| 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 | 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 |
|
| 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 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. |
|
| 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 (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 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 premedication
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 different 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 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 3yrs 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. Chronic liver disease Child Pugh class B\C |
|
| 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 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. |
|
| 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. Up to 6 months
4. up to 12 months
5. Throughout the duration of the study. |
|
| 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 | No |
| 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 | 10 |
| 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 |
| Bulgaria |
| Czech Republic |
| Germany |
| Hungary |
| Macedonia, the former Yugoslav Republic of |
| 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
|
12 months after the first scheduled treatment visit of the last
randomized subject, or once 82 events are accumulated, whichever is
later.
Randomization will cease after stopping the study at the interim
analysis for overwhelming efficacy/futility, or when achieving 82
events is assured. If not stopped after the interim analysis, up to 300
subjects will be recruited.
In case of a significant result for the primary endpoint at the Interim
Analysis, an earlier End of Study may be determined |
|
| 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 |
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