BGC101 (EnEPC) Autologous Cell Therapy From Patient's Own Blood for Treatment of Critical Limb Ischemia (CLI)

Study Overview
=================
Brief Summary
-----------------
Evaluate the feasibility of an autologous cell preparation composed of a mixture of cells enriched for endothelial progenitor cells (EnEPCs) and multipotent adult hematopoietic stem/progenitor cells (HSPC) (BGC101), in the treatment of patients suffering from peripheral arterial disease (PAD) with critical limb ischemia (CLI) who have not responded to optimal pharmacological treatment or control of risk factors and/or had a revascularization failure, and do not have the option of further revascularization treatment.

Detailed Description
-----------------
BGC101 is designed to treat peripheral vascular disease in patients suffering from Critical Leg Ischemia (CLI) also referred to as chronic limb threatening ischemia (CLTI). This part of the study is designed as a placebo double-blind randomized controlled trial (CRT) assessing the safety and efficacy of BGC101 in 45 eligible subjects in 2 Arms: Arm A: BGC101 treatment and Arm B: Placebo treatment. The Arm A:Arm B ratio is 2:1 A single dose treatment of the personalized cells by intramuscular injections into the affected leg takes less than 10 minutes. Cells from a standard blood draw (with no pre-treatment, bone marrow aspiration, mobilization or apheresis) are transformed, within a day, into the investigational medicinal product BGC101. BGC101, intended for autologous use, is a 'ready-to-use' cell suspension in prefilled syringes.

Official Title
-----------------
Phase 1/2, Open Label & Double Blind Randomized Placebo-controlled Study to Assess the Feasibility of BGC101 (EnEPC) in the Treatment of Peripheral Arterial Disease (PAD) With Critical Limb Ischemia (CLI)

Conditions
-----------------
Critical Limb Ischemia, Peripheral Arterial Disease, Peripheral Vascular Disease

Intervention / Treatment
-----------------
* Biological: BGC101 (autologous EnEPC preparation)
* Biological: Control medium


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Have the time and ability to complete the study and comply with instructions. Capable of understanding of the purpose of the study and the contents of the informed consent form. Aged at least 18 years. Non-pregnant and non-lactating female patients. Have the clinical indications diagnostic of CLI based on Rutherford category 4-5 Have at least one of the hemodynamic indicators of severe peripheral arterial occlusive disease (WIfI ischemia grade 2): Toe pressure < 40 mmHg Ankle pressure < 70 mmHg TcPO2 < 40mmHg Meeting one of the following conditions: Poor candidate for standard revascularization treatment for peripheral arterial disease due to unfavorable anatomy or high surgical/intervention risk based on the patient's underlying comorbidities. After undergoing clinically ineffective revascularization. Six weeks or more after undergoing a prior index limb revascularization the patient demonstrates: No improvement in clinical signs and symptoms of CLI as evidenced by lack of improvement in rest pain (when not under increased pain relief) and/or inadequate wound healing or progression of tissue loss despite adequate standard treatment. Ongoing ischemia as defined above in the criterion 6. The patient is no longer amenable to further interventional or surgical revascularization (see inclusion criterion 7). Exclusion criteria: Severe and uncorrected aorto-iliac and/or common femoral artery disease, i.e. absence of femoral pulse or monophasic common femoral artery doppler waveform. Concurrent therapy that, in the Investigator's opinion, would interfere with the evaluation of the feasibility of the study medication. Treatment with any investigational product within the last 6 months or enrollment in any active study involving the use of investigational devices or drugs. Presence of any other condition or circumstance that, in the judgment of the investigator, might negatively impact the outcomes of the treatment under investigation. Prognosis of a major amputation (below or above the knee), within 4 weeks after screening. Severe wound (WIfI wound grade 2 or 3). Significant ongoing infection (WIfI infection grade 2 or 3). Relative or absolute contraindications for intramuscular injections at the intended treatment site, in cases such as severe skin lesions, severe edema or morbid obesity, based on clinician opinion. Blood transfusions during the preceding 4 weeks (to exclude the potential of non-autologous cells in the harvested blood). Heart failure (New York Heart Association [NYHA] 3-4). Patient suffering from active vasculitis. Hemoglobin (Hb) less than 9 g/dL. Patient with HbA1C > 8.5% Myocardial infarction, brain infarction, uncontrolled myocardial ischemia or persistent severe heart failure (ejection fraction [EF] < 25%) during the preceding 3 months. Significant valvular disease or valve replacement (based on medical record). Renal failure (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m², chronic kidney damage stage 4-5). Liver failure, Model for End-stage Liver Disease (MELD) scores 15 and higher. Liver function tests more than three times normal upper limit (normal limits being defined in each local laboratory) (glutamic-oxaloacetic transaminase [GOT], glutamic-pyruvic transaminase [GPT], alkaline phosphatase [AlkP], gamma-glutamyl transferase [GGT], lactate dehydrogenase [LDH]). Abnormal coagulation tests when not under warfarin (normalized prothrombin time [PT INR] >2). Pregnant or lactating women at entry of study. People who are unwilling to agree to use acceptable methods of contraception during the study. Malignancy within the preceding 3 years, except basal cell carcinoma. Concurrent acute infectious disease with septicemia Chronic infectious disease (human immunodeficiency virus-1 [HIV-1], human immunodeficiency virus-2 [HIV-2], hepatitis B virus [HBV], hepatitis C virus [HCV]). Immunodeficiency syndrome. Raynaud's syndrome Systemic treatment with cytotoxic and/or immunosuppressive treatment. Inability to communicate (that may interfere with the clinical evaluation of the patient). Patient unlikely to be available for follow-up.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Intramuscular injection of control medium only | Biological: Control medium<br>* Intramuscular injections - single treatment session<br>|
| Experimental: BGC101<br>Intramuscular injection of BGC101 (autologous EnEPC preparation) | Biological: BGC101 (autologous EnEPC preparation)<br>* Intramuscular injections - single treatment session<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (Incidence of adverse events) | Incidence and proportion of incidence between treatment arms of adverse events of specific interest (AESI) and injection-related AE Incidence of serious adverse events (SAEs) including SAEs related or probably related to the treatment Vital signs, physical examination, and electrocardiogram (ECG) Safety laboratory values of hematology, blood chemistry, and urinalysis Local tolerability (injection site reaction) | 12 Months | 
| Efficacy (Improvement of indication signs) | Major amputation (below or above the knee) rate at Month 12 Major amputation-free survival (AFS) rate at Month 12 | 12 Months |