E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Critical Limb Ischemia (CLI) |
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E.1.1.1 | Medical condition in easily understood language |
Severe obstruction of the arteries causing reduction in blood flow to the leg resulting in severe pain, skin wounds, and/or gangrene. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058069 |
E.1.2 | Term | Critical limb ischemia |
E.1.2 | System Organ Class | 100000004866 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 lowering agents according to acceptable international guidelines. |
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E.4 | Principal 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 sympathectomy. 25. Exposure to allogeneic cell based therapy in the past or exposure to autologous cell therapy in the last 12 months before screen 26. Known allergies to any of the following: dimethyl sulfoxide, hum serum albumin, bovine serum albumin. 28. History of screening story of allergic/hypersensitivity reaction to any substance having required hospitalization and/or treatment with intravenous steroids/epinephrine, known allergy to more than 3 different allergens, or in the opinion of the Invest the subj is at high risk of developing severe allergic/hypersensitivity reactions. 29. History of severe atopic disease (including but not limited to chronic urticaria, allergic reaction with respiratory symptoms requiring systemic steroids), or history of uncontrolled Asthma (Global Initiative for Asthma III-IV). 30. Pulmonary disease requiring supplemental oxygen treatment on a daily basis. 31. History of acute transfusion reaction. 32. History of autologous/allogeneic hematopoietic cell transplantation for bone marrow replacement or solid organ transplantation. 33. Active malignancy or history of malignancy within 3 years prior to screening except for successfully resected skin basal cell carcinoma or skin squamous cell carcinoma not located on the index leg. 34. Immunocompromised subj for any reason, including immunosuppressive therapy, at screening. 36. Chronic liver disease Child Pugh class B\C |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time (days) from randomization to occurrence of major amputation of the index leg or death (AFS). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout duration of study. |
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E.5.2 | 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 Doubling of total ulcer area from baseline in the index leg. o De novo necrosis in the index leg. o All-cause mortality
2. 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 De novo necrosis in the index leg. o All-cause mortality.
3. Time (days) from randomization to major amputation of the index leg.
4. Proportion of subjects with complete healing of all ischemic lesions i.e., ulcers and necroses in the index leg at 12 months.
5. Change from baseline in ischemic pain as assessed by numerical rating scale (NRS) at 6 months.
6. Time (days) from randomization to occurrence of death or major amputation or adjudicated major amputation of the index leg.
7. Time (days) from randomization to occurrence of all cause death.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Throughout the duration of the study. 2. Throughout the duration of the study. 3. Throughout the duration of the study. 4. up to 12 months 5. up to 6 months 6. Throughout the duration of the study.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Bulgaria |
Czech Republic |
Germany |
Hungary |
Macedonia, the former Yugoslav Republic of |
Poland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |