A Randomized Double Blind Placebo Controlled Clinical Study to Assess Blood-Derived Autologous Angiogenic Cell Precursor Therapy in Patients With Critical Limb Ischemia (ACP-CLI)
Phase: PHASE2
Conditions: Critical Limb Ischemia
Sponsor: Hemostemix

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Clinical Protocol 
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A Randomized Double Blind Placebo Controlled Clinical Study to 
Assess Blood-Derived Autologous Angiogenic Cell Precursor Therapy 
in Patients with Critical Limb Ischemia (ACP-CLI) 
 
CLINICAL PROTOCOL 
 
 
 
Study No.: HS 12-01 
Version: 5.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Clinical Protocol 
Date:  October 18, 2019 
 
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Document 
Version Date 
Summary of Changes 
Amendment 1 
24-Nov-15 
To amend the primary endpoint of the study to a combined endpoint 
of time to de novo gangrene, or doubling of wound size, or major 
amputation, or death, the following sections have been updated: 
Section 2, Section 20. 
  
  
To account for the updated statistical analysis plan, approximately 
95 subjects will be randomized and treated in the study.  
  
  
To revise the secondary endpoints and exploratory endpoints, the 
following sections have been updated: Section 1, Section 7, Section 
20 
  
  
The following sections have been updated to conduct an interim 
analysis for futility: Section 1, Section, 10, Section 20. 
  
  
To provide clarity whilst enabling operational efficiency and 
maintaining the safety of subjects, the following sections have been 
updated: List of abbreviations, Section 1, Study Design Section 6, 
Section 7, Section 8, Section 14, Section 15, Section 16, Section 
17, Section 18, Section 19, Section 20, Section 21, Section 22, 
Section 23 
  
  
To correct typographical and language errors and to account for 
administrative updates, the following sections have been amended: 
Title, Protocol Signature Page, Table Of Contents, Section 2, 
Scientific Section 3, Section 4, Section 5, Section 6, Section 7, 
Section 8, Section 9, Section 10, Section 11, Section 12, Section 
13, Section 14, Section 15, Section 16, Section 17, Section 18, 
Section 19, Section 20, Section 21, Section 22, Section 23 
Amendment 2 
20-Nov-17 
Updated Protocol number and date 
  
  
Section 7.0 was amended to reflect the change in location of the 
cell manufacturing facility from Israel to the US.  
  
  
Sponsor approval signatures updated 
  
  
Sponsor contact information added 
Amendment 3 
8-May-18 
Various typographical and language errors in the List of 
Abbreviations, section 7.2.1, 7.4 
  
  
Section 7.1 and 7.4.1 Added Rutherford Assessment  
  
  
7.2.1 typographical error licocaine changed to lidocaine 
  
  
Section 14 Clinical Studies Procedure Table – added Rutherford 
assessment at screening and visits 6-10. Window between 
screening visit 1 and visit 3 IMP injections was increased to 30 days 
total.  

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7.4.5 Visit 10: Removed the requirement of 2 consecutive ABI 
assessments 1 week apart. 
Amendment 4 
10-Dec-18 
Updated Protocol number and date 
  
  
Updated Sponsor contact and signatory information 
  
  
Removal of Section 2.3.1 that is duplicated in Protocol Synopsis 
and Section 8.1.1 and 8.1.2 
  
  
Section 3 Introduction - added technical term Thromboangiitis 
obliterans to differentiate from Berger's disease IgA nephropathy. 
  
  
Section 8.1.1 clarifies revascularization history in C and adds an 
upper age limit in E 
  
  
Section 8.1.2 adds the wording “of the affected limb” for clarification 
and includes the weight less than 69.9kg as exclusion E (reordering 
subsequent exclusions F through Z 
  
  
Section 7.1, 7.2 and 7.4 – added Rutherford Assessment to visit 
descriptions, making the descriptions consistent with the table in 
Section 14. 
  
  
Section 7.1.2 – Added a second check of selected screening blood 
tests to confirm the patient continues to meet study eligibility 
criteria.  
  
  
Section 7.2 – Added recheck of wound size and photography to 
ensure the patient continues to meet study eligibility criteria.  
  
  
Section 7.2.1 includes clarification of the unblinded physician role 
and pain management 
  
  
Section 12.4 - The shipping temperature for the blood bag was 
revised to 2-80C to meet current regulations/standards for the 
shipping of whole blood. 
  
  
Section 14 Clinical Studies Procedure Table – added the following:  
  
  
• 
Rutherford assessment at visit 3. 
  
  
• 
Ulcer size measurement and photography (with scale 
bar/ruler in place) at visit 3. 
  
  
• 
changed lower bound of Consecutive visit day for screening 
Visit 1 to day -7, ensuring consistency with section 7.1.1 on 
page 25. 
  
  
• 
blood work to Visit 2 to confirm eligibility 
  
  
• 
note to table that all imaging be completed within the last six 
(6) months. 

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Amendment 5 
27-Dec-18 
Updated Protocol Number and date 
  
  
Section 7.1 Clarification and addition of blood tests 
  
  
Section 14 Deletion of historic inclusion procedures and blood 
testing duplication 
Amendment 6 
18-Oct-19 
Updated Protocol Version Number and date 
  
  
Updated Sponsor representatives, Sponsor contacts and TOC 
Minor formatting changes 
  
  
Section 7: Clarified study periods, visit numbers and visit days 
 
 
Section 7 Visit 1: Added bilateral leg assessment to Visit 1 
Section 7 Visit 4: Clarified vital signs and ECG performed at end of 
2 hour observation. 
 
 
Section 7 All Visits: Clarified ankle and toe pressure measurements 
are bilateral, leg assessments are bilateral, and assessment of leg 
ulcers, ulcer measurement and ulcer photography are bilateral. 
 
 
Section 7 Visits 6-10: Added C-reactive protein to follow-up blood 
tests 
 
 
Section 8 Exclusion Criteria E: Changed to body weight less than 
45 kg. 
 
 
Section 14: Clinical Study Procedure Table: Clarified ankle and toe 
pressure measurements bilateral, leg assessment bilateral, 
assessment of leg ulcers, ulcer measurement and ulcer 
photography bilateral. 
 
 
Section 16.2 Serious Adverse Event: Clarified requires in-patient 
hospitalization ≥ 24 hours. 
 
 
Section 20.2 Futility Analysis: Changed to Interim Analysis and 
specified interim analyses 
 
 
Section 20.4 Sample Size: Added Sample Size Re-estimation 
 
 
Section 20.7.1 Primary Endpoint: Removed subjects lost to follow-
up considered as treatment failures 
 
 
Section 20.7.3 Exploratory Outcome Measures: Removed reduction 
in hospitalization time 
 
 
Section 20.8 Clinical Laboratory Tests, and Vital Signs and ECG: 
Clarified that each will be summarized using descriptive statistics 
and removed that criteria will be specified in more detail in SAP 
 
 
Section 23 References: Added statistical references 
 
 
 

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SPONSOR CONTACTS: 
Role in Study 
Name 
Contact Information 
Chief Medical Officer 
Alan Jacobs, MD, PhD 
Hemostemix Inc. 
300 5th Ave SW, Suite 2150 
Calgary, AB T2P 3C4 
Tel: 650-575-5260 
Email: ajacobs@hemostemix.com 
Cell Processing Facility 
Nermin Gerges 
Aspire Health Sciences 
2100 N. Alafaya Trail Suite 600 Orlando, 
FL 32826 
Tel: 407-420-7246 
 
 
 
Hemostemix Representatives: 
 
Reviewed and Approved by: 
Chief Medical Officer 
 
Alan Jacobs, 
MD, PhD   
 
 
 
 
 
Function 
Name 
Signature 
Date 
18 OCT 2019

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Protocol Signature Page 
Protocol Title: A Randomized Double Blind Placebo Controlled Clinical Study to Assess Blood-
Derived Autologous Angiogenic Cell Precursor Therapy in Patients with Critical Limb Ischemia (ACP-
CLI) 
Study No.: 
HS 12-01 
Version: 
5.5 
Study Phase: 2 
Sponsor: 
Hemostemix Inc.  
 
Principal/ Qualified Investigator  
By signing below, I, the Investigator, approve the protocol and agree to conduct the clinical trial 
according to all stipulations of the protocol as specified in both the clinical and administrative sections, 
Case Report Forms and any protocol-related documents (subject to any amendments agreed to in 
writing between the Sponsor and Principal/ Qualified Investigator). I agree to comply with the ICH-GCP, 
World Medical Association Declaration of Helsinki (and relevant updates) and applicable local 
regulations. I agree to ensure that confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of Hemostemix Inc. I understand that the study may be terminated or enrollment suspended at 
any time by the Sponsor, or by me, at my center, if it becomes necessary in my opinion, to protect the 
best interests of the study subjects/participants.  
 
_________________________________________________________________ 
Name 
 
_________________________________________________________________ 
Signature 
 
_________________________________________________________________ 
Date 
 
 

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TABLE OF CONTENTS 
 
1. 
List of Abbreviations ........................................................................................................................ 10 
2. 
Protocol Synopsis ............................................................................................................................ 11 
2.1. ACPs’ role in the treatment of peripheral arterial disease .................................................................. 11 
2.2. Study design .................................................................................................................................. 11 
2.3. Study population ............................................................................................................................. 12 
3. 
Introduction ...................................................................................................................................... 12 
4. 
Scientific Background ...................................................................................................................... 13 
5. 
Hemostemix’s clinical experience with ACPs ................................................................................. 16 
5.1. Pilot clinical trial for CLI .................................................................................................................. 16 
5.2. Phase 1b clinical trial for CLI........................................................................................................... 16 
5.3. Clinical trial for angina pectoris ....................................................................................................... 18 
5.3.1. 
Safety data .......................................................................................................................... 19 
5.3.2. 
Efficacy data ........................................................................................................................ 20 
5.4. Conclusion ..................................................................................................................................... 21 
6. 
ACPs in a rat model of acute myocardial infarction........................................................................ 21 
7. 
Study design ..................................................................................................................................... 22 
7.1. Screening Period ............................................................................................................................ 23 
7.1.1. 
Visit 1: Day –30 to -7 ........................................................................................................... 23 
7.1.2. 
Visit 2: Day -7 ± 1 day .......................................................................................................... 24 
7.2. Visit 3: Treatment (Day 0) ............................................................................................................... 24 
7.2.1. 
IMP administration ............................................................................................................... 25 
7.3. Safety Monitoring after IMP administration  ..................................................................................... 28 
7.3.1. 
Visit 4: First 48 hours after IMP Administration ..................................................................... 28 
7.3.2. 
Visit 5: 48-72 hours after IMP administration ........................................................................ 29 
7.3.3. 
Detection of possible infection.............................................................................................. 29 
7.4. Follow-up Period ............................................................................................................................ 29 
7.4.1. 
Visit 6: One Month follow-up visit (30 ± 5 days) .................................................................... 30 
7.4.2. 
Visit 7: Three Month Follow-up (90 ±7 days) ........................................................................ 30 
7.4.3. 
Visit 8: Six Month Follow-up (182 ±14 days)  ........................................................................ 31 
7.4.4. 
Visit 9: Nine Month Follow-up (270 ±14 days) ...................................................................... 32 
7.4.5. 
Visit 10: Twelve Month Follow-up (365 ±14 days)  ................................................................ 32 
8. 
Study population .............................................................................................................................. 33 
8.1. Criteria for subjects ......................................................................................................................... 33 

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8.1.1. 
Inclusion Criteria .................................................................................................................. 33 
8.1.2. 
Exclusion Criteria ................................................................................................................. 34 
9. 
Trial objective ................................................................................................................................... 36 
10. Assessment of functional parameters ............................................................................................. 36 
10.1. Primary endpoints........................................................................................................................... 36 
10.1.1. 
The primary efficacy endpoint for this study is the earlier time from treatment with IMP to either 
de-novo gangrene, or doubling of wound size, or major amputation, or death. ...................... 36 
10.1.2. 
Safety of intramuscular injection of ACP-01. ........................................................................ 36 
10.2. Secondary endpoints ...................................................................................................................... 36 
10.2.1. 
Change from Baseline in VAS pain score. ............................................................................ 36 
10.2.2. Change from Baseline in Ulcer Size. ....................................................................................... 36 
10.3. Exploratory Outcome Measures ...................................................................................................... 36 
10.3.1. 
Change from baseline in the dose and quantity of analgesic drugs used by the subject. ....... 36 
10.3.2. 
Reduction in total hospitalization time of subjects treated with ACP-01 compared to subjects 
treated with placebo. ............................................................................................................ 36 
10.3.3. 
Change from Baseline in Quality of Life. .............................................................................. 36 
10.3.4. 
Change from Baseline in Ankle Pressure. ............................................................................ 36 
10.3.5. 
Change from Baseline in Toe Pressure. ............................................................................... 36 
11. Amendments to the protocol ........................................................................................................... 36 
12.  Test material .................................................................................................................................... 37 
12.1. Investigational Medicinal Product .................................................................................................... 37 
12.2. Biological activity analyses ............................................................................................................. 37 
12.3. Safety analyses .............................................................................................................................. 38 
12.3.1. 
Sterility ................................................................................................................................ 38 
12.3.2. 
Bacterial Endotoxin Test ...................................................................................................... 38 
12.3.3. 
Gram stain ........................................................................................................................... 38 
12.3.4. 
Mycoplasma ........................................................................................................................ 38 
12.4. Culture preparation ......................................................................................................................... 38 
13. Concomitant treatment ..................................................................................................................... 39 
14. Clinical study procedure .................................................................................................................. 40 
15. Protocol for cases of suspected infection ....................................................................................... 41 
16. Adverse Experiences ........................................................................................................................ 42 
16.1 Adverse event (AE) ........................................................................................................................ 42 
16.2. Serious Adverse Event (SAE) ......................................................................................................... 42 
16.3. Relationship to the IMP ................................................................................................................... 43 
16.4 Severity of adverse experience ....................................................................................................... 44 

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16.5 Actions to be undertaken by the PI ................................................................................................. 44 
16.6. Expected adverse events................................................................................................................ 45 
17. Data Safety Monitoring Board (DSMB) ............................................................................................ 45 
18. Withdrawal of subjects from trial ..................................................................................................... 45 
19. Ethical and regulatory issues .......................................................................................................... 45 
19.1. Informed consent ............................................................................................................................ 45 
19.2. Ethical principles ............................................................................................................................ 46 
19.3. Laws and regulations ...................................................................................................................... 46 
19.4 Research Ethics Board/Institutional Review Board/Independent Ethics Committee (REB/IRB/IEC).. 46 
20. Statistical methodology.................................................................................................................... 46 
20.1. Randomization Procedure .............................................................................................................. 47 
20.2. Interim Analysis .............................................................................................................................. 47 
20.3. Significance Level........................................................................................................................... 47 
20.4. Sample Size ................................................................................................................................... 47 
20.5. Analysis Sets .................................................................................................................................. 48 
20.6. Demographics and Baseline Characteristics ................................................................................... 49 
20.7. Efficacy Assessment....................................................................................................................... 49 
20.7.1. 
Primary End-Point and Principal Analysis............................................................................. 49 
20.7.2. 
Key Secondary Endpoint Analyses ...................................................................................... 50 
20.7.2.a. Change from Baseline in VAS pain score ............................................................................. 50 
20.7.2.b. Change from Baseline in Ulcer Size ..................................................................................... 50 
20.7.3. 
Exploratory Outcome Measures ........................................................................................... 50 
20.8. Safety Assessment ......................................................................................................................... 51 
20.8.1. 
Adverse Events ................................................................................................................... 51 
20.8.2. 
Clinical Laboratory Tests ..................................................................................................... 51 
20.8.3. 
Vital Signs and ECG ............................................................................................................ 51 
20.8.4. 
Statistical Analysis Plan (SAP) ............................................................................................. 51 
20.8.5. 
Statistical Software .............................................................................................................. 52 
21. Study Monitoring .............................................................................................................................. 52 
21.1. Responsibilities of the Investigator(s) .............................................................................................. 52 
21.2. Responsibilities of the Sponsor ....................................................................................................... 52 
22. Confidentiality ................................................................................................................................... 52 
23. References ........................................................................................................................................ 53 
24. Appendix 1- List of expected adverse events. ................................................................................ 57 
24.1. Expected adverse events related to the medical procedure ............................................................. 57 

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24.2. Expected adverse events related to the administration of the IMP ................................................... 58 
 
 
 
1. 
LIST OF ABBREVIATIONS 
ABI 
Ankle Brachial Index  
Ac-LDL 
Acetylated Low Density Lipoprotein 
ACP 
Angiogenic Cell Precursor 
ACP-01 
Name of Product that contains ACPs  
AE 
Adverse Event   
ANCOVA 
Analysis of Covariance 
CD 
Cluster of Differentiation  
CLI 
Critical Limb Ischemia  
DSMB 
Data Safety Monitoring Board  
GFR 
Glomerular Filtration Rate 
HbA1c 
Hemoglobin A1c 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus  
HIV 
Human Immunodeficiency Virus  
HTLV 
Human T-Cell Lymphotropic Virus  
IMP 
Investigational Medicinal Product (includes Placebo and ACP-01) 
INR 
International Normalized Ratio 
ITT 
Intent-to-Treat  
LOV 
Last Observed Value 
LSM 
Least Squares Means 
mITT 
Modified Intent-to-Treat  
PAD 
Peripheral Arterial Disease  
PP 
Per-Protocol 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
PVR  
Pulse Volume Recording  
QoL 
Quality of Life  
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SCP 
Synergetic Cell Population  
ST Analysis Set 
Safety Analysis Set 
TASC 
Trans-Atlantic Inter-Society Consensus 
TBI 
Toe Brachial Index  
VAS 
Visual Analogue Scale  
 

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2. 
PROTOCOL SYNOPSIS 
2.1. ACPs’ role in the treatment of peripheral arterial disease  
Peripheral arterial disease (PAD), which is caused by atherosclerotic occlusion of the arteries to the 
legs, is a manifestation of systemic atherosclerosis. Treatment of PAD is an unmet medical need 
presenting a highly prevalent worldwide condition (10-14 million people in the US) that affects men and 
women equally. It is estimated that worldwide, 1% of adults over 50 years of age suffer from critical limb 
ischemia (CLI) (approximately 1.5–2 million CLI patients in Europe and the US). 
Hemostemix Inc. (Hemostemix) has developed a proprietary technology to generate lineage specific 
precursor cells from blood-derived adult mononuclear cells. A peripheral blood-derived progenitor cell 
population, named synergetic cell population (SCP), can be harvested and then induced to differentiate 
in vitro, under specific culture conditions, into angiogenic (angiogenic cell precursors – ACPs, see 
below), myocardial or neural lineages. 
ACPs are characterized by similar features as endothelial progenitor cells. They secrete tissue survival 
and regeneration-supporting growth factors and cytokines, which also facilitate the mobilization of 
additional progenitor cells and other important elements involved in the healing process of ischemic 
tissues. ACPs facilitate vasculogenesis and angiogenesis. The potent combination of all these beneficial 
capabilities makes ACPs a potentially effective treatment for severe vascular disorders. 
Positive evidence of the use of the ACP product arises from three clinical studies in which a total of forty 
subjects were treated. Two of the clinical studies demonstrated primarily the safety of the cellular therapy 
in critical limb ischemia (CLI), while the third showed a positive effect of the treatment in angina pectoris.  
Blood samples will be collected from subjects. A certain fraction of peripheral blood mononuclear cells 
will be isolated and then grown under conditions that induce differentiation of those cells into ACPs. 
Following this differentiation stage, the ACPs will be harvested, vialed, transported to the hospital and 
injected into the ischemic limb of the subjects. 
2.2. 
Study design 
This is a prospective, randomized, double-blind, placebo-controlled study to assess the efficacy and 
safety of autologous ACPs administered intramuscularly into the gastrocnemius and dorsal foot muscles 
of one affected limb in subjects with CLI with no surgical or endovascular revascularization options.  
A total of approximately 95 subjects will be randomized to treatment with ACP-01 or placebo using a 2:1 
randomization scheme, respectively, stratified by site. Study will be continued until all subjects treated 
with the IMP have been followed for 52 weeks.  One futility analysis for potentially stopping enrolment 

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into the study will be performed when approximately 42 subjects have completed at least 26 weeks of 
follow-up.  
2.3. 
Study population  
Subjects diagnosed with critical limb ischemia (CLI) and hemodynamic indicators of severe peripheral 
arterial occlusive disease who are not a candidate for revascularization treatment. 
 
3. 
INTRODUCTION 
Peripheral arterial disease (PAD), which is caused by atherosclerotic occlusion of the arteries to the 
legs, is a manifestation of systemic atherosclerosis. Other manifestations of atherosclerosis are 
coronary and cerebral artery disease. Treatment of PAD is an unmet medical need, representing a highly 
prevalent worldwide condition (10-14 million people in the US) that affects men and women equally 
(Criqui et al., 1985, Hiatt et al., 1995). The major risk factors for peripheral arterial disease are old age, 
smoking, and diabetes mellitus. Hyperlipidemia and hypertension are also important risk factors (Hiatt 
et al.,1995, Newman et al.,1993). Other etiologies of PAD besides atherosclerosis are Thromboangiitis 
obliterans (Buerger’s disease) and arteritis. 
Approximately one third of patients with peripheral arterial disease typically suffer from pain in one or 
both legs during walking (primarily in the calves), which does not vanish with continued walking and is 
relieved by rest (Rose et al., 1968). This symptom is known as claudication. In a certain group of the 
patients with claudication, the severity of the condition increases gradually until it develops into critical 
limb ischemia (CLI); the end stage of the disease. 
Approximately 15% to 30% of patients with lower extremity arterial disease will progress from 
intermittent claudication to CLI over the course of their disease (Dormandy et al., 1989, McDaniel et al., 
1989). It is estimated that, worldwide, 1% of adults over 50 years of age suffer from CLI (McDaniel et 
al., 1989) (a total of 1.5–2 million CLI patients in Europe and the US) (McDaniel et al.,1989, Weitz et 
al.,1996) 
According to the Trans-Atlantic Inter-Society Consensus (TASC) document on management of 
Peripheral Arterial Disease II (2007), the clinical definition of CLI should be used for all patients with 
chronic ischemic rest pain, ulcers or gangrene attributable to objectively proven arterial occlusive 
disease. The term CLI implies chronicity and is to be distinguished from acute limb ischemia (Norgren 
et al., 2007). 
Patients with CLI may need prompt percutaneous transluminal or open surgical revascularization in 
order to avoid limb loss. It is estimated that 160,000 amputations are carried out in the US annually due 
to failure of revascularization (Wolfe et al., 1986, Fisher et al., 1999).   

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Hemostemix intends to use autologous Angiogenic Cell Precursors (ACPs) to treat patients suffering 
from CLI and who do not have surgical or endovascular revascularization options. The use of Angiogenic 
Cell Precursors aims at promoting natural revascularization in the limb and as a consequence, 
attenuating ischemia. 
Blood samples will be collected from subjects. A certain fraction of peripheral blood mononuclear cells 
will be isolated and then grown under conditions that induce differentiation of those cells into ACPs. 
Following this augmentation stage the ACPs will be harvested, vialed, transported to the hospital and 
injected into the ischemic limb of the subjects. 
4. 
SCIENTIFIC BACKGROUND  
Hemostemix has developed a proprietary technology to generate lineage specific precursor cells from 
blood-derived adult mononuclear cells. This was previously considered impractical for therapeutic use 
because of the small number of adult progenitor cells in the peripheral circulation. Hemostemix has 
shown that a blood-derived progenitor cell population, named synergetic cell population (SCP), can be 
harvested from peripheral blood and then induced to differentiate in vitro, under specific culture 
conditions, into angiogenic (angiogenic cell precursors – ACPs, see below), myocardial or neural 
lineages (Porat et al., 2006). 
ACPs are characterized by similar features as endothelial progenitor cells (EPCs). They secrete tissue 
survival and regeneration-supporting growth factors and cytokines, which also facilitate the mobilization 
of additional progenitor cells and other important elements involved in the healing process of ischemic 
tissues (Porat at al., 2007, Badorff et al., 2003, Urbich et al., 2004). ACPs facilitate the formation of new 
blood vessels de novo by vasculogenesis, or from pre-existing blood vessels by angiogenesis. The 
potent combination of all these beneficial capabilities makes ACPs a potentially effective treatment for 
severe vascular disorders. The first evidence indicating the presence of EPCs in the adult circulation 
was obtained when mononuclear blood cells from healthy human volunteers were shown to acquire an 
endothelial cell–like phenotype in vitro and to incorporate into capillaries in vivo (Asahara et al., 1997).  
The fact that EPCs can take part in the formation of new blood vessels was first observed by 
Bhattacharya and colleagues who showed the formation of capillary-like structures from hematopoietic 
stem early progenitor cells or ex-vivo expanded EPCs (Bhattacharya et al., 2000, Kaushal et al., 2001). 
The contribution of bone marrow-derived EPCs, to neovascularization after ischemic injury in vivo, was 
shown in experiments using labeled populations of progenitor cells to reconstitute lethally irradiated 
mice. The cells or their progeny were shown to migrate into ischemic cardiac muscle and blood vessels, 
differentiate to cardiomyocytes and endothelial cells, and contribute to the formation of functional tissue 
(Jackson et al., 2001). Other work, involving a mouse retinopathy model, demonstrated the important 
role that the recruitment of endothelial precursors to sites of ischemic injury plays in neovascularization 
(Grant et al., 2002).  

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ACPs are a unique population of cells that stain CD31Bright, demonstrate uptake of Ac-LDL and secrete 
IL-8 and angiogenin. Similar to EPCs, ACPs simultaneously express Ulex-lectin and uptake of Ac-LDL, 
a molecule rapidly internalized by endothelial and angiogenic cells. Other cells included in the cellular 
product express the hematopoietic stem cell (HSC) markers CD34, CD133, and CD117, as well as the 
angiogenic cell markers VEGFR2, Tie-2, CD144, and von Willebrand factor. 
The majority of EPCs reside in the bone marrow and have been shown to mobilize (i.e. migrate in 
increased numbers from the bone marrow into circulation) in patients with vascular trauma or acute 
myocardial infarction (AMI) (Gill et al., 2001, Shintani et al., 2001) or in response to administration of 
VEGF via gene transfer (Kalka et al., 2000, Iwagaro et al., 2002).  
Considerable work has been carried out over the last few years to elucidate the mechanisms behind 
EPC mobilization, localization and function. Progress has also been achieved by establishing 
therapeutic protocols for progenitor cells to treat a variety of conditions, such as peripheral limb 
ischemia, acute myocardial ischemia and infarction and congestive heart failure. 
The source of autologous EPCs varies and includes bone marrow, peripheral blood and various 
mesenchymal organs. In this proposed trial, APCs will be harvested from the peripheral blood without 
pre-administration of G-CSF or AMD3100, or any other drug used to recruit progenitor cells from the 
bone marrow (Jamiolkowski et al., 2015). 
Significant research has been carried out in humans during the last few years to examine the potential 
benefits of using progenitor cells to treat cardiovascular disease. Many studies that enrolled hundreds 
of subjects have been carried out with various types of progenitor cells to treat peripheral arterial disease 
or its late deleterious effects (Shimamura et al., 2013). In these trials the cell source was either 
autologous, harvested from bone marrow or peripheral blood, or allogeneic, from umbilical cord blood. 
In most cases, the cells were injected into the muscle of the affected limb. As early as 2002, researchers, 
especially in Japan, initiated clinical trials to assess the effect of autologous progenitor cells as a 
treatment for limb ischemia. Miyamoto et. al., for example, investigated the safety and efficacy of 
implantation of autologous bone marrow mononuclear cells in refractory chronic peripheral arterial 
disease of limbs (Miyamoto et. al. 2004). The treatment was effective in relieving severe pain, including 
rest pain in the legs in 11 of the 12 patients treated. Resting ABI in legs implanted with bone marrow 
mononuclear cells also improved. Significant perfusion improvement was demonstrated by 99mTc-
tetrofosmin perfusion scintigraphy. No serious adverse events were reported. 
Since then, the rationale of treating CLI patients with progenitor cells was welcomed by a large number 
of medical groups which translated into many clinical studies treating hundreds of patients (Shimamura 
et al., 2013). Although some of the studies were relatively small, open label with few control groups, the 
results were very encouraging.  

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The relatively low risk and early success of the various progenitor cell-based therapies tried in those 
studies led several sponsors to undertake larger, placebo-controlled studies. In the last few years, 
several large placebo-controlled Phase 1b and Phase 2 clinical trials were initiated to assess the effect 
of various types of adult progenitor cells in the treatment of peripheral arterial disease. Some of the 
therapies used progenitor cells harvested from the patients’ bone marrow by using various devices and 
immediately administered to the target area, while in other studies, the cells were harvested, expanded 
and differentiated ex vivo for a certain period and only then given to the patient. Several examples are 
listed in Table 1. 
 
 
 
 
Table 1: List of randomized, placebo-controlled clinical trials assessing progenitor cell therapies for CLI 
Sponsor 
Cell type 
Number of 
patients 
Study design 
Outcome 
Baxter 
(completed 
July 
2011) 
Autologous CD34+ cells 
(harvested from peripheral 
blood) 
28 
Randomized, placebo-
controlled. 
Results not yet 
published 
Aastrom 
Biosciences 
(completed 
July 
2011) 
Autologous bone marrow 
cells 
harvested 
directly 
from the hip bone and then 
expanded ex vivo. 
150 
Phase 
2 
study 
Randomized, placebo-
controlled.  
Improved limb 
salvage 
and 
other vascular 
parameters  
Aldagen 
(completed 
May 
2011) 
Autologous bone marrow-
derived 
Aldehyde 
DehydrogenaseBright 
(ALDHbr) cells vs. 
unfractionated autologous 
mononuclear bone marrow 
20 
Randomized, 
controlled 
Treatment 
well tolerated 
and 
improvement 
of treated limb 
J.W. 
Goethe 
University 
Hospitals 
Bone 
Marrow 
Mononuclear Cells 
40 
Randomized, placebo-
controlled 
Improved 
healing 
of 
ulcers 
University 
of 
Wisconsin, 
Madison 
autologous CD133+ cells 
24 
Randomized, placebo-
controlled 
Study ongoing 
Leiden University 
Medical Center  
bone 
marrow 
derived 
mononuclear cells 
108 
Randomized, placebo-
controlled 
Study ongoing 
Harvest 
Technologies  
Autologous Bone Marrow 
Aspirate 
Concentrate 
(using a bed-side device)  
210 
Randomized, placebo-
controlled. 
Study ongoing 
Biomet Biologics, 
LLC 
Bone Marrow concentrate 
(MarrowStim PAD Kit) 
152 
Randomized, placebo-
controlled (sham bone 
marrow 
aspiration, 
Study ongoing 

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Sponsor 
Cell type 
Number of 
patients 
Study design 
Outcome 
sham 
delivery 
of 
placebo 
5. 
HEMOSTEMIX’S CLINICAL EXPERIENCE WITH ACPS 
Positive evidence of the use of Hemostemix’s ACP-01 arises from three clinical studies and one animal 
study described below. Two of the clinical studies demonstrated primarily the safety of ACP-01 as well 
as encouraging results suggesting the possibility of its efficacy in the treatment of CLI, while the third 
study showed the effect of the treatment in subjects with angina pectoris. The animal work demonstrated 
the engraftment of ACPs into the myocardium of rats resulting in improved cardiac function. 
5.1. 
Pilot clinical trial for CLI 
A pilot non-randomized, open-label study was carried out in six patients with the permission of the Ethics 
Committee, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (Mutirangura et 
al., 2009). The patients enrolled suffered from severe symptoms of CLI (Fontaine stage III and IV), such 
as ischemic rest pain, ischemic non-healing ulcers and digital gangrene. In addition, limb hemodynamic 
assessment indicated limb threatening ischemia with ankle brachial index (ABI) below 0.4, and/or toe 
brachial index (TBI) below 0.24. The goals of the study were to assess the safety and feasibility of the 
implantation of ACPs in patients with CLI who were poor candidates for standard revascularization 
treatment options. 
Six patients with CLI due to infra-popliteal artery occlusive disease were recruited in the study and after 
signing the informed consent form underwent intramuscular injections of autologous ACPs into the 
ischemic limbs.  
There was no evidence of local or systemic complications related to the procedure. Five of the six 
patients showed clinically significant improvement of the circulation in the distal limb. Four of them had 
complete healing of ischemic ulcers and stumps of toe amputation. However, one patient with adequate 
granulation tissue at the stump of the left first toe amputation subsequently suffered from severe foot 
infection originating from the other toes and eventually underwent below the knee amputation. One 
patient underwent a major amputation since no improvement of circulation at the distal limb could be 
induced after ACP administration. The result of this preliminary trial showed that ACP therapy is 
potentially safe and could provide benefits in the improvement of circulation in patients with CLI.  
5.2. 
Phase 1b clinical trial for CLI 
Hemostemix (formerly TheraVitae Ltd.) provided ACPs to Salus Ltd, the clinical development arm of 
Kelen Hospital in Hungary to conduct a larger controlled clinical study at two medical centers in 
Budapest, Hungary (Szabó et al, 2013). The local Sponsor obtained all the necessary approvals 

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required by the authorities in order to perform the studies. Ominis Research was retained as the Contract 
Research Organizations (CRO) by the Hungarian Sponsor to monitor and ensure the quality of the study 
in accordance with the requirements of the local authorities. 
The safety and feasibility of intramuscular administration of ACPs was assessed in 20 patients with 
severe CLI (Fontaine phase III-IV) with high risk of amputation of an affected limb. Half of the patients 
were treated with ACPs while the other half, the control patients, received standard of care medical 
therapy. The patients were followed for 3 months post treatment. 
The primary endpoints of the study were to assess the safety of ACP administration as well as its 
effect in the prevention of limb loss. Secondary endpoints were ulcer healing, improvement of 
circulation in the affected limb as assessed by the ankle-brachial index and transcutaneous CO2 
pressure (TCO2).  
No adverse events related to the IMP were observed. During the 3 months follow-up in the control group, 
one death occurred due to septicemia and six major amputations were performed. In the treated group, 
there were no deaths or major amputations, one patient had an hallux amputation and another patient 
had a trans-metatarsal amputation (Figure 1). The difference of limb loss was statistically significant 
(p=0.01) between the two groups. In the treatment group, one amputation occurred at 4 months. At 2-
year follow-up in the control group, two deaths and six major amputations occurred; in the treated group, 
there were three major amputations. 
 
 

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Figure 1: Amputation-free interval in treated and control Subjects 
 
 
At 3-month follow-up, the change in hemodynamic parameters showed improvement in the ACP-treated 
group. Other efficacy data parameters are not reviewed due to the small number of patients left in the 
control group without major amputation or death. Improvements in pain score, wound healing and walk 
test were reported at 2 years 
5.3. 
Clinical trial for angina pectoris 
An open label clinical trial was conducted to assess ACP administration for severe angina pectoris at 
Siriraj Hospital in Bangkok, Thailand, the largest and most renowned academic hospital in Thailand 
(Tresukosol et al., 2006). The study was approved by the hospital’s ethics committee, which is the 
regulatory body in charge with supervising clinical trials in Thailand. 
Similar to the CLI pilot study, maximal efforts were made to ensure proper conduct and supervision of 
the clinical trials in compliance with Good Clinical Practices. As required by international standards of 
clinical trials, Hemostemix (formerly TheraVitae Ltd.) established a dedicated team of professionals to 
supervise and monitor both clinical trials in Thailand (CLI and angina pectoris). The team was led by a 
practicing Israeli-licensed physician with extensive clinical experience.  
The objectives of the trial were to determine the safety and feasibility of intracoronary injection of blood-
derived autologous ACPs in relieving symptoms of angina pectoris in patients on standard of care with 
no option for revascularization procedures (angioplasty or CABG). 
Twenty-four patients with chronic stable angina pectoris on standard of care drug therapy were enrolled 
and signed the informed consent. ACPs (32.3x106±4.2x106) were injected via a catheter with proximal 

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balloon occlusion of the coronary artery supplying the ischemic myocardium. The patients were 
assessed prior to and 3 and 6 months after the treatment by using the Canadian Cardiovascular Scale 
(CCS), the six-minute walking test (6MW), their exercise capacity (METs), and perfusion defect 
measurements.  
5.3.1. Safety data 
All adverse events were recorded, monitored and reported throughout the study (Table 2). Safety results 
were analyzed and the PI determined if there was a relation to cell administration. 
One patient died from a myocardial infarction that occurred one month after the administration of the 
cells, which according to coronary catheterization occurred in a region of the heart supplied by another 
stented coronary artery and not the one in which the cells were injected. The study PI concluded that 
the death was not related to the administration of the cells or to the cells themselves. There were no 
other deaths among the study population. 
Three patients developed transient ventricular fibrillation, which is an expected occurrence as a result 
of catheterization. One of these events occurred during the catheterization procedure, which was treated 
successfully and the other two during angiography six months after the procedure. All three patients 
recovered. The PI determined that these events were unrelated to the cell administration, but rather to 
the catheterization procedures. Seven patients developed minor transient adverse events, which 
included: elevated erythrocyte sedimentation rate (ESR, 2 patients), transient chest pain during 
catheterization, hypoglycemia, leg pain, upper respiratory tract infection (URTI), oral paresthesia, 
urticaria (2 patients), and a hematoma at the groin puncture site. These findings subsided after a short 
period without affecting the patient's clinical condition.  
 
 

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Table 2:  Summary of safety results of the clinical trial that tested the safety and efficacy of the administration of 
blood-derived autologous APCs to alleviate anginal symptoms and myocardial ischemia in patients with severe 
anginal syndrome.  
 
Serious Adverse Events 
Adverse Events 
Number of 
patients: 24 
Deaths 
Other Serious Adverse 
Events 
Number of 
Adverse Events 
1  
3 in 3 patients 
10 in 7 patients 
 
Myocardial infarction 
due to obstruction of 
a non-injected 
stented artery, 
1month following 
procedure 
Transient ventricular 
fibrillation during 6 month 
follow up catheterization 
(2) 
Transient ventricular 
fibrillation during 
procedure 
Elevated Erythrocyte Sedimentation 
Rate (2) 
Chest pain during procedure 
Hypoglycemia 
Upper respiratory tract infection 
Oral paresthesia 
Urticaria (2) 
Hematoma at puncture site 
Leg Pain 
Numbers in parenthesis ( ) indicate more than one event. 
5.3.2. Efficacy data 
Symptoms and perfusion defects were significantly improved relative to baseline. CCS decreased from 
2.17±0.18 at baseline to 1.04±0.04 at 3 and 1.13±0.10 at 6 months. Six minute walking ability increased 
from 346.7±27.3 meters to 409.7±25.8 meters and 427±25.6 meters at 3 and 6 months, respectively. 
METs values, analyzed in 20 patients, increased from 5.5±0.49 to 6.5±0.6 and 6.8±0.59 at 3 and 6 
months. Perfusion defects in the territory of the target vessel decreased from 39.37%±5.65% to 
24.38%±5.41% and 24.91±5.57% at 3 and 6 months. The results of this study support the assumption 
that intracoronary injection of autologous ACPs derived from non-mobilized peripheral blood into 
patients with chronic stable angina is safe, improves anginal symptoms, and alleviates myocardial 
ischemia at 3 and 6 months.  
 
 

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5.4. 
Conclusion  
Although very encouraging efficacy was observed in comparison to best available care, the main reason 
to perform a Phase 2 trial is to continue to evaluate the safety of the therapy in parallel with its 
effectiveness in a larger cohort of patients. The data presented show that the therapy demonstrated a 
favourable safety profile in patients suffering from severe heart disease.  
An extensive search of the literature was performed to find potential adverse effects of non-mobilised 
(by G-CSF) autologous blood-derived progenitor cells on patients. The search was performed on the 
database of the US National Library of Medicine and included articles published in the period 1998-
2011. No articles were found that reported potential risks of such an approach. The use of autologous 
blood-derived progenitor cells (mainly bone-marrow derived) dates back decades; their main therapeutic 
use was for hematological malignancies. The potential positive effect that some of those cells may 
demonstrate in cardiovascular disorders was discovered in the last twenty years. However, regardless 
of the indication, the use of these cells does not raise safety concerns. 
It is emphasized that in order to offer the patients the greatest chances of recovery, the best existing 
medical care will be provided to all subjects regardless of the group to which they are randomized. 
6. 
ACPS IN A RAT MODEL OF ACUTE MYOCARDIAL INFARCTION 
An animal study to evaluate the efficacy of intracoronary or intramyocardial human ACP administration 
in nude rats by examining cardiac function was carried out in collaboration with Dr. Ren-Ke Li and his 
team at the University of Toronto (Sun et al., 2008). Cells were prepared by the Company’s scientists 
and shipped to Toronto for administration into the animals. The animal experiments, including the blind 
assessment of the results were performed by the scientists from Dr. Li’s team in Toronto. 
In order to examine ACP function in an in vivo paradigm, myocardial infarction was induced by ligation 
of left anterior descending (LAD) artery in nude rats. Seven days after myocardial infarction the rats 
were injected either intramyocardially (1.5x106 total number of cells, n=10) or intracoronarily (1.5x106 
total number of cells, n=10) with human ACPs or culture medium (n=5). Cardiac function (ejection 
fraction, fractional shortening, functional area contraction and scar area at left ventricular free wall) was 
examined 14 and 28 days following cell or culture medium administration. ACP homing and engraftment 
into the scar border area was examined 28 days following cell administration. 
Two weeks after implantation, ejection fraction, fraction shortening and functional area contraction 
decreased in the control groups but increased in the intramyocardial and intracoronary ACP groups 
(p=0.01 for both groups).  Similarly, four weeks after implantation, ejection fraction and fraction 
shortening were lower in the control groups than those in the intramyocardial ACP and intracoronary 
ACP groups (p=0.01 for both). Dp/dt max (an index of systolic function) evaluated by pressure-volume 
catheter at 4 weeks after cell implantation was greater (p=0.01) in the intramyocardial ACP and 
intracoronary ACP.  Dp/dt min (an index of diastolic function) evaluated by pressure-volume catheter 

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was better (p=0.01) in the two cell-implanted groups. Scar size of the intramyocardial ACP group was 
smaller (p=0.02) than the one in the control group. The scar size was smaller in the intracoronary ACP 
group than the control group, however, the difference was not statistically significant (p=0.06). The 
grafted cells were detected four weeks after implantation by immunohistochemistry: antibodies against 
myosin heavy chain and troponin-I demonstrated muscle-like cells in the scar tissue of the 
intramyocardial and intracoronary ACP groups suggesting possible cell differentiation and thus a 
contribution of the implanted cells to tissue repair.  
Overall, this study demonstrates the engraftment of ACPs within the infarcted myocardium resulting in 
significant beneficial effects, including reduced infarct size and improved cardiac function in rats. 
7. 
STUDY DESIGN 
This is a prospective, randomized, double-blind, placebo controlled study to assess the efficacy and 
safety of ex vivo autologous ACP administered intramuscularly into the gastrocnemius and dorsal foot 
muscles of one limb in subjects with CLI.  
Subjects treated at each investigative site will provide written informed consent prior to the conduct of 
any study-related procedures. Thereafter, they will be screened and those meeting the 
inclusion/exclusion criteria will be enrolled into the trial and undergo all the study procedures including 
intramuscular injection of autologous ACPs or placebo. The autologous ACPs or placebo will be 
administered in addition to any conventional treatment that the subject is receiving.  
To enable blinding of the assessors and the subjects, the control group will undergo a similar procedure 
as the treatment group and receive injections into the gastrocnemius and dorsal interossei foot muscles.  
Blood samples and cells that are not used in the treatment of subjects with ACPs, e.g., from the placebo 
group, will be de-identified and may be utilized for manufacturing and quality control testing such as for 
the development of potency and release assays. Results from the assays and tests may be used to 
retrospectively examine cell and product characteristics in CLI patients and/or the response to treatment 
with ACPs.   
The placebo will consist of a growth medium, the same medium used in the ACP product suspension. 
The physician performing the administration of the cells or the placebo may become unblinded to the 
group to which the subject is randomized while performing the injections of the IMP. Therefore, he/she 
will not participate in the assessment of the subjects that he/she injected. In the event that the 
administrator becomes aware of the treatment assigned, every effort will be made to maintain 
appropriate blinding. All other participants in the study (PI, clinical investigators, other physicians, the 
subjects, study nurses, coordinators, etc.) will not be aware of the subjects’ randomization and will 
therefore remain blinded to the study.  

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The study consists of four periods: Screening, Treatment, safety monitoring and Long-term follow-up 
periods. Subjects will be followed for one year post treatment. 
7.1. 
Screening Period 
Screening follows informed consent and begins with the evaluation of the subject at the investigative 
site to assess eligibility according to the inclusion/exclusion criteria and ends just prior to the 
administration of the IMP. After signing the informed consent form, the subject will have been formally 
recruited into the study. The PI or one of the clinical investigators (CI) will decide which leg needs to be 
treated according to the severity of the disease. In general, the more ischemic limb should be injected.  
During this period the following clinical and laboratory examinations will be performed in order to obtain 
baseline values and verify inclusion/exclusion parameters: 
7.1.1. Visit 1: Day –30 to -7  
1) Evaluation according to the inclusion/exclusion criteria to determine eligibility. 
2) Obtain and record medical history including current clinical condition, chronic disabilities and 
current medication/therapy, obtain and record demographical data, review angiography or color 
flow duplex ultrasound imaging results.  
3) Assessment of pain on a visual analogue scale (VAS). 
4) Type and dose of analgesic drug taken by subject. 
5) Physical examination including Rutherford Assessment. 
6) Measurement of blood pressure, heart rate, ECG, and temperature (to reduce the likelihood of 
infection prior to administration of the IMP). 
7) Leg assessment, including skin color, swelling, limb temperature, presence of ulcers or 
gangrene, bilaterally. 
8) Measurement of resting ankle blood pressure using an appropriate adult cuff, bilaterally 
9) Measurement of toe blood pressure using an appropriate cuff, bilaterally. 
10) Assessment of leg ulcers, measurement of ulcer size and ulcer photography, bilaterally. 
11) Vascular quality of life (QoL) questionnaire (Morgan et al., 2008). 
12)  Blood tests: 
• 
Hematology: RBC; Hemoglobin; Hematocrit; WBC; Neutrophils; Lymphocytes; 
Monocytes; Platelet count, PT (or INR), and aPTT 

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• 
Blood Chemistry:  Blood glucose; Blood urea nitrogen (BUN); Serum creatinine; C-
reactive protein; Serum chloride; Serum potassium; Serum sodium; Serum magnesium; 
Serum albumin; Total serum protein; SGOT/AST; SGPT/ALT; Alkaline phosphatase; 
Total bilirubin, Creatine phosphokinase (CPK), HbA1c. 
• 
Pregnancy test (serum Beta-hCG), if female of childbearing age. 
• 
Screening for severe contagious infections: HIV-1, HIV-2, HTLV-1, HTLV-2, HBV, HCV. 
7.1.2. Visit 2: Day -7 ± 1 day 
The following activities should be performed under the supervision of the PI: 
1) Blood tests: 
• 
Hematology: RBC; Hemoglobin; Hematocrit; WBC; Neutrophils; Lymphocytes; 
Monocytes; Platelet count, PT (or INR), and aPTT. 
• 
Blood Chemistry: Blood glucose, Blood urea nitrogen (BUN); Serum creatinine; C-
reactive protein; Serum chloride; Serum potassium; Serum sodium; Serum 
magnesium; Serum albumin; Total serum protein; SGOT/AST; SGPT/ALT; Alkaline 
phosphatase; Total bilirubin, Creatine phosphokinase (CPK), HbA1c. 
2) Obtain up to 500 ml of the subject’s blood by venipuncture (equivalent to typical blood 
donation volume). The site should be swabbed with betadine solution followed by 70% 
alcohol swab. Allow to dry by evaporation. A 16g needle is to be used to obtain the blood 
that will be collected in a transfusion bag containing anticoagulant. It is strongly 
recommended to draw the entire volume of blood into only one transfusion bag. 
3) Obtain and send an additional 10 ml blood for blood bacterial culture tests (tested locally 
at the investigative site’s laboratory). 
4) Complete forms, label blood bag and package for transport to the manufacturing facility. 
5) Pack the blood and ship to the manufacturing facility. 
7.2. 
Visit 3: Treatment (Day 0)  
Preparation of the subject for the treatment procedure will be initiated upon communication by 
Hemostemix’s representative of the estimated date of the investigational product delivery. 
If the batch is not released due to failure to meet release specifications, the subject will undergo a repeat 
Visit 2 within 21 days of the first Visit 2.   
If the batch of IMP produced from the second blood also fails to meet specified release criteria, the 
subject will be withdrawn from the study.  

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The following clinical assessments will be performed just prior to the administration of the IMP.  
• 
Physical examination, including Rutherford Assessment. 
• 
Standard preoperative monitoring of heart rate, blood pressure, ECG, and body temperature. 
• 
Assessment of ulcers including measurement of area in cm2 based on photography of lesions. 
7.2.1. IMP administration  
The subject will be taken to a treatment room.   
The unblinded treating physician, at their discretion, may administer intravenous, intramuscular, and/or 
oral analgesic medications alone, or in combination with conscious sedation, sufficient to alleviate pain 
associated with the injection of the investigational product. Additionally, at the discretion of the unblinded 
treating physician, EMLA (lidocaine and prilocaine) Cream may be applied to the dorsal aspect of the 
foot to alleviate pain as needed, provided no contraindications for its use exist and the application will 
not interfere with standard sterilization procedures for the preparation of the injection site. Impaired 
kidney function may slightly prolong the recovery from conscious sedation.  
Under sterile conditions, the subject will then receive a dose of not more than 200 million ACPs in total, 
containing at least 5x106 CD31Bright x AcLDL cells and at least 1x106 CD34 positive cells (which constitute 
at least 1.5% of the total number of cells injected). The cell suspension will be injected approximately 
1.5 cm deep into a minimum of 24 locations in the gastrocnemius muscle of the affected limb and at 6 
locations into the dorsal interossei foot muscles (extensor digitorum brevis and extensor hallucis brevis 
muscles). The 6 injections into the foot should be approximately in one line at the midline of the 
metatarsus. 
The general goal should be to deliver ACPs to the entire ischemic tissue. Since the bulk of the ischemic 
tissue is in the leg, it is this part of the limb that should receive the bulk of cells. It is therefore required 
that at least 24 injections of approximately 1ml are administered into the leg. 
The following recommendations should also be followed: 
• 
The unblinded investigator should try to avoid injections in the proximity of gangrene. 
• 
The unblinded investigator must under no circumstances inject into areas that show signs of 
cellulitis.  
• 
The unblinded investigator should try to cover the entire ischemic tissue and not inject 
specifically around chronic wounds. 
• 
The unblinded investigator should start with the injections into the foot. The injections should 
be performed slowly in order to avoid spill out of liquid containing cells. If the investigator 
notices that some of the volume injected spills out, he/she should assume that there is not 

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sufficient space to inject the entire 1 ml into each location in the foot. Therefore, a smaller 
volume should be injected into the remaining spots in the foot and save the additional volume 
for the leg injections. This additional volume of cells/placebo should be injected into 
additional spots in the leg. Thus, in such cases, there may be 1-2 additional injections into 
the leg. A treatment diagram (example shown below) will be used to document the injections 
administered to each subject.  
• 
The measurements in the diagram below are only suggestions and the investigator should 
keep in mind that the principle is to cover as much of the ischemic area as possible. 
Therefore, he/she may need to reduce or increase the distance between the injection sites 
depending on the length of the limb. 
The administration of the IMP is expected to take no longer than 20-30 minutes, after which the subject 
will continue to be tightly monitored for a period of 2 hours. The total volume will be 30 ml and 
approximately 0.75 -1 ml of cell suspension will be implanted into each of 30 injection sites, using a grid. 
A 23–gauge needle will be used.  
 
 
 
 
 
 
 
 
 
 
 
       1.5 cm    
 
             
            
 
                                           
*    *    *    *    *    *     *    *                     *      *                                 
*    *    *    *    *    *     *    *                     *      *        
*    *    *    *    *    *     *    *                     *      *          
 
1    2   3   4    5   6    7    8                   9      10 
 
The unblinded investigator should ensure that there are no clinical concerns that may prevent the subject 
from being able to receive the injection on the intended injection date. If the subject is not fit on the 
planned injection day, he/she should not be injected with the IMP (ACPs/placebo). This subject should 
be discontinued and if his/her health condition improves he/she can be re-screened into the study.  
Reasons for being unfit on the injection day include, but are not limited to: acute ischemia, cellulitis or 
other severe infection in the intended injection leg, wet gangrene, significant deterioration of clinical 
status, suspected severe concurrent disease with fever > 38.4 0C, etc. 
The rationale for the dose of cells and volume is based on several literature reports. Specifically, based 
on studies of human EPC transplantation into nude mice, Iwaguro et al., calculated that satisfactory 
reperfusion of the hind limb would require 0.5 to 2x104 endothelial progenitor cells/gram of animal weight 
Proximal 
gastrocnemiu
s 
Distal 
gastrocnemiu
s 
 
Metatarsus 
1.5 cm 
1.5cm 
Level 

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(approximately 25 grams) (Iwaguro et al., 2002). Since the authors injected the cells systemically, it 
would be expected that a significantly lower number of cells reached the ischemic tissue. It is difficult to 
extrapolate the therapeutic equivalence of mouse EPCs and human ACPs. However, the general 
principle was used in the calculation of the putative dose. Therefore, the minimal dose of the CD31+ 
and Ac-LDL-uptaking subpopulation of ACPs to be used for subjects will be 5 million cells, which is 
approximately the average of 10,000 cells per gram of tissue.  
A review of the literature was performed and the information was found to support the cell dose proposed 
in the present study. Elliott et al., 1997,  report the volume of the gastrocnemius muscle in 7 patients. 
Assessments were done by MRI and the approximate volume of the gastrocnemius muscle (Lateral and 
medial gastrocnemius muscles taken together) was 435-475 cc. Since the density of mammalian 
skeletal muscle tissue is approximately 1.06 kg/liter, one can assume the approximate weight of the 
gastrocnemius muscle, with differences depending on the height of the patient, to be approximately 500 
grams.  
The release specification for ACPs used in the clinical trial for severe angina pectoris and for patients 
suffering from ischemic heart disease treated on a compassionate basis was 3 million ACPs. In those 
patients, the treatment with cells showed a good safety profile and encouraging efficacy. The weight of 
the human heart is roughly 300 grams. By applying the same rationale, since in this proposed study 
tcells will be injected intramuscularly into the gastrocnemius (which roughly weighs 500 grams), the 
release specification was set to a minimum of 5 million cells expressing the CD31 marker and uptake of 
Ac-LDL. 
The rationale behind the administration of the treatment is to ensure that the cells can induce their 
therapeutic effect by being applied across the entire ischemic tissue. It is assumed that intra-muscular 
injections offer optimal delivery of the cells to reach the ischemic tissue and remain within it. The 
underlying principle of intramuscular injection is the creation of a cell depot with paracrine activity in the 
ischemic area that can induce neovascularisation and vasculogenesis most efficiently.  
These assumptions are in line with other reports from the literature (Rutherford et al., 1997, Fadini et 
al., 2010). 33 of 37 reported trials using cells for critical limb ischemia utilized intramuscular rather than 
intra-arterial injections. Most of the studies used between 20 and 60 injections that were delivered into 
the gastrocnemius muscle along a symmetric grid. Furthermore, meta-analysis of the 37 studies showed 
that the intramuscular approach is effective in improving critical CLI endpoints, such as ulcer healing, 
ankle-brachial index and tissue O2 tension, while intra-arterial injections did not impact those 
parameters (Fadini et al., 2010). 
If a subject is randomized into the control group, he/she will receive placebo which consists of X-Vivo™ 
15 only, the same medium in which the ACPs are suspended.   

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7.3. 
Safety Monitoring after IMP administration  
7.3.1. Visit 4: First 48 hours after IMP Administration 
Acute monitoring will be performed after IMP administration, and will include monitoring of body 
temperature, heart rate, systolic and diastolic blood pressure, ECG, including blood tests as described 
below.  
The first 5 subjects in the study will be hospitalized for 24 hours following the administration of the IMP. 
Unless a serious adverse event emerges, the subject will be released from the hospital after 24 hours 
from the administration of the IMP. 
If no severe adverse events related to the IMP are recorded during the first 48 hours from the 
administration of the IMP in the first 5 subjects enrolled in the study, the rest of the subjects will not be 
hospitalized. These remaining subjects will be supervised for 2 hours after the administration of the IMP 
at the hospital and then released to their homes if the clinical investigator determines that their clinical 
condition permits it. Vital signs and ECG will be performed at the end of this 2-hour period. No additional 
blood tests will be required.  
On the same day, before bed time, if applicable, the subject will be assessed in person or by telephone 
by a member of the clinical team.  All the information reported by the subject will be noted and reported 
in the Case Report Forms (CRF).  
Approximately 24 hours after the administration of the IMP another telephone (or in person) assessment 
will be done by a member of the clinical team.  
All the subjects will return for a scheduled follow-up visit on the second day after injection.  
The following physical and laboratory examinations will be performed on the first 5 subjects enrolled in 
the trial on Day 2 after administration of the IMP: 
1) Monitoring of blood pressure, heart rate, ECG and body temperature. 
2) Physical examination, including local examination of the injected leg. 
3) Pain scale assessment (VAS). 
4) Blood tests: Hematology: RBC; Hemoglobin; Hematocrit; WBC; Neutrophils; 
Lymphocytes; Monocytes; Platelet count, PT (or INR), and PTT (48 hours after 
administration of ACPs, just prior to release from hospital). Blood Chemistry: blood 
glucose level; Blood urea nitrogen (BUN); Serum creatinine; Serum chloride; Serum 
Potassium; Serum sodium; Serum magnesium; Serum albumin; Total serum proteins; 
SGOT/AST; SGPT/ALT; Alkaline phosphatase; Total bilirubin, Creatine phosphokinase 
(CPK), Blood cultures: To proactively detect any potential infection, approximately 48 

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hours after administration of the investigational medicinal product blood samples will be 
taken for aerobic and anaerobic bacterial cultures. 
Following acute monitoring according to the procedures listed above, the subject may be released 
from the hospital. Continued hospitalization until completion of Visit 5 without any deterioration in 
the subject’s clinical condition will not be considered an adverse event. 
7.3.2. Visit 5: 48-72 hours after IMP administration 
If not hospitalized, the subject will return to the hospital 48-72 hours after the administration of the 
IMP. The following examinations will be performed on all patients: 
1) Monitoring of blood pressure, heart rate, ECG and body temperature. 
2) Physical examination, including local examination of the injected leg. 
3) Pain scale assessment (VAS) 
7.3.3. Detection of possible infection 
Infection will be suspected if either the subject develops fever, or if the bacteriological cultures of the 
product are found to be positive. Depending on subject’s condition and other details of the case, a 
suitable treatment procedure will be followed (see Section 14). 
7.4. 
Follow-up Period 
The subjects will be followed, with general as well as specific safety and efficacy parameters according 
to the established routine for such cases.. Follow-up visits will take place at 1 month, 3 months , 6 
months, and 12 months after administration of the IMP. 
 
 

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7.4.1. Visit 6: One Month follow-up visit (30 ± 5 days)  
The following will be performed: 
1) Assessment of pain on the visual analogue scale. 
2) Assessment of analgesic drug types and doses. 
3) Physical examination, including Rutherford assessment. 
4) Blood pressure, heart rate, body temperature and ECG. 
5) Leg assessment, including skin color, swelling, limb temperature, presence of 
ulcers or gangrene, bilaterally. 
6) Measure resting ankle pressure using an appropriate adult cuff, bilaterally. 
7) Measure resting toe pressure, bilaterally. 
8) Assessment of leg ulcers, measurement of ulcer size and ulcer photography, 
bilaterally. 
9) Vascular QoL questionnaire. 
10) Blood tests:  
• 
Hematology: RBC; Hemoglobin; Hematocrit; WBC; Neutrophils; Lymphocytes; 
Monocytes; Platelet count, PT, (or INR), and PTT.  
• 
Blood Chemistry: blood glucose level; Blood urea nitrogen (BUN); Serum 
creatinine; C-reactive protein; Serum chloride; Serum Potassium; Serum sodium; 
Serum magnesium; Serum albumin; Total serum proteins; SGOT/AST; 
SGPT/ALT; Alkaline phosphatase; Total bilirubin, Creatine phosphokinase (CPK), 
HbA1c.   
7.4.2. Visit 7: Three Month Follow-up (90 ±7 days) 
The following will be performed: 
1) Assessment of pain on the visual analogue scale. 
2) Assessment of analgesic drug types and doses. 
3) Physical examination, including Rutherford Assessment. 
4) Blood pressure, heart rate, body temperature and ECG. 
5) Leg assessment, including skin color, swelling, limb temperature, presence of 
ulcers or gangrene, bilaterally. 

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6) Measure resting ankle pressure using an appropriate adult cuff, bilaterally. 
7) Measure resting toe pressure, bilaterally. 
8) Assessment of leg ulcers, measurement of ulcer size and ulcer photography, 
bilaterally. 
9) Vascular QoL questionnaire. 
10) Blood tests:  
• 
Hematology: 
RBC; 
Hemoglobin; 
Hematocrit; 
WBC; 
Neutrophils; 
Lymphocytes; Monocytes; Platelet count, PT, INR.  
• 
Blood Chemistry:  blood glucose level; Blood urea nitrogen (BUN); Serum 
creatinine; C-reactive protein Serum chloride; Serum Potassium; Serum 
sodium; Serum magnesium; Serum albumin; Total serum proteins; 
SGOT/AST; SGPT/ALT; Alkaline phosphatase; Total bilirubin, HbA1c. 
7.4.3. Visit 8: Six Month Follow-up (182 ±14 days)  
The following will be performed: 
1) Assessment of pain on the visual analogue scale. 
2) Assessment of analgesic drug types and doses. 
3) Physical exam, including Rutherford Assessment. 
4) Blood pressure, heart rate, body temperature and ECG. 
5) Leg assessment, including skin color, swelling, limb temperature, presence of 
ulcers or gangrene, bilaterally. 
6) Measure resting ankle pressure using an appropriate adult cuff, bilaterally. 
7) Measure resting toe pressure, bilaterally. 
8) Assessment of leg ulcers, measurement of ulcer size and ulcer photography, 
bilaterally. 
9) Vascular QoL questionnaire. 
10) Blood tests:  
• 
Hematology: 
RBC; 
Hemoglobin; 
Hematocrit; 
WBC; 
Neutrophils; 
Lymphocytes; Monocytes; Platelet count, PT, (or INR), and PTT.  

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• 
Blood Chemistry: blood glucose level; Blood urea nitrogen (BUN); Serum 
creatinine; C-reactive protein; Serum chloride; Serum magnesium; Serum 
Potassium; Serum sodium; Serum albumin; Total serum proteins; 
SGOT/AST; SGPT/ALT; Alkaline phosphatase; Total bilirubin, HbA1c. 
7.4.4. Visit 9: Nine Month Follow-up (270 ±14 days) 
The following will be performed: 
1) Assessment of pain on the visual analogue scale. 
2) Assessment of analgesic drug types and doses. 
3) Physical exam, including Rutherford Assessment. 
4) Blood pressure, heart rate, temperature and ECG. 
5) Leg assessment, including skin color, swelling, limb temperature, presence of 
ulcers or gangrene, bilaterally. 
6) Measure resting ankle pressure using an appropriate adult cuff, bilaterally. 
7) Measure resting toe pressure, bilaterally. 
8) Assessment of leg ulcers, measurement of ulcer size and ulcer photography, 
bilaterally. 
9) Vascular QoL questionnaire. 
10) Blood tests:  
• 
Hematology: 
RBC; 
Hemoglobin; 
Hematocrit; 
WBC; 
Neutrophils; 
Lymphocytes; Monocytes; Platelet count, PT, (or INR), and PTT.  
• 
Blood Chemistry: blood glucose level; Blood urea nitrogen (BUN); Serum 
creatinine; C-reactive protein; Serum chloride; Serum Potassium; Serum 
magnesium; Serum sodium; Serum albumin; Total serum proteins; 
SGOT/AST; SGPT/ALT; Alkaline phosphatase; Total bilirubin, HbA1c. 
7.4.5. Visit 10: Twelve Month Follow-up (365 ±14 days)  
The following will be performed: 
1) Assessment of pain on the visual analogue scale. 
2) Assessment of analgesic drug types and doses. 
3) Physical exam, including Rutherford Assessment. 

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4) Blood pressure, heart rate, temperature and ECG. 
5) Leg assessment, including skin color, swelling, limb temperature, presence of 
ulcers or gangrene, bilaterally. 
6) Calculate resting ankle pressure using a standard adult cuff, bilaterally. 
7) Calculate resting toe pressure, bilaterally. 
8) Assessment of leg ulcers, measurement of ulcer size and ulcer photography, 
bilaterally. 
9) Vascular QoL questionnaire. 
10) Blood tests:  
• 
Hematology: 
RBC; 
Hemoglobin; 
Hematocrit; 
WBC; 
Neutrophils; 
Lymphocytes; Monocytes; Platelet count, PT, (or INR), and PTT.  
• 
Blood Chemistry: blood glucose level; Blood urea nitrogen (BUN); Serum 
creatinine; C-reactive protein; Serum chloride; Serum Potassium; Serum 
sodium; Serum magnesium; Serum albumin; Total serum proteins; 
SGOT/AST; SGPT/ALT; Alkaline phosphatase; Total bilirubin, HbA1c. 
8. 
STUDY POPULATION  
8.1. 
Criteria for subjects 
8.1.1. Inclusion Criteria 
A. Subject is diagnosed with critical limb ischemia according to the Trans-Atlantic Inter-
Society Consensus (TASC) II definition (2007): “The term critical limb ischemia should 
be used for all [subjects] with chronic ischemic rest pain, ulcers or gangrene attributable 
to objectively proven arterial occlusive disease. The term CLI implies chronicity and is to 
be distinguished from acute limb ischemia” (Norgren et al., 2007). 
B. Subject has one or more of the following hemodynamic indicators of severe peripheral 
arterial occlusive disease  
i. Systolic ankle pressure ≤ 70 mmHg, 
ii. Toe systolic pressure ≤ 50 mmHg (or absent 
palpable pedal pulse). 
In cases where the pulse volume recording (PVR) is flat or barely pulsatile, patients with 
higher systolic blood pressures may be included after Sponsor review with the 
investigator. 
C. Subject is not a candidate for standard revascularization treatment options for peripheral 

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arterial disease because of no distal target as seen on angiography or by color flow 
duplex ultrasound imaging (completed within six (6) months of screening visit), without 
patent runoff vessels below the knee to enable a distal bypass or following a failed 
revascularization attempt. In addition, the subject will not be considered a candidate for 
revascularization treatment if open surgical or revascularization attempts pose a high risk 
to the subject’s life. Examples include subjects suffering from very severe cardiac disease 
(as determined by a cardiologist), are bedridden, suffer from paralysis of at least one limb 
or are in poor general health, or suffer from any other severe condition that the PI 
considers as high-risk.  
D. Subjects must be on standard of care medical therapy for peripheral vascular disease 
such as 1) control of hyperlipidemia with statins or other anti-hyperlipidemic drugs as 
indicated, 2) control of hypertension as indicated, 3) antiplatelet therapy with aspirin, 
clopidogrel (Plavix), or other anticoagulant therapy, and/or cilostazol (unless medically 
contraindicated, e.g., bleeding or allergy), 4) control of hyperglycemia as indicated. 
E. Male or female age 18 to 86, inclusive. 
F. Non-pregnant, non-lactating female. 
G. Subject is able to understand and provide voluntary signed informed consent. 
8.1.2. Exclusion Criteria 
A. Subject having on angiography (or other appropriate imaging modality) uncorrected 
aorto-iliac occlusive disease down to the origin of the profonda-femoris artery of the 
affected limb. 
B. Subjects who, in the opinion of the investigator, have a vascular disease prognosis that 
indicates they would require a major amputation (at or above the ankle) within 
approximately 4 weeks after administration of the IMP. 
C. Advanced CLI presenting as severe ischemic ulcers ˃ 10 cm2 or dry gangrene proximal 
to the metatarsophalangeal joint heads or lower extremity wet gangrene. 
D. Lower extremity non-treated active infection, e.g., wet gangrene, purulent discharge, 
cellulitis, MRSA infection. 
E. Body weight less than 45 kg (99 lbs). 
F. Hypercoagulable state, which is already known from the documented history. 
G. Subject received blood transfusion during the previous 4 weeks (to exclude the potential 
of non-autologous ACPs in the harvested blood). 

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H. Subject’s condition precludes - in 2 consecutive attempts - the manufacturing of batches 
that pass release specifications. 
I. 
Inability to communicate (that may interfere with the clinical evaluation of the subject). 
J. Major non-vascular operation during the preceding 3 months. 
K. Myocardial infarction or uncontrolled myocardial ischemia or persistent severe heart 
failure (New York Heart Association (NYHA) class IV) during the preceding 3 months. 
L. Severe aortic stenosis  
M. Renal failure where GFR is < 30 mL/min/1.73 m2. 
N. Hepatic failure (Child-Pugh class C). 
O. Anemia (Hemoglobin lower than 11g/dl). 
P. Major stroke within the preceding 3 months resulting in debilitating hemiplegia. 
Q. Diagnosis of malignancy within the preceding 3 years (excluding non-melanoma skin 
cancers and non-metastatic prostate cancer). 
R. Concurrent chronic or acute infectious disease and uncontrolled infectious symptoms. 
S. Severe concurrent disease, e.g., septicemia, evident severe osteomyelitis, HIV-
1,2/HBV/HCV/HTLV infections, poorly controlled insulin-dependent diabetes mellitus 
(HbA1c >10%), systemic lupus erythematosus, multiple sclerosis, amyotrophic lateral 
sclerosis, nephrotic syndrome, connective tissue disorders or arteritis (e.g., Takayasu 
arteritis). 
T. Bleeding diathesis. 
U. Participation at the same time in another investigational medicinal product or device 
study. 
V. Chronic immunomodulating or cytotoxic drug treatment. 
W. Subjects who have a temperature of above 38.40C for 2 consecutive days during and 
immediately prior to the time the subject is about to receive the investigational medicinal 
product. 
X. Life expectancy of less than 6 months. 
Y. Subject unlikely to be available for follow-up. 
Z. Acute worsening of CLI. 

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9. 
TRIAL OBJECTIVE  
To determine the efficacy and safety of intramuscular injection of ACP-01, containing blood-derived 
autologous ACPs, in subjects with critical limb ischemia who are on standard of care therapy and who 
have no endovascular or surgical revascularization options. 
10. 
ASSESSMENT OF FUNCTIONAL PARAMETERS 
10.1. Primary endpoints 
10.1.1. The primary efficacy endpoint for this study is the earlier time from treatment 
with IMP to either de-novo gangrene, or doubling of wound size, or major amputation, 
or death. 
10.1.2. Safety of intramuscular injection of ACP-01. 
10.2. Secondary endpoints  
10.2.1. Change from Baseline in VAS pain score. 
10.2.2. Change from Baseline in Ulcer Size. 
10.3. Exploratory Outcome Measures  
10.3.1. Change from baseline in the dose and quantity of analgesic drugs used by 
the subject. 
10.3.2. Reduction in total hospitalization time of subjects treated with ACP-01 
compared to subjects treated with placebo. 
10.3.3. Change from Baseline in Quality of Life. 
10.3.4. Change from Baseline in Ankle Pressure. 
10.3.5. Change from Baseline in Toe Pressure. 
 
11. 
AMENDMENTS TO THE PROTOCOL 
 
The approval of the Ethics Committees/IRBs will be obtained before any changes are implemented. 

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12. 
 TEST MATERIAL  
12.1. Investigational Medicinal Product  
The active substance being tested is a mixture of cells (ACPs) consisting of at least 5 million autologous 
CD31+ and Ac-LDL+ and at least 1 million CD34+ cells (constituting at least 1.5% of the total number of 
cells in the product). In addition to CD31+ and Ac-LDL+ and CD34+ cells, the product consists of other 
cellular subpopulations considered not to be the effector cells. The maximal number of cells injected will 
not exceed 200 million. The cells are isolated from the subject’s peripheral blood and then cultured ex 
vivo under sterile conditions. The product will be provided in 6 separate syringes (5 ml each) to be 
administered by 30 injections. 
The placebo is X-Vivo™ 15, the same medium for the production of the ACP product. It will be 
administered to the subjects in the same type and number of syringes and in the same volume as the 
cell-containing product. X-Vivo™ 15, is a chemically defined, serum-free growth medium used for the 
cultivation of a variety of cell types, including progenitor cells. 
12.2. Biological activity analyses  
Acceptable culture parameters as assessed by microscopy flow cytometry and ELISA will be in 
accordance with the following specifications:  
• 
Cell viability – > 75% 
• 
Morphology – spindle-shaped, large cells forming long thread-like structures. 
• 
Angiogenic capacity is assessed by flow cytometry. The following cell markers are 
evaluated: CD31bright and uptake of Acetylated-Low Density Lipoprotein (Ac-LDL). 
• 
Stemness capacity is also assessed by flow cytometry and is defined by the percentage 
and number of cells expressing the CD34 marker. 
• 
Physiological activity specific for ACPs is assessed by secretion of IL-8 by the cultured 
cells and is assessed by ELISA. 
• 
Angiogenin, a potent angiogenic cytokine will also be assessed and potentially correlated 
with the clinical outcome of the subjects. 
• 
Cell migration – the cells’ ability to migrate towards angiogenic or stem cell factors will be 
assessed and potentially correlated with the clinical outcome of the subjects. 

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12.3. Safety analyses  
12.3.1. Sterility 
Sterility tests will be performed according to 21 CFR 610.12. Assessment of cell culture sterility will be 
performed on samples of the cell fraction supernatant following cell washing. Interim negative sterility 
results of all samples taken at different stages of the culture will be compulsory for the release of the 
final product. 
12.3.2. Bacterial Endotoxin Test  
The Bacterial Endotoxin test will be performed according to current USP 28 chapter <85>. The Lymulus 
Amebocyte Lysate (LAL) test will be performed on a sample of supernatant taken from the cells and the 
final washing medium of the cells before vialing. Endotoxin levels below the acceptable limits will be 
compulsory for the release of the final product. 
12.3.3. Gram stain  
Gram stain will be used as a rapid and qualitative method for assessing bacterial contamination of tissue 
culture samples. Negative results of the Gram stain performed on samples taken from the cells and the 
final washing medium of cells before vialing will be compulsory for the release of the final product. 
12.3.4. Mycoplasma  
Mycoplasma contamination will be tested and the results of the test will be obtained before the 
administration of the product, but after the shipment of the product to the clinical site. Immediately, upon 
receipt of the test results, they will be communicated to the clinical site. 
12.4. Culture preparation 
The isolation and incubation of autologous ACPs will be performed in a specially designed and dedicated 
clean room of Class 10,000, in a Class 100 laminar flow biological safety cabinet. 
Approximately two hundred and fifty milliliters of peripheral blood will be collected from the subject in a 
standard sterile blood transfusion bag containing CPDA-1 as anticoagulant. In addition, approximately 
10 ml blood will be collected and used for tests performed at the hospital (bacterial cultures and 
mycoplasma). The blood bag will be packed immediately at 2-80C and transported to the manufacturing 
facility.  
Blood samples and cells that are not used in the treatment of subjects with ACPs, e.g., from the placebo 
group, will be de-identified and may be utilized for manufacturing and quality control testing such as for 
the development of potency and release assays.  Results from the assays and tests may be used to 

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retrospectively examine cell and product characteristics in CLI patients and/or the response to treatment 
with ACPs.   
The autologous ACP culture will be prepared and tested according to standard operating procedures. 
The cells will be incubated at 37°C, in a 5% CO2 incubator for approximately 5 days. The final product 
will be obtained and the decision on whether the culture is suitable for administration to human subjects 
will be based on concordance between the analytical results of tests performed after incubation and the 
pre-defined release specifications. 
Concurrently, Gram staining of a sample from the supernatant taken from the culture will be performed 
before sending the cells to the hospital. Negative results of the Gram staining will be compulsory for 
continuation of the procedure. Bacterial cultures started at blood harvesting, and at different stages of 
the cell manufacturing process will be assessed for evidence of bacterial/fungal contamination and 
negative sterility results will be compulsory for continuation of the procedure. 
The final product will be transported back to the hospital for administration to the subject. The 
investigator will receive notice before the arrival of the final product, so that preparations for the 
administration can be completed. 
13. 
CONCOMITANT TREATMENT 
The investigators will not deviate from the standard treatment as practiced in their institution for subjects 
with CLI, except for the administration of the IMP (ACPs or placebo) and the other requirements of the 
protocol. The same principle will guide the management of the subjects after administration of IMP at 
the medical center and after hospitalization. 
 
 
 

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14. 
CLINICAL STUDY PROCEDURE 
Visit type 
Screening 
Adm. 
of 
IMP 
Primary safety Follow-up 
Long-term follow-up 
Visit number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Consecutive visit 
day 
-30 to 
-7 
-7 
±1 
0 
1 (Phone 
f/u except 
for first 5 
patients) 
2-3 
30 ±5 
90 ±7 
182 
±14 
270 
±14 
365 
±14 
Demography 
X 
 
 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
X 
X (only 
first 5 
subjects) 
X 
X 
X 
X 
X 
X 
Rutherford 
Assessment  
X 
 
X 
 
 
X 
X 
X 
X 
X 
Leg assessment, 
bilaterally (skin, 
swelling, 
temperature, 
ulcers, gangrene, 
etc.) 
X 
 
X 
X (only 
first 5 
subjects) 
X 
X 
X 
X 
X 
X 
Heart rate, BP, 
ECG & 
Temperature 
X 
 
X 
(befor
e 
admin 
of 
IMP 
and 2 
hours 
after) 
X (only 
first 5 
subjects) 
X 
X 
X 
X 
X 
X 
Eligibility 
assessment 
X 
 
 
 
 
 
 
 
 
 
Consent form 
signing 
X 
 
 
 
 
 
 
 
 
 
Pain scale 
assessment (VAS) 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Analgesia drugs 
and doses 
X 
 
 
 
 
X 
X 
X 
X 
X 

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Visit type 
Screening 
Adm. 
of 
IMP 
Primary safety Follow-up 
Long-term follow-up 
Visit number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Laboratory tests 
X 
X 
 
 
X (only first 5 
subjects) 
X 
X 
X 
X 
X 
Screening for 
HIV,HTLV, 
HVB,HVC 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
Ankle pressure, 
bilaterally 
X 
 
 
 
 
X 
X 
X 
X 
X 
Toe pressure, 
bilaterally 
X 
 
 
 
 
X 
X 
X 
X 
X 
Vascular Quality of 
Life Questionnaire 
X 
 
 
 
 
X 
X 
X 
X 
X 
Ulcer assessment, 
size and 
photography, 
bilaterally. 
X 
 
X 
 
 
X 
X 
X 
X 
X 
Telephone follow-
up 
 
 
 
X (at 
night) 
 
 
 
 
 
 
Blood cultures 
 
X 
 
 
X (only first 5 
subjects) 
 
 
 
 
 
Blood draw for 
manufacture of 
investigational 
medicinal product  
 
X 
 
 
 
 
 
 
 
 
IMP administration 
 
 
X 
 
 
 
 
 
 
 
 
15. 
PROTOCOL FOR CASES OF SUSPECTED INFECTION 
Possible infection may be suspected in one of the following situations: 
 
Possibility 1: The subject is newly febrile (>38.4°C) and cultures of samples taken from the 
ACP product are positive.  
• 
Obtain blood sample and culture to assess potential bacterial growth and 
sensitivity, evaluate heart function. 
• 
Treat according to culture sensitivities.  

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• 
Treatment guided by Infectious Diseases Expert (ID expert) from the beginning.  
• 
Put recruitment of additional subjects on hold at that site until a report of the 
suspected infection is issued.  
Possibility 2: The subject is newly febrile (>38.4°C) and cultures of samples taken from the 
ACP product are negative.  
• 
Obtain 2 sets of blood cultures, urine culture and urinalysis, WBC-count + 
differential.  
• 
Evaluate heart function. 
• 
Rule-out all other infectious options.  
• 
An ID expert should evaluate the subject and the laboratory data. The treatment 
will be decided upon by the ID expert. 
Possibility 3: The subject is afebrile and cultures of samples taken from the ACP product are 
positive.  
• 
Obtain blood sample(s).  
• 
Do not start antibiotic therapy unless blood culture findings dictate it. 
• 
Follow closely under the supervision of the ID expert. 
16. 
ADVERSE EXPERIENCES 
All adverse experiences (events) will be recorded at each visit throughout the duration of the trial or 
at any other occasion when they are diagnosed. The corresponding information should also be 
documented on the appropriate Case Report Form. The characterization of all adverse events will 
be performed according to the WHO dictionary. The following provides definitions of both adverse 
and serious adverse events that will be used in the trial. 
16.1 
Adverse event (AE) 
An AE is any untoward medical occurrence in a subject or clinical investigation subject administered 
a pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the IMP. 
16.2. Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death, 

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• 
Is life-threatening, 
• 
Requires in-patient hospitalization (≥ 24 hours) or prolongation of existing hospitalization, 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect. 
All fatalities and serious adverse experiences (SAE), including serious clinical laboratory abnormalities 
even those that the investigator considers not to be related to the leg condition or the administration of 
the IMP must be immediately reported by phone, by email, or by fax to Hemostemix or its designee. 
All significant symptoms and signs, which were not present at the previous visits, must be recorded as 
potential adverse experiences to be evaluated by the clinical investigator. Any medical condition present 
at the previous visits that remains unchanged or improves should not be recorded as an adverse 
experience at subsequent visits. However, if there is deterioration of a medical condition that was 
present at the initial visit, then this should also be considered a new adverse experience and reported.  
If an SAE occurs, it will be noted and reported starting from the time point of the subject signing the 
Informed Consent Form, even if causality cannot be attributed to the IMP. AEs will be reported from Visit 
2 onwards (time of blood draw for manufacture of the IMP). 
16.3. Relationship to the IMP 
The investigator, using the following guidelines, should determine relationship between each adverse 
experience and treatment with the IMP.  
Not related: The experience is clearly related to other factors such as the subject’s clinical 
state or other therapeutic intervention. 
• 
Unlikely: The experience was most likely produced by other factors such as the 
subject’s clinical state, other therapeutic interventions, or concomitant drugs administered to 
the subject, and does not follow a known response pattern to the autologous ACP 
administration. 
• 
Possible: The experience follows a reasonable temporal sequence from the time of 
the IMP injection and/or follows a known response pattern to autologous ACP administration, 
but could have been produced by other factors such as the subject’s clinical state, other 
therapeutic intervention, or concomitant drugs administered to the subject. 
• 
Probable: The experience follows a reasonable temporal sequence from the time of 
IMP injection and follows a known response pattern to the autologous ACP administration 
and cannot be reasonably explained by other factors such as the subject’s clinical state, other 
therapeutic interventions, or concomitant drugs administered to the subject. 

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• 
Highly probable: The experience either occurs immediately following the IMP 
injection or there is a positive reaction at the application site, follows a known response 
pattern to the autologous ACP therapy, and cannot be reasonably explained by other factors 
such as the subject’s clinical state, other therapeutic interventions, or concomitant drugs 
administered to the subject. 
16.4 
Severity of adverse experience 
Severity of an adverse experience is defined as a qualitative assessment of the degree of intensity of 
an adverse experience, as is determined by the investigator or reported to him/her by the subject. The 
assessment of severity is made irrespective of relationship to the administration of the IMP or 
seriousness of the experience and should be evaluated according to the following scale: 
• 
1= Mild 
• 
2= Moderate 
• 
3= Severe 
• 
4= Life threatening  
• 
5= Death  
16.5 
Actions to be undertaken by the PI 
AEs/SAEs are captured using an EDC.  The following lists the procedures and written documentation 
for reporting SAEs including deaths: 
1) All deaths have to be reported immediately by telephone to the company and 
subsequently in writing via fax or email within 24 hours using the Serious Adverse 
Experience (SAE) Report form. The corresponding information should also be 
documented in the Adverse Experience (AE) column in the CRF. 
2) SAEs, which the investigator considers are not related to the clinical condition under 
study, must be reported by telephone to the company immediately and subsequently in 
writing using the SAE Report form within 24 hours. This includes SAEs and/or serious 
abnormal laboratory findings occurring during the entire trial period. The corresponding 
information should also be documented on the Adverse Experience (AE) column in the 
CRF. 
3) All adverse experiences will be followed until resolution and/or until the etiology is 
established as not related to the administration of the ACP products using the AE follow-
up CRF for non-serious AEs or the SAE Report form. If a subject requires long-term follow 
up because of a suspected adverse reaction to the IMP, a complete medical summary 

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with pertinent laboratory report is to be submitted to the company at the end of the follow-
up period. 
The investigator must inform the Ethics Committee/REB/IRB of any life-threatening toxicity, and all 
deaths according to local regulatory requirements. 
16.6. Expected adverse events 
A full list of expected adverse events is presented in Appendix 1. 
17. 
DATA SAFETY MONITORING BOARD (DSMB) 
An independent DSMB, comprised of two experienced clinicians with relevant expertise (vascular 
surgery, cardiology, anesthesiology, trauma, stem cell technology) and a biostatistician serving the 
DSMB will blindly review the accumulated study data.  
DSMB members and the unblinded biostatistician cannot be investigators involved in the conduct of 
the clinical trial and should have no vested financial interest in the company or in the outcome of the 
study and are not allowed to possess any shares or stock options in the company. DSMB members 
shall be reimbursed for their time and any out-of-pocket expenses incurred as part of their duties. 
The company may designate one additional member to the DSMB, who will also coordinate the 
activity of the board.  
The DSMB will be provided all study accumulated data. and schedule of meetings and role of DSMB 
will be outlined in a DSMB Charter to be signed and approved by all DSMB members. 
18. 
WITHDRAWAL OF SUBJECTS FROM TRIAL 
The following events are considered sufficient reasons for a subject to discontinue the trial: 
• 
Whenever the subject decides that it is in his/her best interest. 
• 
Whenever the investigator considers it advisable or in the subject’s best interest. 
It is agreed that, for reasonable cause given by either the investigator or the Sponsor, the company may 
terminate this trial, provided a written notice is submitted at a reasonable time in advance of the intended 
termination. 
19. 
ETHICAL AND REGULATORY ISSUES 
19.1. Informed consent 
Informed consent for each subject will be obtained prior to initiating any trial procedures in accordance 
with the statement entitled “Requirements for Informed Consent.” According to the existing laws and 
regulations, one copy of the informed consent form must be given to each subject and one signed copy 
must be retained in the investigator’s trial records. 

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The “Declaration of Helsinki” recommends that consent be obtained from each potential subject in 
biomedical research trials after the aims, methods, anticipated benefits, and potential hazards of the 
trial, and discomfort it may entail, are explained to the individual by the physician. The subject should 
also be informed of his or her right not to participate or to withdraw from the trial at any time. If the 
subject is in a dependent relationship to the physician or given consent under duress, the informed 
consent should be obtained by an independent physician. If the subject is legally incompetent (i.e., a 
minor, or mentally incompetent), informed consent must be obtained from the parent, legal guardian, or 
legal representative in accordance with the law of the country in which the trial takes place. By signing 
this protocol, the investigator agrees to conduct the trial in accordance with the “Declaration of Helsinki.” 
19.2. Ethical principles 
This trial complies with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) 
and all applicable amendments laid down by the 18th World Medical Assemblies, and the ICH guidelines 
for Good Clinical Practice. 
19.3. Laws and regulations 
This Clinical Trial will be conducted in compliance with the International and National laws and 
regulations of the country(ies) in which this Clinical Trial is performed, as well as any applicable 
guidelines. 
19.4 
Research Ethics Board/Institutional Review Board/Independent 
Ethics Committee (REB/IRB/IEC) 
The Investigator must submit this protocol to the appropriate Ethics Committee (REB/IRB/IEC), and is 
required to forward to the Sponsor a copy of the written and dated approval signed by the Chairperson 
of such committee (REB/IRB/IEC). 
20. 
STATISTICAL METHODOLOGY 
A total of approximately 95 subjects will be randomized to treatment with ACP-01 or placebo using a 2:1 
randomization scheme, respectively, stratified by site. Study will be continued until all subjects treated 
with the IMP are followed-up for 52 weeks. 
One futility analysis for potentially stopping enrolment into the study will be performed when 
approximately 42 subjects have completed at least 26 weeks of follow-up but no more than 52 weeks 
from IMP administration or experienced before that time point the study event. 

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20.1. Randomization Procedure 
After a subject meets the eligibility criteria, he/she will be randomized to one of the two treatment groups, 
based on a randomization procedure employing a 2:1 assignment ratio, i.e., treatment with ACP-01 or 
placebo, respectively, using permuted blocks stratified by centers. # 
20.2. Interim Analysis 
Interim analyses will be conducted according to the Lan & Demets (1983) maximum information group 
sequential test, in which the Type I error spent at each analysis k is a function of the observed 
information level, using the error spending function family 
f(t)= min{αtρ, α}, 
 
where t = fraction of the maximum anticipated information obtained at the time of analysis k. To maintain 
the blind, interim analyses will be conducted by an independent party without unblinding either the 
Sponsor or Investigators to the treatment assignments. 
 
20.3. Significance Level 
The overall significance level for this study will be 5% using two-tailed tests. The study will have one 
primary endpoint and 2 secondary end-points ordered in a hierarchy, and analyses will utilize the 
gatekeeping approach to maintain the experiment-wise type-I error of 5%. The order of the hierarchy of 
the secondary endpoints testing following the primary end-point testing is as follows: 
• 
Change from Baseline in VAS pain score 
• 
Change from Baseline in Ulcer Size 
20.4. Sample Size 
Sample size calculations were performed under the following assumptions: 
• 
The primary study endpoint is the earlier time from treatment with study IMP to either de-
novo gangrene, or doubling of wound size, or major amputation, or death. 
• 
Randomization will allocate subjects to autologous ACPs or placebo using a 2:1 
assignment ratio, respectively, stratified by site. 
• 
The expected median time to study event as defined by the primary efficacy endpoint, 
assuming exponentially distributed time to event, is 3 months for placebo-treated subjects 
and 7 months for the ACP-treated arm.  

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• 
The anticipated monthly randomization and study IMP administration rate is 6 subjects 
per month. 
• 
The minimal follow-up period of a subject will be 26 weeks if the primary endpoint is not 
reached, and the maximal follow-up period will be 52 weeks. 
• 
Final analysis, under these assumptions is planned to be conducted at approximately at 
22 months from first subject IMP treatment including a total of 95 subjects. 
• 
As the effect of the early futility analysis is marginal, the final analysis will use a two-sided 
alpha level of 0.05  
Under the above assumptions, a total of 95 subjects treated with the study IMP will provide 94% power 
to detect a statistically significant result at a two-sided alpha level as specified above. 
Sample Size Re-estimation 
Periodic, blinded review of the overall, pooled event rate will be conducted using the method of Gould 
and Shih(1992).  If the observed overall event rate is lower than anticipated at study initiation, this 
procedure will allow for adjusting the sample size without altering the significance level.  Consistent with 
FDA guidance (2018), Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry, 
such sample size adjustments require no adjustment of Type I error:  
In general, adequately prespecified adaptations based on non-comparative data have a 
negligible effect on the Type I error probability. 
 
20.5. Analysis Sets 
• 
Intent-to-Treat (ITT) Analysis Set: The intent to treat (ITT) analysis set will consist of all 
subjects who have been randomized to the study. In accordance with the ITT principle, 
all subjects randomized will be kept in their originally assigned treatment group. This 
analysis set will serve as the primary analysis set for efficacy inference. 
• 
Modified Intent-to-Treat (mITT) Analysis Set: The mITT analysis set is a subset of the 
ITT analysis set. This set will consist of data from all subjects who have been randomized 
to the study and administered the IMP and had at least one treatment visit post IMP 
administration. 
• 
Per-Protocol (PP) Analysis Set: The per protocol (PP) analysis set is a subset of the mITT 
analysis set and will consist of all subjects with no major protocol violations as will be 
defined in a more detailed Statistical Analysis Plan (SAP) to be written prior to revealing 
of the blind and having follow up assessments available. 

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• 
Safety (ST) Analysis Set: The safety analysis set (ST) will consist of all subjects who 
have been randomized and received the Study IMP. This analysis set will be used as the 
primary set for safety inference. 
20.6. Demographics and Baseline Characteristics 
Demographics and baseline data will be described for the ITT analysis set. Subject demographics and 
baseline characteristics, including underlying disease history, medical history and prior medications will 
be compared between the study groups to assess baseline comparability. Continuous variables (e.g., 
subject age, weight, height, and body mass index (BMI)) will be summarized using descriptive statistics 
(number [n], mean, standard deviation, and standard error, median, minimum, and maximum) 
Categorical variables will be summarized using subject counts and percentages. Categories for missing 
data will be presented if necessary. 
20.7. Efficacy Assessment 
The following trial end-points will be calculated and statistically analyzed for the ITT cohort which will 
serve as the primary analysis set for efficacy inference. 
20.7.1. Primary End-Point and Principal Analysis 
The primary efficacy end-point for this study is the erlier time from treatment with IMP to either de-novo 
gangrene, or doubling of wound size, or major amputation, or death. The time to the primary end-point 
will be presented by Kaplan-Meier curves stratified by treatment group.  
The time form day of treatment with the IMP to the earlier time of either de-novo gangrene, or doubling 
of wound size, or major amputation, or death will be right censored by the subject’s last follow-up date 
in the study.  
The primary analysis for the between study groups comparison will be conducted utilizing the baseline 
adjusted Cox’s proportional hazards (PH) model (SAS® PROC PHREG). In addition to treatment group 
and study site, baseline prognostic factors as will be defined in a more detailed SAP written prior to 
revealing of the blind will be included as covariates in the model. 
The adequacy of the proportional hazards (PH) assumption will be confirmed by including a time 
dependent covariate for the active treatment group (as dummy variable) by log (time) interaction in the 
primary analysis model and testing it using 5% significance level. In case the PH assumption will be 
rejected the log rank test (SAS® PROC LIFTEST) will be used for statistical inference.  A detailed 
sensitivity analysis of the principal analysis of the primary endpoint will be provided in a more detailed 
SAP to be sent to the Division prior to revealing of the blind and conduct of the pre-defined futility 
analysis. 

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20.7.2. Key Secondary Endpoint Analyses 
20.7.2.a. 
Change from Baseline in VAS pain score 
The change from baseline in VAS pain score is defined at the difference between the Last Observed 
Value (LOV) of an individual subject substracted from the last measurments taken prior to study IMP 
administration. Subjects who early terminated from the study or met the study event will be imputed a 
value according to the worst-case scenario; the worst recorded measurement of change of the entier 
study population. 
The model baseline adjusted Least Squares Means (LSM) of the change from baseline to LOV of this 
endpoint will be compared the two study groups by applying an ANCOVA model (SAS® MIXED 
procedure). The model will include treatment group, study site and baseline pain measurement.  
20.7.2.b. 
Change from Baseline in Ulcer Size 
The change from baseline in Ulcer Size (cm2) is defined at the difference between the Last Observed 
Value (LOV) of an individual subject substracted from the last measurments taken prior to study IMP 
administration. Subjects who early terminated from the study or met the study event will be imputed a 
value according to the worst-case scenario; the worst recorded measurement of change of the entier 
study population. 
The model baseline adjusted Least Squares Means (LSM) of the change from baseline to LOV of this 
endpoint will be compared the two study groups by applying an ANCOVA model (SAS® MIXED 
procedure). The model will include treatment group, study site baseline ulcer size measurement.  
The model adjusted Least Squares Means (LSM) of the change from baseline to LOV of this endpoint 
will be compared by applying an ANCOVA model (SAS® MIXED procedure). The model will include 
treatment group, study site and baseline toe pressure measurement.  
20.7.3. Exploratory Outcome Measures 
Additional exploratory endpoints as described below will be analyzed for further exploration of the ACP 
treatment effect with no multiplicity adjustment. Assessments will be done for Study Week 13 and Week 
26 and will be described in a more detailed SAP to be sent to the Division prior to revealing of the blind 
and conduct of the pre-defined futility analysis. The pre-defined exploratory outcome measures are:  
• 
Change from baseline in the dose and quantity of analgesic drugs used by the subject. 
• 
Change from Baseline in Quality of Life 
• 
Change from Baseline in Ankle Pressure 
• 
Change from Baseline in Toe Pressure 

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• 
Proportion of subjects with an improvement in VAS pain score  
• 
Change from baseline in Ulcer Size. 
20.8. Safety Assessment 
Safety assessments, which will be performed for the Safety Analysis set only, will include the following: 
20.8.1. Adverse Events 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries will be presented for all adverse events (overall and by severity), adverse events determined 
by the investigator to be treatment-related (overall and by severity), serious adverse events, adverse 
events causing early termination and non-serious adverse events. The incidence of adverse events will 
be summarized using descriptive statistics by system organ class and preferred term. Subjects are 
counted only once in each system organ class category, and only once in each preferred term category. 
Treatment-related adverse event summaries will include adverse events with missing relationship to 
study drug. For the summaries by severity, subjects are counted at the greatest severity. Adverse events 
missing the flag indicating serious will be excluded from the summary of serious adverse events but 
included in the summary of non serious adverse events. Listings for deaths, serious adverse events, 
adverse events leading to discontinuation, MedDRA dictionary terms for adverse event descriptions, 
and adverse event preferred terms by subject number will be presented. 
20.8.2. Clinical Laboratory Tests 
Summary statistics for laboratory tests will be presented at baseline and consecutive scheduled 
treatment visits.  Laboratory tests results and changes from baseline to each visit and endpoint will be 
summarized using descriptive statistics.  Shifts (below, within, and above the normal range) from 
baseline to each visit and endpoint will be summarized using subject counts.  The incidence of clinically 
significant abnormal results will also be summarized for laboratory data using descriptive statistics.  
20.8.3. Vital Signs and ECG 
Summary statistics for vital signs and ECG will be presented at baseline and consecutive scheduled 
treatment visits.  Vital signs values and changes from baseline to each visit and endpoint will be 
summarized using descriptive statistics. The incidence of clinically significant abnormal values will be 
summarized for selected vital signs using descriptive statistics.. 
20.8.4. Statistical Analysis Plan (SAP) 
A more detailed SAP will be developed while the study is still ongoing, prior to revealing of the study 
blind and the conduct of the futility analysis and will be submitted for the review of the Division. This 

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SAP will also outline the sensitivity analyses to be performed for the primary study endpoint using other 
set of methods accounting for the missingness mechanism as well as assessment of other analysis sets 
allowing to evaluate the robustness and internal consistency of primary results and conclusions. 
20.8.5. Statistical Software 
The data will be analyzed using the SAS® version 9.4 or higher (SAS Institute, Cary North Carolina). 
21. 
STUDY MONITORING 
21.1. Responsibilities of the Investigator(s) 
The Investigator(s) undertake(s) to perform the study in accordance with this protocol, Good Clinical 
Practices and the applicable regulatory requirements. 
The Investigator is required to ensure compliance with the schedule and procedures required by the 
clinical protocol. The Investigator agrees to provide all information requested in the Case Report Form 
in an accurate and legible manner according to the instructions provided and to ensure direct access to 
source documents to Sponsor representatives. 
21.2. Responsibilities of the Sponsor 
The Sponsor of this study is responsible to Health and Regulatory Authorities for taking all reasonable 
steps to ensure the proper conduct of the study in regards to ethics, protocol compliance, integrity and 
validity of the data recorded on the Case Report Forms. Thus, the main duty of the Monitoring Team is 
to help the Investigator and the Sponsor maintain a high level of ethical, scientific, technical and 
regulatory quality in all aspects of the study. 
22. 
CONFIDENTIALITY 
All materials, information (oral or written) and unpublished documentation provided to the Investigators 
(or any company/institution acting on their behalf), inclusive of this protocol, the subject Case Report 
Form and the Investigator's Brochure, are the exclusive property of the Sponsor and may not be given 
or disclosed, either in part or in whole, by the Investigator or by any person under his/her authority to 
any third party without the prior express consent of the Sponsor. 
However, the submission of this protocol and other necessary documentation to the REB/IRB/IEC is 
expressly permitted, the REB/IRB/IEC members having the same obligation of confidentiality. 
The sub-investigators shall be bound by the same obligation as the Investigator. The Investigator shall 
inform the sub-investigators of the confidential nature of the clinical trial. 
The Investigator  and the sub-investigators shall use the information solely for the purposes of the clinical 
trial. 

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23. 
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24. 
APPENDIX 1- LIST OF EXPECTED ADVERSE EVENTS. 
24.1. Expected adverse events related to the medical procedure  
a. Anemia - probability – low 
Due to blood draw - subjects with severe anemia will not be included in the trial and the 
volume of blood drawn is not expected to cause severe anemia. 
b. Local infection – probability - low 
Strict antiseptic procedures will be carried out.  
c. Systemic infection - probability – low 
Due to injection of infected product – cGMP with strict sterile production will be implemented 
including sterility testing to ensure the sterility of the product.  
d. Muscular compartment syndrome - probability – low 
Due to multiple injections into the partially ischemic gastrocnemius muscle – the total volume 
of injections is restricted to 30 ml.  
e. Deep vein thrombosis - probability – low 
Due to general thrombogenic diathesis – subjects will continue to receive anticoagulant 
therapy.  
f. Adverse events due to conscious sedation - probability – low 
Adverse events related to conscious sedation may include hypoxemia (reversible to 
profound), respiratory arrest, aspiration pneumonia, hypotension, or death. The risk of these 
events is minimized since sedation is administered by a trained medical professional.  
g. Discomfort/pain at injection site - probability – high 
Transient pain/discomfort at the injection site will be minimized through the adherence to 
standard phlebotomy and injection techniques, performed by trained medical personnel.  
h. Nerve damage – probability – low 
Blood collection and injection may cause nerve damage secondary to trauma from puncture 
needles or compression secondary to hematoma; however, this risk will be minimized by 
adhering to standard phlebotomy and injection techniques carried out by a trained health 
care professional.  
 
 

Hemostemix Inc.  
Confidential  
 
 
 
Version Number: 5.5 
Clinical Protocol 
Date:  October 18, 2019 
 
58 
 
 
 
 
i. Embolism - probability - low 
Due to the risk of inadvertent injection into a vessel, there is a risk of causing an embolism, 
e.g., air, cellular material. This risk will be minimized through adherence to standard injection 
techniques by a trained health care professional.  
j. Bleeding/Hematoma - probability - low 
There is a risk of inadvertent perforation of a blood vessel with or without the formation of a 
hematoma. This risk is minimized through use of a small gauge needle (23 gauge) and 
careful consideration of the injection sites. 
k. Elevation of skeletal muscle enzymes/proteins - probability - low 
The injection into the muscular tissue may cause transient increase in skeletal muscle 
proteins including but not limited to total serum creatinine kinase.  
24.2. Expected adverse events related to the administration of the IMP 
a. Immunological reaction - probability – low 
In order to avoid rejection reactions, subjects who had blood transfusions within the previous 
3 months, are excluded from the trial and minimizing the possibility of immune reactions. 
Further, through the ex vivo culture of the cellular product a potential risk of immunological 
reaction exists; however, the investigational medicinal product has never been reported to 
elicit adverse clinical immunological reactions. 
b. Ectopic Tissue Formation - probability - low 
Due to the injection of a progenitor cell containing product, a theoretical risk of ectopic tissue 
formation exists. However, there are no known reports suggesting ectopic tissue formation 
in prior clinical or preclinical experience with the investigational medicinal product.  
c. Long term complications including tumor formation - probability - low 
Due to the injection of a cell containing product, a theoretical risk of tumor formation exists, 
however this event has never been reported with the investigational medicinal product.  
Based on the worldwide experience of over 11 years with autologous EPC therapies there 
are no long-term complications that have been reported.