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: 20.0Level: LLTClassification code 10058069Term: Critical limb ischemiaSystem Organ Class: 100000004866; Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

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

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-07-26
• Last Update Posted: 19 April 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 PAD due to atherosclerosis at the stage of CLI, with minor tissue loss 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 and TP is not measureable, 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 (unsuitability to revascularization should be 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 recent 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 to where they potentially require a major amputation within 1 month.
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 and an anti-platelet agent (e.g., clopidogrel, ticlopidine, 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. Signed informed consent form.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 74
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 172

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. If there is clinical suspicion of osteomyelitis, imaging per local medical practice should be performed. If the subject had osteomyelitis within the last 3mths, recovery should be determined by the Investigator, supported by imaging as per local medical practice
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 within 1mth of study entry upon Investigator’s judgment
6. Aortoiliac stenosis or common femoral artery stenosis =70%, or otherwise suspicion of inadequate inflow to the index leg at the time of screening (according to last imaging)
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 screening
9. Severe congestive heart failure symptoms (New York Heart Association Stage 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 should be no evidence of proliferative retinopathy in a retinal examination performed within 3mths before First Screening Visit)
14. Known active 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 with persistent international normalized ratio (INR)>2.5 or subjects who are on anticoagulant therapy with persistent INR>2.5 at screening, unless this therapy can be safely discontinued or modified around the time of PLX-PAD/placebo injections based on the study Investigator’s discretion. For subjects treated with new oral anti-coagulant therapy, decision on inclusion should be made as per 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 with eGFR<15mL/min/1.73m2 (based on MDRD equation)
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 >7.5mg/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. Current use, planned use, or use wi

Study & Design

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

Primary Outcome Measures

Name	Time	Method
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.