, after which the subject may begin 
the screening procedures for the study.  The following screening procedures must be completed 
within a 30 day period (unless other time period windows have been documented for the 
procedure, for example ECG) prior to randomization and the receipt of study product on Day 0: 
1. Subject Consent 
2. Medical History including assessment of diabetes status, alcohol and tobacco use 
3. Demographics 
4. Physical Examination (see Section 4.3) 
5. Concomitant Medication review 
6. 12-Lead ECG (up to 6 months prior to Day 0) 
7. Peripheral Vascular Intervention History 
8. Assessment of CLI 
9. Ulcer photographs of largest ulcer on the index leg and the index leg to include all 
ulcers/gangrene (at least 2 photos).  Ulcer debridement, if necessary, should occur prior 
to photography. 
10. Ulcer tracing of the largest ulcer of the index leg, with ulcer debridement occurring prior 
to tracing as necessary. 
11. Hemodynamic measurements (ankle and toe pressures and estimation of Ankle Brachial 
Index (ABI) and Toe Brachial Index (TBI)) 
12. Aorto-iliac Angiogram Assessment (performed within the 3 months prior to screening 
unless subject has shown considerable deterioration in that time or subject has undergone 
a bypass or endovascular intervention within the previous 3 months).   
13. Ischemic Rest Pain severity measured using the VAS pain scale (see Appendix E) 
14. Collect Laboratory Test samples for the following:  Hematology, Chemistry, CBC, 
HbA1c, FBG, Urinalysis, FHS/estradiol for women 55 years and younger and Urine 
Pregnancy test (if applicable) 
15. Retinopathy Examination (up to 6 months prior to Day 0) 
16. Height, weight and vital signs assessment 
5.2. 
Confirmation of Subjects’ CLI Stability Pre-Dose 
Sites must perform an assessment of the subject’s CLI status in order to confirm stability prior to 
dosing.  The stability assessment should occur on Day 0 prior to dosing (≥ 2 weeks between the 
screening and the Day 0 assessments), and should include ulcer and leg photography and tracings 
of the largest ulcer on the index leg (with ulcer debridement, if necessary, occurring prior to 
photography and tracing), hemodynamic measurements, and measurement of ischemic rest pain 

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severity.  The assessment will confirm that the ulcer(s) and gangrene have not increased in size 
excessively so that the subject requires a surgical intervention or decreased in size excessively so 
that the subject’s lesions will heal spontaneously without study product.  The assessment will 
also confirm that hemodynamic measurements have not changed markedly (± > 0.1 ABI or TBI) 
and the ischemic rest pain has not increased or decreased greatly despite continuing the same 
dose of analgesics.  Subjects with unstable CLI will not be randomized.  They will be considered 
screen failures.  The entry committee will verify the CLI stability post-randomization 
5.3. 
Dosing Visit Study Procedures:  Day 0 
5.3.1. 
Pre-Dosing Procedures 
1. Medical History Review 
2. Physical Exam 
3. Peripheral Vascular Intervention Update 
4. Assessment of CLI status (associated measurements are listed separately) 
5. Ulcer tracings as described in Section 5.2 Confirmation of Subjects’ CLI Stability Pre-
Dose 
6. Ulcer photographs as described in Section 5.2  
7. Hemodynamic measurements (ankle and toe pressures and estimation of ABI and TBI) 
8. QOL Measurements (VascuQol Questionnaire) 
9. Ischemic Rest Pain severity measured using the VAS pain scale (see Appendix E) 
10. Collect Laboratory Test samples for the following:  Hematology, Chemistry, CBC, 
Urinalysis, Urine Pregnancy test, if applicable (see Appendix G), and anti-HGF antibody 
sample  
11. Collect Pre-dose samples for the Serum HGF protein assay and the PCR for HGF 
Plasmid DNA assay 
12. Concomitant Medication review 
5.3.2. 
Dosing Procedures:  Day 0 
After successful completion of the pre-dose procedures and confirmation that the subject’s CLI 
status is stable, the subject may receive the first dose of study product.  Study product should be 
administered to the subject by 8 IM injections in the index leg utilizing the appropriate 21G 
needle and syringe as described in the Study Drug Administration Instructions.  The 8 injection 
site locations will have been determined based on the location of the diseased vessels.  
Additionally, duplex scanning must be used during the injection procedure to further clarify the 
injection site locations (See Appendix A).   
The injection sites will be marked with a tattoo or similar pen prior to injecting the study product 
on Day 0.  The procedure will be repeated on injections made on Day 14, Day 28, and Day 42 
using a different color tattoo or similar pen to track the injections.  The Day 14, Day 28, and Day 
42 injection sites will be 1-2 cm initially proximal to the Day 0 injection then 1-2 cm distal and 

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subsequently 1-2 cm lateral, respectively.  No more than 3 injections should be made into the 
anterior or lateral compartments on any dosing visit. 
The subject should remain in a supine position to receive all injections. For each of the 8 
injections, 3 mL of AMG0001 will be injected in about 3 seconds with a 21G needle.  Each of 
the injection sites will be marked with a tattoo pen.  At completion of study product 
administration, photographs must be taken of the injection sites.  In the injection site photo, a 
ruler should be placed alongside the index leg to assist with the accuracy of the subsequent 
injection site locations in case one or more of the tattoo pen marks cannot be seen. 
The subject must remain in a supine position for 15 minutes post injections.  The time of the 
study product administration should be noted in the subject’s source documentation. 
5.3.3. 
Post-Dosing Procedures:  Day 0 
Adverse events, if any, should be documented during and subsequent to the injection of the study 
product. 
A blood sample will be obtained four (4) hours after the study product injections are completed 
for measurement of serum HGF protein and HGF plasmid DNA 
Subject will be discharged from the clinic when clinically stable. 
5.4. 
PK Sampling Visit:  Days 4  
A blood sample will be obtained at the Day 4 Visit to measure the serum HGF protein and the 
HGF plasmid DNA. In the first 5 subjects studied, similar sampling will occur 4 days after the 
Month 9 Visit. 
5.5. 
Dosing Visit Study Procedures:  Days 14 (± 2 days), 28 (± 2 days), 
and 42 (± 2 days)  
Pre-Dosing Procedures: Days 14 (± 2 Days), 28 (± 2 Days), and 42 (± 2 Days) 
1. Medical History review 
2. Abbreviated Physical Examination 
3. Peripheral Vascular Intervention Update  
4. Assessment of CLI 
5. Ulcer/gangrene and Index Leg Photography (after debridement, if necessary) 
6. Collect Pre-dose blood samples for the Serum HGF protein assay and the PCR for HGF 
Plasmid DNA assay  
7. Adverse Event review 
8. Concomitant Medication review 
9. Weight and Vital Signs assessment 
 
Dosing Procedures:  Days 14 (± 2 days), 28 (± 2 days), and 42 (± 2 days) 

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Please Note:  If subject experiences a significant intercurrent illness, the Investigator may 
postpone a subsequent injection of study product within or as near to the dosing visit window.  If 
a subject experiences an acceptable adverse event (e.g., hematoma) the Investigator may 
postpone administration of the study product for a few days.  If the adverse event is unacceptable 
the study product administration should be stopped but the subject should continue to be 
followed as per protocol.  If there are no drug-related adverse events and no significant 
intercurrent illnesses, the subject will receive the subsequent doses of study product. 
After successful completion of the pre-dose procedures, study product should be administered to 
the subject by 8 IM injections in the index leg utilizing appropriate 21G needle and syringe 
indicated in (see Appendix A)   The 8 injection site locations must be determined based on the 
final diagram provided to the site by an independent vascular surgeon.  Additionally, duplex 
scanning must be used during the injection procedure to further clarify the injection site locations 
(See Appendix A ) 
The injection sites that were marked with a tattoo pen on Day 0 will be identified.  The injection 
procedure will be repeated on Day 14, Day 28, and Day 42 using a different color tattoo pen to 
track the injections.  The Day 14, Day 28, and Day 42 injection sites will be 1-2 cm initially 
proximal to the Day 0 injection then 1-2 cm distal and subsequently 1-2 cm lateral, respectively.  
No more than 3 injections should be made into the anterior or lateral compartments on any 
dosing visit. 
The subject should remain in a supine position to receive all injections. For each of the 8 
injections, 3 mL of AMG0001 will be injected in about 3 seconds with a 21G needle.  
At completion of study product administration, photographs must be taken of the injection site 
locations (with ruler).  The subject must remain in a supine position for 15 minutes post 
injections.  The time of the study product administration should be noted in the subject’s source 
documentation. 
Note: for the purposes of this study a month is defined as 30 days; days 14, 28 and 42 are 
calculated from either Day 0, Month 3, Month 9 or Month 12. 
Post-Dosing Procedures:  Days 14 (± 2 days), 28 (± 2 days), and 42 (± 2 days) 
These post-dosing procedures are the same as the post-dosing procedures of Day 0 in Section 
5.3.3 
5.6. 
Dosing Visit Study Procedures:  Month 3 (± 7 days) 
Pre-Dosing Procedures: Month 3 (± 7 days) 
1. Medical History Review 
2. Physical Exam 
3. Peripheral Vascular Intervention Update 
4. Assessment of CLI status (associated measurements are listed separately) 
5. Ulcer photographs  
6. Hemodynamic measurements (ankle and toe pressures and estimation of ABI and TBI) 
7. QOL Measurements (VascuQol Questionnaire) 

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8. Ischemic Rest Pain severity measured using the VAS pain scale (see Appendix E) 
9. Collect laboratory test samples for the following: Hematology, Chemistry, CBC, 
Urinalysis, Urine Pregnancy Test, if applicable (see Appendix G), and anti-HGF antibody 
sample 
10. Collect samples for a pre-dose Serum HGF protein assay and a PCR for HGF Plasmid 
DNA Assay (See Section 4.10, #4) 
11. Adverse Event review 
12. Concomitant Medication review 
13. Weight and Vital Signs assessment 
Dosing Procedures:  Month 3 (± 7 days) 
The dosing procedures are the same as the dosing procedures of Days 14, 28, and 42 in 
Section 5.3.2 . 
The Month 3 injection site should be the same injection site as Day 0. 
5.6.1. 
Post-Dosing Procedures:  Month 3 (± 7 days) 
These post-dosing procedures are the same as the post-dosing procedures of Day 0 in Section 5.3.3 
5.6.2. 
Dosing Visit Study Procedures:  Month 3+14 days (± 2 days), Month 3+28 days 
(± 2 days), and Month 3+42days (± 2 days) 
Pre-Dosing Procedures: Month 3+14 days (± 2 days), Month 3+28 days (± 2 days), and 
Month 3+42 days (± 2 days) 
1. Medical History review 
2. Abbreviated Physical Examination 
3. Peripheral Vascular Intervention Update  
4. Assessment of CLI 
5. Ulcer/gangrene and Index Leg Photography (after debridement, if necessary) 
6. Collect a pre-dose blood draw for the Serum HGF protein assay and the PCR for HGF 
Plasmid DNA assay,  
7. NOTE:  Collect samples for BOTH assays at Month 3+42 days 
8. NOTE:  Collect only one (1) sample for the PCR for HGF plasmid DNA assay at Month 
3+14 and 28 days 
9. Adverse Event review 
10. Concomitant Medication review 
11. Weight and Vital Signs assessment 
Dosing Procedures:  Month 3+14 days (± 2 days), Month 3+28 days (± 2 days), and Month 
3+42 days (± 2 days) 
These dosing procedures are the same as the dosing procedures of Days 14, 28, and 42 in Section 5.5. 

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The Month 3+14 days, Month 3+ 28 days, and Month 3+ 42 days injection sites should be the 
same injection sites as on Days 14, 28, and Day 42, respectively. 
Post-Dosing Procedures:  Month 3+14 days (± 2 days), Month 3+28 days (± 2 days), and 
Month 3+42days (± 2 days) 
Adverse events should be documented during and subsequent to the injection of the study 
product. 
Four hours after the injections are completed, a blood sample will be obtained for measurement 
of serum HGF protein and HGF plasmid DNA. 
Please note: At the Month 3+14 and 28 day visits, only a sample for the HGF plasmid DNA will 
be obtained, but at the Month 3+42 day visit a sample for both assays should be obtained. 
Subject will be discharged from the clinic when clinically stable. 
5.7. 
Follow-Up Visit Study Procedures:  Month 6 (± 7 days) 
1. Medical History  
2. Physical Examination 
3. Peripheral Vascular Intervention Update 
4. Assessment of CLI (associated measurements are listed separately) 
5. Ulcer/gangrene and Index Leg Photography (after debridement, if necessary) 
6. Injection Site Photography/Marking (to ensure the markings will still be visible at the 
next dosing visit (Month 9) 
7. Hemodynamic Measurements  
8. QOL Measurements (VascuQol Questionnaire) 
9. Ischemic Rest Pain severity measured using the VAS pain scale (see Appendix E) 
10. Collect Laboratory Test samples for the following: Hematology, Chemistry, and CBC,  
Urinalysis, and an anti-HGF antibody assay 
11. Collect a blood sample for the PCR for HGF Plasmid DNA assay  
12. Adverse Event review  
13. Concomitant Medication review 
14. Weight and Vital Signs assessment 
5.8. 
Dosing Visit Study Procedures:  Month 9 (± 7 days) 
ALL PROCEDURES FOR THE MONTH 9 VISIT ARE THE SAME AS THOSE OF THE 
MONTH 3 VISIT.  See Section 5.6. 
 

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5.9. 
Dosing Visit Study Procedures:  Month 9+14 days (± 2 days), Month 
9+28 days (± 2 days), and Month 9+42 days (± 2 days) 
Pre-Dosing Procedures: Month 9+14 days (± 2 days), Month 9+28 days (± 2 days), and 
Month +42 days (± 2 days) 
1. Medical History review 
2. Abbreviated Physical Examination 
3. Peripheral Vascular Intervention Update  
4. Assessment of CLI 
5. Ulcer/gangrene and Index Leg Photography (after debridement, if necessary) 
6. (ONLY AT MONTH 9+42 days VISIT) Collect a pre-dose blood sample for the PCR 
for HGF Plasmid DNA assay 
7. Adverse Event review 
8. Concomitant Medication review 
9. Weight and Vital Signs assessment 
Dosing Procedures:  Month 9+14 days (± 2 days), Month 9+28 days (± 2 days), and Month 
9+42days (± 2 days) 
These dosing procedures are the same as the dosing procedures of Days 14, 28, and 42 in Section 
5.5. 
The Month 9+14 days, Month 9+ 28 days, and Month 9+ 42 days injection sites should be the 
same injection sites as on Days 14, 28, and Day 42, respectively. 
Post-Dosing Procedures:  Month 9+14 days (± 2 days), Month 9+28 days (± 2 days), and 
Month 9+42days (± 2 days) 
Adverse events should be documented during and subsequent to the injection of the study 
product. 
ONLY FOR MONTH 9+42 DAY VISIT - Four hours after the injections are completed, a blood 
sample will be obtained for measurement of serum HGF protein and HGF plasmid DNA.  Please 
note: At the Month 9+14 and 28 day visits, there is no requirement for a four-hour post dose 
blood draw. 
Subject will be discharged from the clinic when clinically stable. 
5.10. 
Dosing Visit Study Procedures:  Month 12 (± 7 days) 
ALL PROCEDURES FOR THE MONTH 12 VISIT ARE THE SAME AS THOSE OF THE 
MONTH 3 VISIT (See Section 5.6).   
In addition to the procedures in Section 5.6, the following procedures should also be performed 
pre-dose: 
 Retinopathy Exam 

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5.11. 
PK Sampling Visit:  Month 12 + 4 Days  
A blood sample will be obtained at the Month 12 + 4 Days Visit for subjects enrolled in the 
study to measure the serum HGF protein and the HGF plasmid DNA. 
5.12. 
Dosing Visit Study Procedures:  Month 12+14 days (± 2 days), Month 
12+28 days (± 2 days), and Month 12+42days (± 2 days) 
ALL PROCEDURES FOR MONTH 12 + 14, 28 and 42 DAY VISITS ARE THE SAME AS THOSE OF 
THE MONTH 9 + 14, 28 and 42 DAY VISITS.  For a list of the procedures to be performed at these 
dosing visits (see Section 5.9) 
5.13. 
Follow-Up Visit Study Procedures:  Month 15 (± 7 days) 
1. Medical History  
2. Physical Examination 
3. Peripheral Vascular Intervention Update 
4. Assessment of CLI (associated measurements are listed separately) 
5. Ulcer/gangrene and Index Leg Photography (after debridement, if necessary) 
6. Hemodynamic Measurements  
7. QOL Measurements (VascuQol Questionnaire) 
8. Ischemic Rest Pain severity measured using the VAS pain scale (see Appendix E) 
9. Collect Laboratory Test samples for the following:  Hematology, Chemistry, CBC,  
Urinalysis, and an anti-HGF antibody 
10. Collect samples for the Serum HGF protein assay, and the PCR for HGF Plasmid DNA 
assay 
11. Adverse Event review  
12. Concomitant Medication review 
13. Weight and Vital Signs assessment 
5.14. 
Follow-Up Visit Study Procedures:  Month 18 (± 7 days) 
1. Medical History  
2. Physical Examination 
3. Peripheral Vascular Intervention Update 
4. Assessment of CLI (associated measurements are listed separately) 
5. Ulcer/gangrene and Index Leg Photography (after debridement, if necessary) 
6. Retinopathy Examination 
7. Hemodynamic Measurements  
8. QOL Measurements (VascuQol Questionnaire) 

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9. Ischemic Rest Pain severity measured using the VAS pain scale (see Appendix E) 
10. Collect Laboratory Test samples for the following:  Hematology, Chemistry, CBC,  
Urinalysis, and an anti-HGF antibody 
11. Adverse Event review  
12. Concomitant Medication review 
13. Weight and Vital Signs assessment 
5.15. 
Assessments to Complete Prior to a Planned Intervention (Surgical 
Revascularization or Major Amputation) 
1. Details of planned Intervention (type, date, etc) 
2. Assessment of CLI (associated measurements are listed separately) 
3. Ulcer/gangrene Photographs of Index Leg (after debridement) 
4. Angiogram Assessment 
5. Hemodynamic Measurements 
6. QOL assessment using VascuQol Questionnaire 
7. Ischemic Rest Pain severity measured using the VAS pain scale  
8. Adverse Event review 
9. Concomitant Medication review 
10. Weight and Vital Signs assessment 
5.16. 
Interim Telephone Contacts 
The data collected during the entire study period are critical for the safety and efficacy 
assessments. Every effort will be made to bring the subject back to the study site for all 
scheduled visits.  Due to the long time period between the Month 6 and Month 9 visits and the 
Month 15 and Month 18 visits, Study Personnel must make and document a telephone contact 
with each subject at Month 7.5 (± 5 days) as well as at Month 16.5 (± 5 days). 
5.17. 
Unscheduled Visits 
If the site is notified (e.g., at an Interim Telephone Contact) that the subject has experienced an 
AE that appears to be serious (see Section 8.2.2) or a significant deterioration in CLI status an 
attempt will be made to evaluate the subject at an unscheduled visit by the study staff unless the 
subject has been hospitalized remotely.  If the subject has been hospitalized remotely details of 
the illness and treatment will be obtained and documented in the CRF.  
Subjects who require 2-week confirmation of largest ulcer healing should also be evaluated at an 
unscheduled study visit by the study staff.   
Data from unscheduled clinic visits will be collected in the CRF. 

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5.18. 
Ulcer Healing 
Ulcer healing of the largest ulcer on the index limb (determined at Screening) will be assessed 
clinically by the Principal Investigator by direct visual inspection at each study visit.  If the 
largest ulcer on the index leg is considered completely healed, photographs of the healed ulcer 
area must be captured.  If the ulcer heals completely during the study period, the ulcer must be 
re-evaluated 2 weeks after healing to confirm it has remained healed for a period of 2 weeks. 
Confirmation of complete ulcer healing must be made by an outside physician unconnected with 
the study and nominated for this purpose 
5.19. 
Diabetic control 
Every effort will be made to ensure good diabetic control (HbA1c ≤ 7%), which will not only 
include maintaining ideal blood glucose levels, and appropriate foot care, but also managing 
diabetic complications such as diabetic retinopathy, neuropathy, and nephropathy. Ideally 
diabetic subjects should have their diabetes managed by a diabetic specialist (endocrinologist) 
throughout their participation in the study. 
5.20. 
Documentation of Deaths 
In cases where death is the outcome of a Serious Adverse Event (SAE), or occurs suddenly 
without apparent cause, appropriate documentation will be requested by the Sponsor.   
All deaths including cases where death is due to subjects’ worsening CLI,  must be supported by 
source documentation such as a hospital discharge summary, death certificate, autopsy report or 
a doctor’s report/letter.  All serious adverse events with the outcome of death will be reported 
immediately to the Sponsor on the CRF via email or fax.   
6. 
SCREEN FAILURES AND SUBJECT WITHDRAWALS 
6.1. 
Withdrawals 
A subject may refuse any or all treatment or study procedures at any time during the study. 
Participation is voluntary, and refusal to participate will involve no penalty or loss of benefits to 
which the subject is otherwise entitled. A subject who refuses to participate after receiving one 
or more doses of the study product should be encouraged to continue follow-up as per protocol 
including the safety follow-up program (See Section 10) Safety Follow-up Program regarding 
safety follow-up procedures). 
If the subject wishes to withdraw study consent, every effort must be made to encourage the 
subject to return to the study site for safety evaluation purposes for all remaining study visits.  
Subjects who wish to withdraw from the study prematurely and have had at least one dose of 
study product will be requested to return to the study site for study specific safety and efficacy 
assessments.  
If the subject withdraws prior to Month 6, the procedures for the Month 6 visit should be 
completed as the exit visit.  If the subject withdraws between Month 6 and Month 18, the 
procedures for the Month 18 visit should be completed as the exit visit. Additionally, every effort 
will be made to obtain and record information regarding revascularization by surgery, major 

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amputation, myocardial infarction, stroke, and death even if the subject does not return for an 
exit visit. In case any of these events have occurred, evidence from source documents will be 
obtained for confirmation.  Prior informed consent will have been obtained from the subject to 
gain access to these documents.  If the subject refuses any continued study participation, decline 
of study participation should be documented in writing.  If the subject refuses to communicate 
with the study site, final attempts to contact the subject should be documented with a certified 
letter to the subject’s last known address.  
The Principal Investigator is permitted to discontinue the subject from receiving study product 
for medical reasons at any time. However, the subject will continue to return for protocol 
dictated follow-up visits for the remainder of the total study period (18 month visit) including the 
safety follow-up program. 
6.2. 
Screen Failures 
Screen failures will include any subject who was consented, but subsequently did not meet the 
entry criteria in order to receive study product. Subjects who fail screening will not be followed 
for safety or efficacy assessment, and no other study procedures will be performed. Appropriate 
screen failure data including reason for ineligibility will be collected on the CRF. 
6.3. 
Study Suspension or Termination 
The IRB, the Sponsor, the FDA, or other regulatory health agencies may choose to voluntarily 
suspend or terminate some or all activities of the study at any time if they judge that it is in the 
best interest of the subject. They may also suspend or terminate the study for various other 
reasons. They can do this without the consent of the subject. 

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7. 
STUDY PRODUCT 
7.1. 
Product Description 
Active Drug: AMG0001 (Figure 1) is a clear liquid with a pH of approximately 4.5 to 7.5 
containing 2.5 mg/mL AMG0001 (plasmid construct pVAX1 HGF/MGBI) dissolved in 
physiological saline in a 2.10 mL volume (5.25 mg plasmid).  
Name:  AMG0001 may also be named “HGF” or “HGF Plasmid” 
 
Figure 1: 
Schematic representation of AMG0001 
 
 
 
 
 
7.2. 
Packaging and Labeling 
The study product will be provided in 3 mL glass vials. Each subject package and vial is labeled 
to indicate the unique vial number, vial volume, date of manufacture, and the following 
statement “CAUTION: New Drug - for investigational use only.”  
7.3. 
Storage 
Details regarding storage of both undiluted and diluted investigational product are available in 
the Pharmacy Manual.  Upon receipt the Investigational Product should immediately be stored in 
a freezer at -15⁰C to -25⁰C (5⁰F to -13⁰F).  Freezers should not have an autodefrost feature and 
must have continuous temperature monitoring as described in the Pharmacy Manual.  Once the 
vial is thawed at the clinical center, it should not be refrozen.  Details for storage of the undiluted 
and diluted investigational product are available in Appendix A and the Pharmacy Manual. 
pVAX1
pVAX1HGF/MGBI
HGF/MGBI
(5.18 
(5.18 kbp
kbp)
HGF fragment (2.2 
HGF fragment (2.2 kbp
kbp)
Bam HI
Bam HI
Not I
Not I
pVAX1
pVAX1
(3.0 kb)
(3.0 kb)
Bam HI/ Not I sites
Bam HI/ Not I sites
pCMV
pCMV
hHGF
hHGF
BGH 
BGH pA
pA
Kanamycin
Kanamycin
pMB1 
pMB1 ori
ori
pVAX1
pVAX1HGF/MGBI
HGF/MGBI
(5.18 
(5.18 kbp
kbp)
HGF fragment (2.2 
HGF fragment (2.2 kbp
kbp)
Bam HI
Bam HI
Not I
Not I
pVAX1
pVAX1
(3.0 kb)
(3.0 kb)
Bam HI/ Not I sites
Bam HI/ Not I sites
pCMV
pCMV
hHGF
hHGF
BGH 
BGH pA
pA
Kanamycin
Kanamycin
pMB1 
pMB1 ori
ori
HGF fragment (2.2 
HGF fragment (2.2 kbp
kbp)
Bam HI
Bam HI
Not I
Not I
pVAX1
pVAX1
(3.0 kb)
(3.0 kb)
Bam HI/ Not I sites
Bam HI/ Not I sites
pCMV
pCMV
hHGF
hHGF
BGH 
BGH pA
pA
Kanamycin
Kanamycin
pMB1 
pMB1 ori
ori

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7.4. 
Study Product Accountability 
Upon receipt, the Investigator is responsible for taking an inventory of the study product.  A 
record of this inventory must be kept and usage must be documented on study product 
accountability logs provided by the Sponsor.  Study product accountability logs will be examined 
and reconciled by the study monitor. 
In accordance with federal regulations (21 CFR 312.62), all Investigators are required to keep 
accurate records showing final disposition of all investigational drugs/study product. These 
records must be available to the Sponsor on request, showing accurate reconciliation of each and 
every shipment of study product and all activity of study product at the site (storage, dispensation 
to subjects, etc).  The Investigator is also required to ensure adequate storage of study product, 
which includes appropriate documentation of such storage conditions (e.g., maintaining 
temperature logs, etc). 
Ultimate accountability for the receipt, dispensation and record-keeping of the study product lies 
with the Investigator. Federal regulation requires that storage of the substance be in a secure 
enclosure, access to which is limited, to prevent theft or diversion. Neither the Pharmacist nor 
Investigator may supply the study product to any person outside of this protocol. 
Dosing must be documented on the CRF for each subject in addition to the study product 
accountability logs. 
Any unused vials must be retained at the study site until reconciliation by the study monitor. 
Opened (used) vials must be maintained until the study monitor confirms accountability. Once 
the study monitor completes accountability procedures, the used (opened) vials and any unused 
vials will be disposed of using each institution’s recommended investigational drug and 
biohazard material disposition procedures. 
The study product provided by the Sponsor for use in this study is intended for use only in the 
clinical trial outlined in this protocol and will be administered only to subjects appropriately 
enrolled in this trial. The use of the drug for other clinical or pre-clinical situations is strictly 
prohibited. AMG0001 is an investigational medication for use only in Clinical Trial AG-CLI-
0209. The possession and use of AMG0001 must be closely controlled and monitored by 
Investigators. Upon completion of the study, the study monitor will arrange for return or 
destruction of all used or unused vials of study product. 

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8. 
SAFETY REPORTING 
8.1. 
Adverse Events and Serious Adverse Events 
The protocol has been designed with an understanding of the underlying cardiovascular disease 
and associated co-morbidities in the study population, and the unknown potential angiogenic 
effects of AMG0001.  Although to date there are no indications that AMG0001 increases the 
incidence of serious nonfatal or fatal events, an evaluation of adverse events will be performed at 
each visit. The subject will be questioned in a non-leading manner to determine if any adverse 
events have occurred during product administration and during the post-treatment study period.  
An event that occurs during the Screening Period (from the time informed consent to just 
prior to the first dose of study product administration) must be documented as part of the 
Medical History. 
Adverse Events should be documented and followed from the start of the first dose of study 
product (Day 0), until the final outcome is known or until the end of the study safety follow-up 
period.  AEs (including SAEs) that have not resolved by the end of the study follow-up period 
should be recorded in the CRF as “ongoing”.  If it is not possible to obtain a final outcome for a 
SAE, the reason that a final outcome could not be obtained must be documented (e.g., 
completion of follow up, subject has moved and cannot be contacted, etc.). 
Each Adverse Event or Serious Adverse Events should be adequately described in the subject’s 
medical record. The description of AEs or SAEs will include the nature of the event, the time of 
onset, the duration and severity of each event, the Investigator's opinion regarding the causal 
relationship to study product or the subject’s CLI, the action taken, and the outcome of the event. 
All adverse events (excluding events related to the worsening of CLI as described below) will be 
reported and recorded in the subjects’ source documentation and the appropriate CRF. 
Any serious adverse event (see definition below) observed by the Investigator or study staff or 
reported by the subject that occurs within the study period will be recorded on the appropriate 
CRF. These events will be reported regardless of the perceived relationship of the event to the 
study product. 
8.1.1. 
Adverse Events Associated with Worsening CLI 
Adverse Events relating to the worsening of CLI that occur in the index limb such as increased 
rest pain, new ischemic ulceration or increase the size of the ulcer, gangrene, cellulitis or 
osteomyelitis, that are related to the study disease and are symptoms/signs of progression of 
study disease will not be recorded as adverse events (unless the speed or extent of the 
symptoms/signs are unexpected based on the natural history or bear a strong temporal 
relationship to the study product as determined by the Investigator). Data on the subject’s CLI 
status of the index limb will be recorded in detail on non-AE CRFs and not required to be 
documented as an AE or SAE, unless the outcome of the event is death. 
Systemic or metabolic complications (e.g., diabetic ketoacidosis, renal failure, etc.) that ensue 
subsequent to worsening CLI of the index leg should be reported as AEs or SAEs.   SAEs due to 
systemic complications include events such as septicemia, pneumonia, multi-organ failure and 
events resulting in death. These events should be reported as an SAE. 

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Limb specific events that occur in the non-index limb such as increased rest pain, new ischemic 
ulceration or increase in the size of the ulcer, gangrene, minor or major amputations, will be 
recorded as an AE or SAE on the AE CRF 
8.1.2. 
 
SAEs Associated with Worsening CLI 
Serious Adverse Events relating to the worsening of CLI that occur in the index limb such as 
gangrene, cellulitis or osteomyelitis, are related to the study disease and are symptoms/signs of 
progression of study disease will not be recorded as serious adverse events (unless the speed or 
extent of the symptoms/signs are unexpected based on the natural history or bear a strong 
temporal relationship to the study product as determined by the Investigator).Data on the 
subject’s CLI status of the index limb will be recorded in detail on non-AE CRFs and is not 
required to be documented as an SAE. Frequently worsening of CLI may lead to hospitalization 
followed by local or systemic treatment or surgical intervention (minor amputation, surgical 
revascularization or major amputation).  The entries for the above events will be made in the CLI 
section of the CRF.  However, in the case of serious intercurrent illness or systemic 
complications like septicemia, multi-organ failure, or pneumonia, these events will be captured 
in the AE or SAE section of the CRF. 
8.1.3. 
 
Deaths Following Worsening of CLI 
CLI-Related Adverse Events or CLI -Related Serious Adverse Events that result in death will be 
reported.  The death will be captured on the SAE CRFs. 
CLI-Related Deaths include but are not limited to the following: 
 Deaths due to infected ulcers/gangrene that lead to septicemia/organ failure 
 Perioperative Deaths following revascularization 
 Perioperative Deaths following major amputation 
 Worsening of CLI leading to death resulting from complications of Diabetic 
Ketoacidosis/Renal Failure 
8.1.4. 
Deaths 
All deaths will be documented in the CRFs in a specified section.  In the event of death, the 
Investigator will seek permission for an autopsy examination. Information on deaths will be 
obtained during the Post-18 month follow-up via questionnaire.  Hospital discharge reports or 
death certificates will be requested from the nearest relative. 
8.2. 
Definitions 
8.2.1. 
Treatment-Emergent Adverse Events 
The following definition of a treatment-emergent adverse event will be used for this study:  
Any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory 
finding that is considered to be clinically significant), syndrome or disease which, either occurs 
during the study, having been absent at baseline, or if present at baseline, appears to have 
worsened in severity or frequency, whether or not the event is considered related to the study 
product. 

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It is the responsibility of the Investigator(s) to perform periodic assessments for adverse events.  
The Investigators and clinical staff will document all adverse events disclosed by the subject at 
baseline and during the treatment and follow-up periods.  All clinical complaints volunteered by, 
or elicited from, the subject during the study or from findings on the subject’s physical 
examination will be recorded in the clinical records and on the Adverse Event CRF.  If any 
adverse event occurs, the subject will receive appropriate medical treatment and supervision.  All 
adverse events will be followed until resolution where possible. 
For the purpose of this study, index leg specific events that relate to the worsening of the 
subject’s CLI will not be reported as Adverse Events unless applicable. (Please see Section 8.1). 
8.2.2. 
Serious Adverse Event 
A serious adverse event (21 CFR 312.32) is defined as any adverse event (excluding worsening 
CLI events if applicable) that suggests a significant hazard, contraindication, side effect or 
untoward medical occurrence that:  
 Results in death,  
 Is life-threatening, 
 Requires (or prolongs) hospitalization,  
 Causes persistent or significant disability/incapacity,  
 Results in congenital anomalies or birth defects, or  
 Other significant medical conditions which in the judgment of the investigator(s) or 
Sponsor represent significant hazards.  
For the purpose of this study, index leg specific events that relate to the worsening of the 
subject’s CLI will not be reported as Serious Adverse Events unless applicable. (Please see 
Section 8.1) 
Any serious and immediately life-threatening adverse event, including death, occurring while 
the subject is receiving an investigational drug or control agent; within 18 months of the first 
administration of study product; and throughout the safety follow-up period, irrespective of the 
Investigator's opinion regarding drug relationship, will be reported by phone to the Sponsor and 
faxed immediately. 
All serious adverse events will be reported by contacting the Sponsor/Safety Medical Monitor. 
The Safety Medical Monitor is available for medical consultation issues related to management 
of serious adverse events. Contact information regarding the Sponsor/Safety Medical Monitor 
can be found in the Study Reference Manual provided at the time of the Initiation Monitoring 
Visit. 
8.2.3. 
Expected Adverse Events 
Adverse events described in the Investigator’s Brochure or that have occurred previously in the 
course of the active studies for this product (unless the frequency/severity or consequences have 
changed) are considered expected adverse events.  

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8.2.4. 
Intensity or Severity of Adverse Events 
Assignment of the grade of severity of adverse events will be based on intensity of symptoms, 
degree of limitation of usual daily activities, or level of abnormality of objective clinical signs or 
laboratory parameters.  Adverse events will be graded according to their severity using the 
following criteria: 
Mild: the adverse event is transient or minimal and either resolves spontaneously or no 
treatment is required. Symptoms do not interfere with subject’s daily activities. 
Moderate: the adverse event required only brief treatment with prescription medication 
and/or intervention but produced no sequelae and required no hospitalization; symptoms 
may interfere with daily activities; symptomatic, moderate change in activity; no change 
in social activities. 
Severe: the event produced sequelae that required prolonged treatment with prescription 
medication, intervention and/or hospitalization; interrupts subject’s usual daily activities; 
incapacitating, requires bed rest, absence from work and/or a decrease in social activities. 
8.2.5. 
Relatedness of Adverse Event to an Intervention 
An adverse event can be assessed as:  
a. Likely Related - The adverse event is likely to be related to the study product(s) 
b. Possibly Related - The adverse event may be related to the study product(s) 
c. Likely Unrelated - The adverse event is unlikely to be related to the study product(s) 
If an adverse event is evaluated as not related to the study product, there must be an alternative 
etiology in the Investigator’s assessment for that event documented in the subject’s medical 
records. 

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9. 
EVALUATIONS AND STATISTICAL METHODS 
9.1. 
Evaluations 
The following evaluations relating to tolerability, safety and clinical benefit will be made: 
1. Adverse events (AEs) suspected to be related to injections of HGF plasmid 
2. Discontinuations related to adverse effects from the injections of HGF plasmid 
3. All AEs up to Month 3, Month 6, Month 12, and Month 18 
4. Serious adverse events (SAEs) up to Month 3, Month 6, Month 12, and Month 18 
5. Number of deaths and cause over the 18 month period up to Month 3, Month 6, Month 
12, and Month 18 
6. Number of subjects in whom the largest ulcer healed completely or gets smaller (photo 
confirmation) at 6, 12 and 18 months (cumulative) 
7. Number of subjects in whom rest pain (based on the 100 mm VAS scale) reduces by  
20 mm or more or was completely relieved at 6, 12 and 18 months (cumulative) 
8. Change in  VascuQol Questionnaire (QOL) score compared to the baseline at 6, 12 and 
18 months  
9. Number of subjects revascularized (bypass or endovascular intervention) up to Month 3, 
Month 6, Month 12, and Month 18 
10.  Number of subjects with minor and number of subjects with major amputations (at or 
above the ankle) up to Month 3, Month 6, Month 12, and Month 18 
9.2. 
Statistical Methods 
All summaries and analyses will be presented in tabular or graphical form.   The study is not 
powered for the statistical inference and the test will be considered to be descriptive.   
9.2.1. 
Disposition, Compliance, Demographic and Background Characteristics 
(Including Medical History) 
The number subjects enrolled, and the number and percent of subjects who completed the study, 
prematurely discontinued, primary reason for discontinuation, and the compliance to the study 
product (number of subjects who received the first course of injections only, both the first and 
subsequent courses of injections) will be summarized. 
The demographic data (age, weight, gender, race), and the prior and concomitant medication will 
be summarized at baseline and during the study.  The use of selective concomitant medication 
such as medications for pain, hypertension, hyperlipidemia, antiplatelet agents will also be 
summarized.  
9.2.2. 
Statistical Analysis for Efficacy and Safety  
Categorical data will be summarized by the use of frequency tables showing the number and 
percentage of subjects falling within a particular category by visit, and detailed line listings of 
subjects will be provided.  

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Continuous data will be summarized by reporting number of observations, mean, standard 
deviation (SD), median, minimum and maximum by visit.  Summary statistics will be provided 
for baseline and the change (with percent change) from baseline. A one-sample t-test will be 
performed on within group change-from-baseline for individual time point (Months 6, 9, 12, 15, 
and 18 with last observation data (assessed prior to intervention or worse score for deaths) carry-
forward (LOCF)).   
9.2.3. 
Windows for time points 
Number of subjects followed up to 3 months: subjects with a follow-up visit at day 90 10 (days 
80 to 100) will be counted.  
For months 6, 9, 12, 15 and 18 evaluation: subjects with follow-up visits at day 182 + 15 (days 
167 to 197), day 273 + 15 (days 258 to 288), day 365 + 30 (days 335 to 395), day 455 +35 (days 
420 to 490), and day 548 + 45 (days 503 to 593) will be counted.  
For 12 months and 18 months evaluations, events occurring up to day 395 and day 593 will be 
taken into account, respectively. 

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10. 
SAFETY FOLLOW-UP PROGRAM 
Since this study uses a DNA plasmid for gene transfer, the Sponsor (AnGes, Inc.) is complying 
with regulatory guidance to conduct long-term safety follow-up to collect safety information on 
all participants who receive the study product. The long-term safety follow-up data will be 
collected every 6 months for an additional 18 months following the Month 18 Visit.  
Adverse Events should be documented and followed from the start of the first dose of study 
product (Day 0), until the final outcome is known or until the end of the study safety follow-up 
period.  AEs (including SAEs) that have not resolved by the end of the study follow-up period 
should be recorded in the CRF as “ongoing”.  If it is not possible to obtain a final outcome for a 
SAE, the reason that a final outcome could not be obtained must be documented (e.g., 
completion of follow up, subject has moved and cannot be contacted, etc.). Serious Adverse 
Events should be reported within 24 hours of site awareness.  
Deaths, major amputations, revascularizations by surgical bypass, stroke, and myocardial 
infarction will be source verified.  An appropriate request/permission for this safety follow-up 
program will be included in the informed consent.  
The data collected during the follow-up period will consist of surgical revascularization, lower 
limb amputation, cancers, eyesight changes, bleeding/blood disorders, autoimmune diseases, 
neurological disorders, hospitalizations, unexpected or significant illnesses including stroke, 
myocardial infarction, and death.  In the event of death, information regarding the above data (as 
best as possible) and date and cause of death will be requested from a spouse or nearest relative.  
The questionnaire is found in Appendix F. 
Site staff should obtain information from the completed questionnaires via phone contact within 
±7 days of the target follow-up contact date. If the subject has experienced any of the events 
types noted in the questionnaire additional information may need to be requested from the 
subject and/or supporting medical records may be required. In the event the subject experiences 
(CLI status of the index limb, revascularization of the index limb, amputation of the index limb, 
cancers, eyesight changes, bleeding/blood disorders, autoimmune diseases, neurological 
disorders, hospitalizations, and unexpected or significant illnesses including stroke, myocardial 
infarction, and death) data on relevant onset/resolution dates, treatments and confirmed diagnosis 
(as and where applicable) will be obtained. 
All information collected by the questionnaire will be submitted periodically to the FDA and any 
other agencies as required.  
All safety information collected by the questionnaire that is not included in the Biologics License 
Application (BLA) will be submitted periodically to the FDA and any other agencies as required.   
Subjects will not be identified in any report, publication, or submission.  All subjects 
participating in the study will receive an explanation of these procedures, and their rights under 
HIPAA, at the time of Informed Consent.   

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11. 
ADMINISTRATIVE PROCEDURES  
11.1. 
Institutional Review Board/ Ethics Committee 
Regulatory Authorities require that an IRB/EC oversee all investigational drug studies (21 CFR 
56). Each IRB/EC must conform to federal regulations and any country, state and local 
guidelines regarding such, will approve all aspects of the study, including but not limited to said 
protocol and written Informed Consent to be used, prior to initiation of the study. The 
Investigator will provide the Sponsor with a copy of the communication from the committee to 
the Investigator indicating approval of the protocol and consent form. All amendments to the 
protocol that affect the conduct of the study must be reviewed and approved prior to 
implementation, except where necessary to eliminate immediate hazards to human subjects. 
As per IRB/EC requirements, the Investigator will be responsible for obtaining IRB/EC 
renewals; submitting expedited and other periodic safety reports to the IRB/EC for the duration 
of the study; and for following any additional reporting requirements by the IRB/EC approving 
study activity at his/her investigational site. Copies of all approvals, renewals and 
correspondence to and from the IRB/EC must be forwarded to the Sponsor. 
11.2. 
Institutional Biosafety Committee (IBC) 
The institution at which a gene transfer trial is being conducted shall establish an Institutional 
Biosafety Committee (IBC) whose responsibilities need not be restricted to recombinant DNA 
products. The IBC is responsible for conformance with the requirements set forth in the NIH 
Guidelines for Research Involving Recombinant DNA Molecules as defined in Section IV-B-2 
for the US. 

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12. 
CONFIDENTIALITY 
All information and data, including this protocol, and all data, clinical results and research 
conducted hereunder concerning the Sponsor’s products and operations including the Sponsor’s 
patent applications, formulas, manufacturing processes, basic scientific data and formulation 
information that has been supplied by the Sponsor and not previously published are considered 
confidential by the Sponsor and will remain the sole property of the Sponsor. The Investigator 
understands and agrees that said proprietary and/or confidential information disclosed to or 
produced by him/her there under is highly valuable to the Sponsor and will be used 
EXCLUSIVELY by the Investigator in accomplishing this study and will not use it for any other 
purposes without the Sponsor’s prior written consent.  
The Investigator agrees that he/she will not use any such proprietary and/or confidential 
information for any other purpose. The Investigator also understands and agrees that such 
disclosure will not be deemed to grant to the investigator a license for use of said proprietary 
and/or confidential information, except as expressly provided herein. It is understood by the 
Investigator that the information developed in the clinical study will be used by the Sponsor in 
connection with the development of AMG0001, therefore, may be disclosed and used solely by 
the Sponsor as required to such third parties and agencies as the Sponsor, in its sole discretion, 
warrants. In order to allow for the use of the information derived from the clinical studies, it is 
understood that there is an obligation to provide to the Sponsor complete test results and all data 
developed in this study. The Investigator agrees to promptly answer all inquiries from the 
Sponsor regarding completion, legibility or accuracy of trial data in the CRF. 
 
 

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APPENDIX A. Study Product Preparation &Administration 
1. SELECTION OF INJECTION SITE LOCATIONS 
AMG0001 injection site locations will be identified using images from contrast arteriograms, 
CTA, or MRA and prior to Day 0.  Injection sites will be determined by the independent vascular 
surgeon. Injection sites will be chosen with the objective of inducing the formation of bridging 
collaterals from areas with normal blood flow.  Desirable locations for injections, above and/or 
below the knee, are areas of musculature proximal and distal to the occluded sites and areas 
adjacent to the occlusion where blood flow through collateral blood vessels is identified on the 
pre-procedure angiogram.  Eight optimal injection site locations will be identified for all subjects 
prior to the planned Day 0.  Injection sites will be indicated on an anatomical diagram prior to 
the planned Day 0.  
 Subjects with no apparent occlusion above the knee will receive all 8 injections below 
the knee.  Injections will be distributed between musculature adjacent to the Anterior 
Tibial Artery, the Posterior Tibial Artery, and the Peroneal Artery.  Areas with good 
collateral flow should be considered ideal for injection site locations.  
 When Subjects do have occlusions noted on the screening angiogram, the number of 
injections administered to each artery will be distributed in proportion to the severity 
of the occlusions at each location.  Injections will be located in the proximity of the 
occlusion.  
Desirable locations for injection are areas of musculature proximal and distal to the sites of 
vessel occlusion, in areas where there is good blood flow.  Areas of ischemia should be avoided 
as sites for injection. The goal of duplex guided injection is to be certain that injection of the 
study product is placed into the muscle in proximity to the diseased vessel and not into the peri-
vascular space.  
It is advised that AMG0001 Injections not be administered into the gastrocnemius muscle due to 
the close proximity of major arterial anatomy.  See Section 4.4 of this Appendix (below) for 
Injection Site Location examples. 
2. SYRINGE PREPARATION 
Only the Principal Investigator or authorized personnel who have been instructed in the proper 
administration and accountability of the study product will administer the investigational study 
product. Study product intended for one subject must not be used for another subject. The 
Investigator must not use material provided for this particular study in another study. 
The pharmacy should confirm that the subject has arrived in the clinic prior to 
preparation of study product. 
Approximately 15 to 20 minutes prior to study product preparation remove the vial from the -
20°C (± 10°C) storage and bring to room temperature. The vial should not be heated or 
microwaved.  The vial should not be shaken.  AMG0001 is stable at room temperature (25°C) 
for up to 6 hours. 
All preparation should be conducted using controlled and validated aseptic techniques under 
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Hood (Biosafety Class 1 or International Organization for Standardization (ISO) Class 5). Use of 
goggles, mask, sterile gloves and lab coat is recommended. 
To prepare one administration of the AMG0001: 
With a 21 Gauge needle, withdraw 1.7 mL contents of one AMG0001 into a syringe and dilute 
into a 30 mL sterile vial containing 23.7 mL sterile saline to provide 25.4 mL of a diluted 0.167 
mg/mL solution.  Slowly invert the 30 mL vial 4 times to provide gentle mixing of study product 
and diluent. Three (3) mL of the solution should be filled in each of 8 (3 mL) syringes provided 
by the Sponsor. Each 3 mL syringe of the diluted solution should be used for each of 8 injections 
during the administration.  Syringes must be labeled with the subject number. The overage is 
provided to ensure that a delivered volume of 3 mL is injected and the residual undelivered 
volume in the vials and all 8 syringes is accounted for properly. Any residual material should be 
disposed of in an appropriate manner for biological waste products. 
After dilution with sterile saline solution, the diluted study product is physically and chemically 
stable for 24 hours at 2°C-8°C.  If the prepared syringes are refrigerated prior to being 
administered, they should be left to reach room temperature prior to the start of the injection 
procedure. 
From a microbiological point of view, the product should be used immediately. The product is 
not intended to be stored after dilution unless this has taken place under controlled and validated 
aseptic conditions. If not used immediately, in-use storage times and conditions are the 
responsibility of the user and would normally not be longer than 6 hours up to 25°C or 24 hours 
at 2°C-8°C. 
DO NOT DISCARD USED STUDY PRODUCT VIALS UNTIL AUTHORIZED BY THE 
STUDY MONITOR. 
3. ADMINISTRATION OF INJECTIONS 
Based on the injection site locations confirmed by the vascular surgeon, Investigators should 
mark the initial 8 injection sites with a tattoo pen prior to injecting the study product on Day 0.  
The procedure will be repeated on injections made on Day 14, Day 28, and Day 42 using a 
different color tattoo pen to track the injections. The Month 3, Month 9, and Month 12 injection 
site locations should mirror that of Day 0.   
Subsequent injection site locations for the Day 14, Day 28, and Day 42 injection sites will be 1-2 
cm initially proximal to the Day 0 injection then 1-2 cm distal and subsequently 1-2 cm lateral, 
respectively.  The Month 3+14 days, Month 3+28 days, Month 3+42 days, Month 9+14 days, 
Month 9+28 days, Month 9+42 days, and Month 12 + 14 days, Month 12 + 28 days, and Month 
12 + 42 days injection site locations should mirror that of Days 14, 28, and 42, respectively. 
No more than 3 injections should be made into the anterior or lateral compartments on any 
dosing visit. 
The Investigator should utilize duplex ultra-sound to guide the 8 IM injections.   
Investigators must utilize a 21 Gauge, 7cm echotip® needle and the 3mL syringes for the IM 
injections of study product. 
Investigators should trace blood vessels from the proximal portion while maintaining the probe 
at a right angle with the color Doppler and identify occluded areas.  Investigators should select 

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injection sites as areas of musculature proximal and distal to the occluded sites and areas 
adjacent to the occlusion where blood flow through the collateral blood vessels.   
Investigators should check pulsation with a color Doppler.  The blood flow wave should also be 
examined with a color Doppler in order to exclude venous blood flow if arterial blood flow is 
poor around the selected injection sites.   
Insert the needle while monitoring it under echographic guidance.    
Confirm the injection into the muscle under B mode echography by injecting a small amount of 
the investigational product.  If the injection is made into the muscle, the drug is shown to 
infiltrate in a spherical form.  This observation cannot be seen if the injection is made into the 
fascia or interstitial tissues.    
Inject the entire 3mL in the syringe in about 3 seconds.   Immediately after completion of 
injection, lightly press the injection site with the finger in order to prevent reflux.   
Do not massage the injection site. 
The subject should remain in a supine position while receiving all 8 injections and for 15 minutes 
post injections.  
The time and details of study product administration should be noted in the subject’s source 
documentation and CRF. 
Photographs of the injection site locations (with ruler) must be taken at the completion of each 
dose. 
4. ADMINISTRATION METHOD 
Below are suggested needle approaches for the administration of study product to muscular 
anatomy supplied by commonly occluded arteries.  The popliteal artery is branched into the 
anterior tibial artery (ATA), posterior tibial artery (PTA), and peroneal artery.  
 

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4.1 OCCLUSION OF THE AREA SUPPLIED BY THE ATA 
ATA is distributed in a deep layer of compartments consisting of a group of extensor muscles 
such as the anterior tibial muscle and the long extensor muscle of the great toe.   Collateral blood 
vessels are also distributed in these compartments.   Apply the echo probe from the lateral site of 
the Tibia and make the injection into these extensor muscles.  The ATA perforates the 
interosseous membrane right beneath the knee joint.   If occlusion occurs in the area proximal to 
this perforation site, no efficacy can be expected even if injection is made into the component 
consisting of extensor muscles.  It is recommended that injection not be made in such 
compartment. 
 
 
 
 

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4.2 OCCLUSION IN THE AREA SUPPLIED BY THE PTA 
The PTA is distributed between the soleus muscle and a deeper compartment.  Collateral blood 
vessels maybe distributed in both compartments.   The surface of the proximal portion of the crus 
(2/3) is covered with the gastrocnemius muscle.   In order to inject the drug into the soleus 
muscle, the gastrocnemius muscle must be perforated with the needle.  When a distal portion of 
the crus is targeted, checking based on ultra-sound guided images and injection are easy since the 
superficial gastrocnemius muscle is thin and the needling depth is shallow.  In contrast, if the 
target tends to be in the deeper proximal areas and observation is difficult, make approach from 
just behind the tibia, i.e., from the medial side and stab the needle into the muscle such as the 
long flexor muscle of the digits. 
 
 

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4.3 STUDY PRODUCT PREPARATION &ADMINISTRATION 
The peroneal artery is distributed into a layer deeper than the long flexor muscle of the digits.   
Make approach from just behind the fibula, identify the deeper long flexor muscle of the digits 
using the fibula as a marker, and stab the needle into this muscle.  
 
 
 
 
In 4.2 and 4.3 above, attention is required not to stab the needle into the gastrocnemius muscle.   
Because blood vessels are more branched in the gastrocnemius muscle than in the popliteal 
region, increases in collateral circuits in the gastrocnemius muscle compartment are not expected 
to contribute to increases in peripheral blood flow in the lower limbs. 
 
 
 

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Examples of Injection Site Location Scenarios are Given Below:  
 
 
 
 
 
①
②
③
④
⑤
⑥
⑦
⑧
Target Muscle
Injection sites
Outside
Inside
Front
Back
Soleus Muscle
Soleus Muscle
Soleus Muscle
Soleus Muscle
Soleus Muscle
Soleus Muscle
Ant. Tibial Muscle
Ant. Tibial Muscle
①
X
②
X
③
X
X     ④
X     ⑤
X     ⑥
X      ⑦
X      ⑧
Example #1- Meeting May 2005
Anterior Tibial Artery and Posterior Tibial 
Artery
Patient ID:
Occlusion and/or 
Stenoses:
①
②
③
④
⑤
⑥
⑦
⑧
Target Muscle
Injection sites
Outside
Inside
Front
Back
Peroneus Longus Muscle
Peroneus Longus Muscle
Soleus Muscle
Soleus Muscle
Soleus Muscle
Ant. Tibial Muscle
Ant. Tibial Muscle
Ant. Tibial Muscle
X     ③
X     ④
⑤
X
X      ⑥
X      ⑦
X      ⑧
①
X
②
X
Pt. 1640 from AG-CLI-0205
Anterior Tibal Artery, Posterior Tibial 
Artery, and Peroneal Artery
Patient ID:
Occlusion and/or 
Stenoses:

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①
②
③
④
⑤
⑥
⑦
⑧
Target Muscle
Injection sites
Outside
Inside
Front
Back
Vastus Medialis
Vastus Medialis
Vastus Lateralis
Vastus Lateralis
Ant. Tibial Muscle
Ant. Tibial Muscle
Ant. Tibial Muscle
Ant. Tibial Muscle
X    ①
X    ②
③
X
④
X
X   ⑤
X   ⑥
X   ⑦
X   ⑧
Pt. 2333 from AG-CLI-0205
Anterior Tibial Artery, Posterior Tibial 
Artery, Peroneal Artery, Femoral Artery, 
and Popiteal Artery
Patient ID:
Occlusion and/or 
Stenoses:
①
②
③
④
⑤
⑥
⑦
⑧
Target Muscle
Injection sites
Outside
Inside
Front
Back
X  ②
X  ④
X   ⑥
X    ⑦
X    ⑧
Soleus Muscle
Soleus Muscle
Soleus Muscle
Soleus Muscle
Soleus Muscle
Flexor Hallucis Longus Muscle
Ant. Tibial Muscle
Ant. Tibial Muscle
①X 
③X
⑤X
Pt. AMG-01-37-01
Anterior Tibial Artery, Posterior Tibial Artery, 
Popiteal Artery, Femoral Artery, Peroneal
Artery, and Artery Distal Ankle Joint 
Patient ID:
Occlusion  and/or 
Stenoses:

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APPENDIX B. HEMODYNAMIC PROCEDURES 
ABI and TBI Assessment 
Explain the procedure, reassure the subject, and ensure that he/she is lying flat and is 
comfortable, relaxed, and rested with no pressure on the proximal lower limb vessels. Laying the 
subject supine reduces the hydrostatic pressure inaccuracies. Reliability and ability to reproduce 
results both over time and between observers was tested and the index was found to vary by 
0.06, which is considered acceptable. Measuring the pressure in both arms and using the higher 
of the two pressures increases the non-invasive accuracy of measurement of central systolic 
pressure but will not eliminate this potential limitation to the method. 
Measure the brachial systolic blood pressure: 
1. Place an appropriately sized cuff around the upper arm  
2. Locate the brachial pulse and apply ultrasound contact gel  
3. Angle the Doppler probe at 45 degrees and move the probe to obtain the best signal  
4. Inflate the cuff until the signal is abolished then deflate the cuff slowly and record the 
pressure at which the signal returns being careful not to move the probe from the line of 
the artery  
5. Repeat the procedure for the other arm  
6. Use the highest of the two values to calculate the ABI  
Measure the ankle systolic pressure: 
1. Place an appropriately sized cuff around the ankle immediately above the malleoli having 
first protected any ulcer that may be present  
2. Examine the foot, locating the dorsalis pedis pulse and apply contact  
3. Continue as for the brachial pressure, recording this pressure in the same way  
4. Repeat this for the posterior tibial artery 
5. Use the highest reading obtained to calculate the ABI for that leg 

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Measure the toe systolic pressure: 
1. Place an appropriately sized cuff around the hallux (1st toe) having first protected any 
ulcer that may be present.  If the 1st toe is unavailable you may use other toes if 
appropriate, this should be documented in the source documents. 
2. Examine the toe with the Doppler or PPG (photoplethysmograph), locating the pulse on 
the dorsal aspect and apply contact. 
 
Note: The same method (Doppler or PPG) must be used on the subject for all 
assessments through study completion. 
3. Continue as for the ankle pressure, recording this pressure in the same way  
4. Repeat this for the plantar toe artery  
5. Use the highest reading obtained to calculate the TBI for that leg 
Problems and errors may arise if: 
1. The cuff is repeatedly inflated or inflated for long periods. This can cause the ankle 
pressure to fall. 
2. The cuff is not placed at the ankle. 
3. The pulse is irregular or the cuff is deflated too rapidly. 
4. The true systolic pressure may be missed and inappropriately high reading will be 
obtained, if the vessels are calcified (associated with diabetes), the legs are large, fatty or 
edematous, the cuff size is too small, or the legs are dependent.  
5. Central systolic pressure may influence the 'normal' range for the ABI.  
For subjects with ankle and toe pressures in the affected limb that are not reliable due to non-
compressible arteries or unattainable due to ulcers on ankle or great toe, there must be 
documentation of diagnosis of severe Rutherford category 4 or Rutherford category 5 and 
angiographic evidence of total occlusion of the superficial femoral, popliteal or at least one of 
the infra-popliteal arteries. 

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APPENDIX C. RUTHERFORD CLASSIFICATION 
Rutherford Categories 
Category          
 
Clinical Description 
 
Asymptomatic 
1. 
Mild claudication 
2. 
Moderate claudication 
3. 
Severe claudication 
4. 
Ischemic rest pain 
5. 
Minor tissue loss 
6. 
Major tissue loss 
 
 
 
 
 
 
 

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APPENDIX D. WOUND CARE GUIDELINES 
The purpose of these guidelines is to ensure that wound care during the study is consistent 
across all study subjects. 
General Guidelines for Wound Care 
All ulcers in both the treatment and control groups will receive wound care as summarized 
below for the duration of the study.  
Debridement 
Sharp or surgical debridement will be performed as deemed necessary by a wound care 
specialist (e.g. doctors/nurses at wound care clinics, orthopedic physicians, podiatrist, etc).  If it 
is deemed necessary for any study subject, this procedure should always precede any 
photographic or ulcer tracing assessment. There are many debriding agents, but there is no 
consensus about the best agent. The method of debridement that is chosen will depend on the 
status of the wound, the resources of the healthcare provider and the overall condition of the 
subject.  When chosen, this procedure should remove crusts as well as necrotic, devitalized 
tissue by surgical, enzymatic, mechanical, biological or autolytic debridement. 
Treatment 
Maintenance of a clean, moist ulcer environment is essential.  Ideally, this should include daily 
dressing changes.  Select a dressing that is cost-effective, appropriate to ulcer etiology, the 
setting and the provider.  Dressing changes once daily or less often should be chosen where 
possible.  Ulcer care products that can be utilized for study subjects include: saline, hydrogel, 
negative pressure dressings and topical antibiotics. Wound care products such as Regranex® 
(rhPDGF), Apligraft®, Dermagraft®, Oasis®, as well as any other skin equivalents or topical 
growth factors are excluded for use during this trial.  Hyperbaric oxygen (HBO) treatment is 
also excluded. 
Continuing education of the subject in regards to risk factor reduction should be addressed as 
frequently as necessary.  This includes cigarette smoking cessation, control of any diabetes, 
elevated homocysteine levels, hyperlipidemia and hypertension.  Additionally, where possible, 
exercise to increase arterial blood flow has been demonstrated to be helpful in long-term 
maintenance and arterial ulcer prevention. 
Pressure relief by off-loading can also be pursued based on recommendations from the wound 
care specialist.  Acceptable offloading methods include crutches, walker, wheelchair, custom 
shoes, depth shoes, shoe modifications, custom shoe inserts, custom relief orthotic walker, 
diabetic boots, forefront and heel relief shoes, and total contact casts. 
 
 
 
 
Ref:  Chronic Wound Care Guidelines, The Wound Healing Society, 341 N. Maitland Avenue, 
Suite 130, Maitland, FL 32751. (407) 647-8839. www.woundheal.org 

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APPENDIX E. THE VISUAL ANALOG SCALE (VAS) PROCEDURES -
MEASURING REST PAIN 
Pain Intensity rating using VAS 
The visual analog scale (VAS) is a 10-cm line, oriented horizontally, with the left end of the line 
(the 0 mark) indicating “no pain” and the right end representing “pain as bad as it can be”. 
1. The subject is asked to mark a place on the line corresponding to the average pain 
intensity experienced in the last seven days. 
2. The distance along the scale is then converted into a numeric reading by measuring the 
distance of the subjects mark in centimeters from the beginning of the scale (the 0 mark). 
THE MEASUREMENT IS RECORDED IN CENTIMETERS FROM 00.0 TO 10.0 ONTO 
SOURCE DOCUMENTATION AND THE CRF. 
The measurements will not be divulged to the subject.  Additionally, the pain scale or VAS score from 
previous visits will not be shown to the subject.

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APPENDIX F. POST 18-MONTH FOLLOW-UP QUESTIONNAIRE 
Instructions: You may wish to seek your doctor’s help in answering these questions.   
Please consult your physician if you need help with any of these medical conditions. 
"Diseased Leg" in this questionnaire refers to the diseased leg that received the injections 
of study product. 
Diseased Leg (circle):    RIGHT    LEFT 
 
Since your last visit or follow-up with this study, have you experienced any of the conditions 
mentioned below? 
 
1. Any new or recurring cancer(s)? 
 YES  
 NO 
a. If yes, what type of cancer and when was it 
diagnosed?__________________________ 
b. What cancer treatment did you receive?None   Surgery   Chemotherapy  
Radiation  Other (describe) ________________________________________ 
 
2. Any new problems with your eyesight? 
 YES  
 NO 
a. Did you see the eye doctor? 
 
 YES  
 NO 
b. If yes, what was the diagnosis and how were you treated? ___________________ 
 
3. Have you had any significant, unexplained bleeding from anywhere? YES 
 NO 
a.  If yes, give details of location, diagnosis and treatment.__________________ 
 
4. Have you been diagnosed with an autoimmune disorder (e.g., Rheumatoid arthritis, 
Lupus, Asthma)?  
 YES  
 NO 
a. If yes, please give details:_____________________________________________ 
b. How were you treated? _______________________________________________ 
 
5. Have you been diagnosed with a blood disorder (e.g., anemia, platelet disorder, low white 
cell count)? 
 
 YES  
 NO 
If yes, please answer the following questions: 
a. When did it happen? _______________________________________________ 
b. What was the diagnosis? ____________________________________________ 
c. What treatment did you receive? ______________________________________ 
d. What was the outcome? _____________________________________________ 
 

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6. Have you been diagnosed with a new nerve disorder or has there been a flare-up of an 
 
existing nerve disorder?  
 YES  
 NO 
If yes, please answer the following questions: 
a. What was the condition? ____________________________________________ 
b. When was it diagnosed? _____________________________________________ 
c. How was it treated? ________________________________________________ 
 
7. Have you had any other unexpected or significant new illness? 
 YES       NO   
If yes, please describe the illness:_____________________________________ 
 
8. Have you been hospitalized?      YES 
 NO,   
If yes, please describe_______________________________________ 
 
9. Have you suffered from a stroke (transient or long-lasting)?  
 YES       NO  
 If yes, please describe__________________________________________ 
 
10. Have you suffered from a myocardial infarction (heart attack)? 
 YES         NO   
If yes, please describe________________________________________________ 
 
11. Have you had any revascularization procedure performed on your diseased leg? 
 
 YES  
 NO   
If yes, please describe and specify which leg:______________________________ 
 
12. How are your symptoms relating to ulcers, gangrene and/or rest pain on your diseased 
leg?   Improved    Same    Worse 
 
13. Have you had an amputation above the ankle of either leg?  YES  NO   
a. If yes, please describe and specify which leg: :_____________________________ 
b. Please indicate date of amputation:___________________________ 

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APPENDIX G. PREGNANCY PREVENTION AND REPORTING 
AG-CLI-0209 is a study in with older population, however due to not having sufficient 
reproductive toxicity data for the study product, per (Guideline on Risk Assessment of Medicinal 
Products on Human Reproduction and Lactation: from Data to Labelling, 
EMEA/CHMP/203927/2005), proper pregnancy prevention and planning needs to be in place. 
Women who have recently been assessed as post-menopausal (<18 months) should have Follicle-
stimulating hormone (FSH) and estradiol levels measured to confirm the post-menopausal state. 
Pregnancy prevention 
In accordance with good clinical practice, to avoid embryo-fetal exposure, AG-CLI-0209 has a 
risk evaluation and mitigation strategy to prevent pregnancy in subjects on study product.  These 
measures help to minimize the possibility of fetal exposure to the investigational product due to 
the unknown risk to the health of the fetus and/or the pregnant woman.  
Precautions include: 
 Exclusion of women with child bearing potential on the AG-CLI-0209 study. 
 Women who are surgically sterile. For the purposes of this study, only women 
with hysterectomy or bilateral oophorectomy will be considered surgically sterile. 
Tubal ligation alone is not sufficient to be considered sterile.  
 Women who have documented primary ovarian insufficiency (premature ovarian 
failure) who are 55 years of age or younger will be given a urine pregnancy test 
within 7 days of Day 0, Month 3, Month 9 and Month 12 to ensure that they are 
not pregnant. 
 
Confirmation of menopause by history of amenorrhea for 18 months or greater in 
the absence of other causes of amenorrhea, serum FSH (30 mIU/mL or higher) 
and serum estradiol (30 pg/mL or less) both consistent with menopause.  
 
A pregnancy test should be conducted at screening.  If pregnancy is confirmed 
prior to the start of the trial in general, the subject should not be enrolled in the 
trial.  
 Male subject commitment to using a reliable method(s) of contraception, and/or 
abstinence, for the duration of therapeutic product exposure (up to 12 weeks post last 
study product dose). Please note that any pregnancy confirmed post that period will 
need to be documented up to the completion of the follow up period. (Reference 
Pregnancy Reporting below). As required, contraception should be extended beyond 
the last dose of the investigational product.  
Contraception Methods 
Male subjects must commit to use a highly effective method of contraception throughout 
treatment cycles through 12 weeks post last study dose.  Effective methods include: 
 Vasectomy 
 Sexual Abstinence 
 Barrier Methods (male or female condom with spermicide) 

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Pregnancy reporting 
Subjects (female and male) should be advised to report, immediately, to the Investigator a 
suspected or confirmed pregnancy that occurs in the course of this clinical trial (including during 
any period of exposure that may exceed the length of the trial). 
Pregnancy of a female subject or female partner of a subject must be reported within 24 hours of 
clinical research site awareness.   
A female subject must discontinue study drug immediately and the investigator should report all 
pregnancies to the Sponsor, using the paper Pregnancy Report Form and SAE form. Please note 
that any pregnancy confirmed during investigational product exposure will need to be 
documented up to the completion of the follow up period.  
Pregnancy of the female partner of a male subject that is within 12 weeks of last dose of study 
product should be reported to the investigator. The investigator should report the pregnancy to 
the Sponsor, using the paper Pregnancy Report Form and SAE form. Please note that any 
pregnancy confirmed during investigational product exposure will need to be documented up to 
the completion of the follow up period.  
Pregnancy exposure to a female partner of a male subject after 12 weeks of last dose of study 
product should be reported to the investigator. The investigator should report the pregnancy to 
the Sponsor, using the paper Pregnancy Report Form only. This pregnancy should not be 
reported as an SAE. 
Follow-up 
Follow-up procedures regarding the course of the pregnancy should be discussed with the 
subject, as appropriate. Follow-up should be done by the investigator throughout the pregnancy 
and for an appropriate period thereafter.  If the pregnancy is experienced by the female partner of 
a male subject, informed consent will be requested for follow up information.  
The outcome of each pregnancy should be recorded and followed-up. For live births, longer term 
follow-up of a child is recommended, when possible and appropriate. 
Miscarriages, Congenital anomalies, and birth defects should be reported as an SAE.  Any 
complication occurring during pregnancy that meets the criteria for SAE should be reported in 
the SAE form.