A placebo-Controlled,Phase III Study to Evaluate the Efficacy, Tolerability and Safety of Intramuscular Injections of PLX-PAD for the Treatment of Patients with Critical Limb Ischemia (CLI) with Minor Tissue Loss who are Unsuitable for Revascularizatio

Phase 1

• Conditions: Critical Limb Ischemia (CLI); MedDRA version: 21.1Level: LLTClassification code 10058069Term: Critical limb ischemiaSystem Organ Class: 100000004866; Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

• Registration Number: EUCTR2015-005532-18-BG
• Lead Sponsor: Pluristem Ltd.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-03-16
• Last Update Posted: 7 June 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 246

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 peripheral artery disease (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 =20 cm2 (not including black toes).
4. Total area of ischemic lesions in the heel =10 cm2.
5. Ankle pressure (AP) =70 mmHg or toe pressure (TP) =50 mmHg in the index leg.
[If a subject has ankle-brachial index (ABI) >1.4 or both AP and TP are not measurable or not reliable, inclusion may be based on transcutaneous oxygen pressure (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 on 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 lowe

Exclusion Criteria

1. Non-atherosclerotic PAD (Buerger's disease [thromboangiitis obliterans], Takayasu’s arteritis…).
2. CLI with major tissue loss (Rutherford Category 6) in either leg.
3. Evid of active inf in either leg (cellulitis, osteomyelitis)...
4. Subj having undergone surgical revascularization or major amputation, in either leg, less than 1 month prior to screen, or endovascular revascularization or minor amputation less than two weeks prior to screen.
5. Planned or potential need for major/minor amputation or any revascularization of either leg during the Screen Period and up to 1 month following random accg to Invest 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 screen by any imaging modality.
7. Current evidence or sign supporting an assessment of life expectancy of less than 6 months.
8. Stroke or acute myocardial infarction/unstable angina within 3 months prior to random.
9. Severe congestive heart failure symptoms (NY Heart Assoc class III-IV) at screen.
10. Life-threatening ventricular arrhythmia - except in subj with an implantable cardiac-defibrillator at screen.
11. Uncontrolled severe hypertension during screen period.
12. Diabetes mellitus with glycosylated hemoglobin (HbA1c) >10% at screen.
13. Current or history of proliferative retinopathy (for all known diabetic subj there will be no evidence of proliferative retinopathy in a retinal examination performed within 3 months before First Screening Visit or during screening).
14. Known active untreated Hep B virus or Hep C virus infec at screen.
15. A subj with known HIV infection, AIDS, severe uncontr inflame disease or severe uncontr autoimmune disease (ulcerative colitis, Crohn's disease…).
16. Pre-existing significant coagulopathies that put the subj at an increased risk of blood clotting or bleeding acc to the Invest judgment.
17. Subj 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 Invest discretion.
18. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3×ULN. Subj with higher levels may be included if the condition associated with the increase in those liver enzymes is known and is considered clinically stable.
19. Subj on renal replacement therapy or planned to start renal replacement therapy within 3 months of first screen visit.
20. Known history of drug or alcohol abuse in the past 3 years.
21. Subj is currently enrolled in, or has not yet completed a period of at least 30 days 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 >5 mg/day, or topical steroids on the index leg.
23. Current use or use within 30 days 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 14 days prior to PLX-PAD treatment (V1) of hyperbaric oxygen therapy, prostanoids, Pentoxifylline, Cylostazole, spinal cord stimulation, or lumbar

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified