Safety and Efficacy of Allogeneic Cells for the Treatment of Intermittent Claudication(IC)

Study Overview
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Brief Summary
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The objective of the study is to establish the safety profile of Intramuscular PLX-PAD injections and to evaluate the clinical efficacy of it in IC subjects comprising of 4 treatment groups: Double treatment of PLX-PAD low dose Double treatment of PLX-PAD high dose Double treatment of Placebo Single treatment of PLX-PAD high dose and additional treatment of Placebo. Subjects will receive the assigned treatment twice to the affected leg, within 12-weeks interval between each treatment. The study will be comprised of 5 stages: Screening period of up to 4 weeks,first treatment of PLX-PAD or placebo followed by additional injection after 12 weeks and with follow-up of 12 months post second injection

Official Title
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A Phase II, Randomized, Double-Blind, Multicenter, Multinational, Placebo-Controlled, Parallel- Groups Study to Evaluate the Safety and Efficacy of Intramuscular Injections of Allogeneic PLX-PAD Cells for the Treatment of Subjects With Intermittent Claudication (IC)

Conditions
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Intermittent Claudication, Peripheral Artery Disease

Intervention / Treatment
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* Biological: PLX-PAD Low dose
* Biological: PLX-PAD high doses
* Biological: Double Placebo
* Biological: high dose +Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female subjects between 45 to 85 years of age (inclusive) at the time of screening visit. Subjects with a diagnosis of peripheral artery disease, secondary to atherosclerosis, confirmed by one of the following criteria assessed at the screening visit: Resting ankle-brachial index (ABI) ≤ 0.80 or Resting ABI ≤ 0.90 and >20% decrease in ABI from rest to exercise when measured within 1 minute after treadmill exercise or Toe-brachial index (TBI) ≤ 0.60 Lifestyle-limiting, moderate to severe claudication (symptoms present and stable for > 6 months and not significantly changed within the past 3 months prior to screening). Evidence of significant (>50%) stenosis infra-inguinal occlusive disease as confirmed by documented results from Duplex, MRA, CTA and/or contrast angiogram completed within 3 months prior to screening. The longest maximal walking distance (MWD) from the Screening Period exercise treadmill tests (ETT), utilizing a modified Gardner Protocol (Appendix I), must be between 1 and 10 minutes (inclusive). Subjects who have persistent claudication symptoms despite having been recommended an exercise program if feasible, and or despite having been on a stable dose of Cilostazol, if indicated. Subjects should be Cilostazol free for at least 2 weeks prior to the first ETT. Subjects should be receiving standard of care drugs for vascular disease including anti-platelet agent(s) and statin medication, as well as anti-hypertensive medication(s) and oral hypoglycemic agents/insulin, if indicated. Signed written informed consent. Exclusion Criteria: Ischemic rest pain; ulceration or gangrene (Fontaine class III-IV; Rutherford category 4-6). Failed lower extremity arterial reconstruction (surgical or endovascular) or sympathectomy within the prior one month of screening. Planned revascularization (surgical or endovascular intervention) within 12 months after screening. Lower extremity arteries inflow obstruction (defined as a greater than 50% stenosis of aorta, iliac and/or common femoral arteries). History of Buerger's disease. Uncontrolled hypertension (defined as diastolic blood pressure > 100 mmHg or systolic blood pressure > 180 mmHg during screening). Uncontrolled diabetes defined as glucose control HbA1c > 9% at screening. Life-threatening ventricular arrhythmia - except in subjects with an implantable cardiac-defibrillator. Serum Creatinine level>2.5mg/dl. SGPT (ALT), SGOT (AST) >2.5 x upper limit of normal range. Hemoglobin < 10 g/dl. Unstable cardiovascular disease defined as myocardial infarction (STEMI or NSTEMI) within 3 months prior to screening, or unstable angina - characterized by increasingly frequent episodes with modest exertion or at rest, worsening severity, and prolonged episodes. Transient Ischemic Attack (TIA)/Stroke within 3 months prior to screening. Subjects with severe congestive heart failure symptoms (i.e. NYHA Stage III to IV). Subjects with Implant of mechanical prosthetic heart valve(s). Pulmonary disease requiring supplemental oxygen treatment on a daily basis. Severe, active infection of the involved extremity(ies), including osteomyelitis, fasciitis, or severe/purulent cellulitis. History of malignancy within 5 years prior screening requiring chemotherapy and/or radiotherapy and/or immunotherapy, excluding basal or squamous cell carcinoma of the skin. Exercise is limited by any condition other than IC, including but not limited to congestive heart failure, chronic pulmonary disease, angina pectoris, or degenerative joint disease. Uninterrupted use of warfarin or non-steroidal anti-inflammatory agents (with the exception of ibuprofen at doses up to 1,200 mg/day or Diclofenac at dose of 75mg/day). Subjects who are on oral anticoagulant therapy (warfarin, dabigatran, apixaban, endoxaban and rivaroxaban). Unless, upon primary care physician and/or Investigator's discretion the subjects who are on warfarin treatment can switch to Low Molecular Weight Heparin treatment (such as: Clexane) 5-7 days prior study treatment administration and return to warfarin treatment 24 hours post study treatment administration. Subjects who are taking immunosuppressive treatment (including high dose steroids). Known allergies to protein products (Bovine serum, or recombinant trypsin) used in the cell production process. Known sensitivity to Gentamycin. Known sensitivity to antihistamine drugs. History of hospitalization due to allergic/hypersensitivity reaction to any substance (e.g. Food or drug). Medical history of Human Immunodeficiency Virus (HIV) or syphilis positivity at time of screening. Known active Hepatitis B, or Hepatitis C infection at the time of screening. Pregnant or breast-feeding women or women of childbearing age not protected by an effective contraceptive method of birth control (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide). In the opinion of the Investigator, the subject is unsuitable for participating in the study. Subject is currently enrolled in, or has not yet completed a period of at least 30 days since ending other investigational device or drug trial(s). Subjects that have prior exposure to gene or cell based therapy. Subjects who are legally detained in an official institute.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PLX-PAD Low dose<br>PLX-PAD double low doses | Biological: PLX-PAD Low dose<br> <br> |
| Active Comparator: PLX-PAD high doses<br>PLX-PAD double high dose | Biological: PLX-PAD high doses<br> <br> |
| Placebo Comparator: Placebo<br>Double Placebo doses | Biological: Double Placebo<br> <br> |
| Experimental: PLX-PAD high dose +Placebo<br>High dose+Placebo | Biological: high dose +Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Log ratio of week 52 maximal walking distance(MWD)to baseline MWD |  | 12 months |