E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Critical Limb Ischemia (CLI) |
|
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. |
|
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 | 20.0 |
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 |
|
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. |
|
E.2.2 | Secondary objectives of the trial |
|
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 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. |
|
E.4 | Principal 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
7. Current evidence or sign supporting an assessment of life expectancy of less than 6mths
8. Transient ischemic attack/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 rate >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 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 >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 within 30days prior to PLX-PAD treatment of hyperbaric oxygen therapy, prostanoids, 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 12mths before screening
26. Known allergies to any of the following: DMSO, human serum albumin, bovine serum albumin
27. Known allergy to the anti-histaminic drug selected by the site as pre-medication
28. History of allergic/hypersensitivity reaction to any substance having required hospitalization and/or treatment with IV steroids/epinephrine, known allergy to more than 3 allergens, or in the opinion of the Investigator the subject is at high risk of developing severe allergic/hypersensitivity reactions
29. History of severe atopic disease
30. Pulmonary disease requiring supplementaloxygen 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 historyof malignancy within 5yrs prior to screening except for successfully resected skin basal cell carcinoma or skin squamous cell carcinoma not located on the index leg
34. Immunocompromised subjects for any reason including immunosuppressive therapy at screening
35. In the opinion of the Investigator the subject is unsuitable for participating in the study
36. Inability to understand and provide an informed consent |
|
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). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout duration of study. |
|
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 . |
|
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.
7. Throughout the duration of the study.
E.6 |
|
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 |
|
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 | 2 |
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 |
Czech Republic |
Germany |
Hungary |
Poland |
United Kingdom |
United States |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
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 |