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

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)

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:

1. Double treatment of PLX-PAD low dose
2. Double treatment of PLX-PAD high dose
3. Double treatment of Placebo
4. 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

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.