Critical Limb Ischemia (CLI) MedDRA version: 21.1 Level: LLT Classification code 10058069 Term: Critical limb ischemia System Organ Class: 100000004866
Conditions
Interventions
Product Name: PLX-PAD
Pharmaceutical Form: Dispersion for injection
INN or Proposed INN: Allogenic ex-vivo expanded placental adherent stromal cells
Current Sponsor code: PLX-PAD
Concentration type: e
Sponsors
Pluristem Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adult male or female subjects between ages 45-99 years of age at the time of screening. 2. Subjects with a diagnosis of PAD due to atherosclerosis at the stage of CLI, with minor tissue loss from arterial disease, up to the ankle level (the line between the top of the two malleoli) (black toe due to CLI is acceptable if not infected). 3. Total area of ischemic lesions =20cm2 (not including black toes). 4. Total area of ischemic lesions in the heel =10cm2. 5. AP =70 mmHg or TP =50 mmHg in the index leg. If a subject has both ABI >1.4 or both AP and TP are not measureable or not reliable, inclusion may be based on TcPO2 =30 mmHg. 6. Subject unsuitable for revascularization (by any method) in the index leg based on unfavorable risk-benefit assessment of a multidisciplinary team including a vascular surgeon, and an interventionist/endovascular specialist (who might be a vascular surgeon, angiologist/cardiologist/internist, interventional radiologist), and, if relevant, an anesthesiologist, confirmed once during Screening Period. Unsuitability to revascularization is based any of the following: ? Anatomic considerations as: inappropriate target artery, diffuse/extensive tibial and/or peroneal artery lesions, inadequate distal run-off ? Technical considerations as: inappropriate bypass conduit ?Failed revascularization (with persistence of CLI as defined in this protocol) ? Medical considerations: subject's comorbidities. 7. Ischemic lesions in the index leg must not have closed during the Screening Period, nor significantly worsened. 8. Ischemic ulcers in the index leg without tendon or bone exposure during Screening Period, unless the exposure is secondary to a minor amputation and there are no signs of osteomyelitis as per clinical assessment and imaging. 9. Under treatment for cardiovascular risk factors: hypertension, hyperlipidemia, diabetes, in accordance with applicable guidelines, in order to achieve their stabilization. Concomitant therapy should include a statin (or other lipid lowering drugs as part of standard of care) and an anti-platelet agent (e.g., clopidogrel, aspirin, etc.) for at least 2 weeks prior to randomization as part of standard of care (unless contraindicated or unless subject is under chronic oral anticoagulation). Subject has received recommendations on lifestyle changes (including smoking cessation) prior to randomization. 10. Women of childbearing potential must have a negative serum pregnancy test at screening and must be willing to use at least one highly effective birth control method throughout the study: a. Oral/intravaginal/transdermal combined estrogen and progestogen containing hormonal contraception for at least 3 months prior to screening b. Oral/injectable/implantable progestogen-only hormonal contraception for at least 3 months prior to screening c. An intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) Any female subject who is surgically sterile, or with bilateral tubal occlusion, or whose partner is vasectomized, or who reliably applies sexual abstinence or who is postmenopausal (2 years without menses) will be considered not of childbearing potential. 11. Subject understood, agreed and provided informed consent. Patients must give written informed consent before any assessment is performed. 12. For Diabetic patients: under treatment with glucose lowering agents according to acceptable international guidelines. Are the trial subjects under 18? no Number of subjects for th
Exclusion criteria
Exclusion criteria: 1. Non-atherosclerotic PAD 2. CLI with major tissue loss (Rutherford Category 6) in either leg. 3. Evidence of active infection in either leg (e.g., cellulitis, osteomyelitis). 4. Subject having undergone surgical revascularization or major amputation, in either leg, less than 1mth prior to screening, or endovascular revascularization or minor amputation less than 2wks prior to screening 5. Planned or potential need for major/minor amputation or any revascularization of either leg during the Screening Period and up to 1mth following randomization according to Investigator's or treating physician judgment/decision. 6. Aortoiliac stenosis or common femoral artery stenosis =70%, or otherwise suspicion of inadequate inflow to the index leg up to 3 months prior to screening by any imaging modality. 7. Current evidence or sign supporting an assessment of life expectancy of less than 6mths 8. Stroke or acute myocardial infarction/unstable angina within 3mths prior to randomization 9. Severe congestive heart failure symptoms (New York Heart Association class III- IV) at screening 10. Life-threatening ventricular arrhythmia except in subjects with an implantable cardiac-defibrillator at screening 11. Uncontrolled severe hypertension during screening period 12. Diabetes mellitus with HbA1c >10% at screening 13. Current or history of proliferative retinopathy (for all known diabetic subjects there will be no evidence of proliferative retinopathy in a retinal examination performed within 3mths before First Screening Visit or during screening) 14. Known active untreated Hepatitis B virus or Hepatitis C virus infections at screening 15. A subject with known human immunodeficiency virus infection, acquired immunodeficiency syndrome, severe uncontrolled inflammatory disease or severe uncontrolled autoimmune disease 16. Pre-existing significant coagulopathies that put the subject at an increased risk of blood clotting or bleeding according to the Investigator's judgment 17. Subjects under chronic anticoagulant therapy taking warfarin with international normalized ratio (INR)>2 or treated with Direct Oral Anticoagulants, for atrial fibrillation and\or prosthetic heart valves, and or thromboembolic events, unless this therapy can be safely discontinued or modified around the time of PLX-PAD/placebo injections based on the study Investigator's discretion. 18. Aspartate transaminase or alanine transaminase >3×ULN. Subjects with higher levels may be included if the condition associated with the increase in those liver enzymes is known and considered clinically stable 19. Subject on renal replacement therapy or planned to start renal replacement therapy within 3 months of first screening visit. 20. Known history of drug or alcohol abuse in the past 3yrs 21. Subject is currently enrolled in, or has not yet completed a period of at least 30days since ending another investigational device or drug trial(s), unless in long-term follow-up phase (in which there is no IP administration) 22. Current treatment with systemic steroids at a dose which is prednisone equivalent >5mg/day, or topical steroids on the index leg 23. Current use or use within 30days prior to PLX-PAD treatment of wound dressing containing cells or growth factors like Apligraf®, or topical platelet derived growth factor 24. Planned use, or use within 14days prior to PLX-PAD treatment (VI) of hyperbaric oxygen therapy, prostanoids, Pentoxifylline, Cylostazole, spinal cord stimulation, or lumbar sym
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The objective of the study is to evaluate the efficacy, tolerability and safety of local intramuscular (IM) injections of PLX-PAD in CLI subjects unsuitable for revascularization.;Secondary Objective: Not applicable;Primary end point(s): Time (days) from randomization to occurrence of major amputation of the index leg or death (AFS).;Timepoint(s) of evaluation of this end point: Throughout duration of study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Time (days) from randomization to first occurrence of any of the following single events: o Major amputation of the index leg. o Revascularization due to worsening of CLI in the index leg. o All-cause mortality. 2. Time (days) from randomization to major amputation of the index leg 3. Change from baseline in ischemic pain as assessed by numerical rating scale (NRS) at 6 months. 4. Proportion of subjects with complete healing of all ischemic lesions i.e., ulcers and necroses in the index leg at 12 months. 5. Time (days) from randomization to occurrence of death.;Timepoint(s) of evaluation of this end point: 1. Throughout the duration of the study. 2. Throughout the duration of the study. 3. Up to 6 months 4. up to 12 months 5. Throughout the duration of the study. | — |
Countries
Austria, Bulgaria, Czech Republic, Germany, Hungary, Macedonia, the former Yugoslav Republic of, Poland, United Kingdom, United States
Contacts
Public ContactVP Clinical & Medical Affairs
Pluristem Ltd
Outcome results
None listed