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    Summary
    EudraCT Number:2015-005532-18
    Sponsor's Protocol Code Number:PLX-CLI-03
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-06-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2015-005532-18
    A.3Full title of the trial
    A Randomized, Double-Blind, Multicenter, Placebo-Controlled, Parallel-Group Phase III Study to Evaluate the Efficacy, Tolerability and Safety of Intramuscular Injections of PLX-PAD for the Treatment of Subjects with Critical Limb Ischemia (CLI) with Minor Tissue Loss who are Unsuitable for Revascularization (PACE Study)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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 Revascularization
    A.4.1Sponsor's protocol code numberPLX-CLI-03
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPluristem Ltd.
    B.1.3.4CountryIsrael
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPluristem Ltd
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPluristem Ltd
    B.5.2Functional name of contact pointVP Clinical & Medical Affairs
    B.5.3 Address:
    B.5.3.1Street AddressMatam Advanced Technology Park, Building #5
    B.5.3.2Town/ cityHaifa
    B.5.3.3Post code3508409
    B.5.3.4CountryIsrael
    B.5.4Telephone number+972747108600
    B.5.5Fax number+972747108765
    B.5.6E-maildanp@pluristem.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePLX-PAD
    D.3.4Pharmaceutical form Dispersion for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAllogenic ex-vivo expanded placental adherent stromal cells
    D.3.9.2Current sponsor codePLX-PAD
    D.3.10 Strength
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20million cell/mL
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Yes
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberTissue-engineered product (Ref: EMA/556256/2015)
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboDispersion for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Critical Limb Ischemia (CLI)
    E.1.1.1Medical 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.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10058069
    E.1.2Term Critical limb ischemia
    E.1.2System Organ Class 100000004866
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal 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 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 following randomization.
    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.4Principal 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 within 1mth following randomization of study entry upon Investigator's judgment
    6. Aortoiliac stenosis or common femoral artery stenosis ≥70%, or suspicion of inadequate inflow to the index leg up to 3 month 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 (NY 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 or during screening)
    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 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 anticoagulant
    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 within 30days prior to PLX-PAD
    treatment 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 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.5.1Primary end point(s)
    Time (days) from randomization to occurrence of major amputation of the index leg or death (AFS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout duration of study.
    E.5.2Secondary 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.5.2.1Timepoint(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 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA31
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 74
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 172
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 218
    F.4.2.2In the whole clinical trial 246
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-01-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-29
    P. End of Trial
    P.End of Trial StatusOngoing
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