Proteomics and Stem Cell Therapy as a New Vascularization Strategy
Condition: Critical Limb Ischemia
MeSH terms: Chronic Limb-Threatening Ischemia; Ischemia; Neovascularization, Pathologic
Study type: Interventional

Summary: 
      Neovascularization (NV) is the innate capability to enlarge collateral arteries
      ("arteriogenesis"), and to stimulate growth of new capillaries, arterioles and venules at the
      tissue level ("angiogenesis"). Patients with Chronic Limb-threatening Ischemia (CLI) present
      with forefoot rest-pain, ulceration and/or gangrene. They require risky and costly
      revascularization operations to avoid amputation. The investigators hypothesize that their
      inadequate NV can be modulated to restore this capability. By correcting impediments to NV in
      an out-patient setting, the investigators expect to facilitate CLI management.

      While the following impediments to NV are complex, the solution is not. Arteriogenesis
      necessitates endothelial cell activation in small collaterals as blood is offloaded away from
      the occluded artery. Shear stress provides this stimulus, but is attenuated caudal to
      multi-level arterial occlusive disease. The "arteriogenesis switch" is not turned on.
      Furthermore, the lack of nutritive oxygenated blood inflow and the accumulation of toxic
      metabolic by-products are adverse to synthetic pathways in the ischemic tissue. Additionally,
      protein "distress" signals cannot be effectively disseminated by the ischemic tissue, and the
      reparative progenitor cells they are supposed to mobilize cannot effectively home back to the
      ischemic tissue to orchestrate NV. The CLI patient is especially disadvantaged by having
      diminished function and number of circulating progenitor cells (CPC). Lastly these elderly,
      often diabetic, patients are less able to fend off infection.

      An FDA approved external programmed pneumatic compression device (PPCD) was used to restore
      the shear stress stimulus required for arteriogenesis. It also enhances oxygenated nutritive
      arterial inflow, clears waste products of metabolism (increased venous and lymphatic
      outflow), and helps distress proteins reach the central circulation and mobilized progenitor
      cells to return to the ischemic tissue. We corrected the progenitor cell and immunologic
      impairment with granulocyte colony stimulating factor (G-CSF), FDA approved for stem cell
      mobilization and immunological boost in the setting of cancer chemotherapy. The preliminary
      data show clinical, angiographic, hemodynamic and biochemical evidence for enhanced NV. The
      purpose for this study is to enroll 25 patients to reproduce the biochemical data to support
      a large scale clinical trial.
    

Detailed description: 
      Twenty-five CLI patients with ischemic forefoot rest pain, non-healing forefoot ulceration,
      or dry forefoot gangrene will be recruited. They will have already undergone standard of care
      evaluation, including hemodynamic testing and duplex ultrasound delineation of the arterial
      anatomy in the Non-invasive Vascular Laboratory. Those with tibial artery occlusive disease,
      with normal or corrected proximal aorto-ilio-femoral arterial anatomy, will be given the
      option of enrollment in lieu of surgery or catheter revascularization.

      The standard vascular assessment data will be reviewed: History and Physical (H&P)
      examination, vascular laboratory hemodynamic data (arterial duplex imaging, ankle and toe
      pressures), and blood tests (complete blood cell count, metabolic and lipid panel, hemoglobin
      A1C if diabetic). Carotid duplex scan, chest X-Ray, electrocardiogram, chemical cardiac
      stress test, and echocardiogram will be reviewed if available. While angiography by magnetic
      resonance imaging (MRI), computed tomography(CT) or catheter may be available, they are not
      required. Data obtained from in-clinic use of LUNA fluorescence angiography may also be
      collected, but is not necessary. To emphasize, all ultrasound, x-ray, CT, MRI and LUNA
      fluorescence data may be collected since imaging is the standard of care for patients being
      evaluated for peripheral vascular disease, but no specific imaging is required and no imaging
      is being studied as part of this protocol.

      PPCD use will continue until the presenting symptoms resolve or traditional revascularization
      becomes necessary to achieve limb salvage. Each patient serves as his/her own control. Three
      "pairs" of blood specimens will be analyzed per patient. A "pair" includes phlebotomy prior
      to and immediately after two hours of PPCD. The first pair is obtained on enrollment in the
      study. The second pair will be done 2 weeks later 18-24 hours after the last dose of G-CSF.
      The third pair will be done 30 days into the study, 18-24 hours after the last dose of G-CSF.
      The patient will return for standard of care clinical evaluation, with repeat hemodynamic
      testing, 6 months after the 30 day clinic evaluation.

      Case Report Forms (CRFs) will be prepared for each subject. Progression of ischemic symptoms
      will result in discontinuation of participation in the trial and immediate standard of care
      treatment, including imaging studies and revascularization, if indicated. Otherwise the
      status of the presenting forefoot symptoms (ischemic rest pain, ischemic ulcers, and
      gangrene) will be documented at Day 1, Day 14, and Day 30. Ischemic rest pain will be scored
      (1 to 10 scale). Pain free walking distance will be measured. Forefoot ischemic lesions will
      be photographed and dimensions recorded on enrollment.

      Baseline visit (Outpatient Care Center):

        1. Patents will undergo standard of care H&P examination.

        2. Upon verification that the patient is eligible (based on the inclusion/exclusion
           criteria), an informed consent form will be explained to the patient to better explain
           the study and ask for authorization to participate.

      Baseline visit (Non-invasive Vascular Ultrasound Laboratory):

      1. Other standard of care tests will include: duplex ultrasound (DUS), ankle and toe
      pressures, if not yet completed prior to the clinic visit.

      Day1 (Clinical Resource Center, University of Illinois at Chicago): The following procedures
      will be done in this order:

        1. Initial blood draw (20 ml)

        2. Patients then will wear the PPCD in seated position (2-hour session).

        3. After the 2-hour use of the PPCD, another blood draw will be done (20 ml).

        4. Each patient will be given a Neupogen shot (10 mcg/kg) subcutaneously

        5. Patient will be given ample time to fill out the quality of life (QOL) questionnaires
           (SF36, EQ5D, VascQoL-6) and a study coordinator will be available at this time to assist
           the patient. Each questionnaire will take about 10 minutes to fill out.

        6. Blood samples will be sent to the Dr. Bartholomew, MD Lab for analysis.

      Days 4, 7, 10, and 13 (at Home or in clinic): The following procedures will be done:

      1. Nurse or PI will administer a Neupogen shot (10 mcg/kg) subcutaneously, every 3rd day, for
      a total of 10 Neupogen shots. Patient will continue use of the PPCD every day, at least 3
      hours a day, till symptoms are resolved.

      Day14 (Clinical Resource Center, University of Illinois at Chicago): The following procedures
      will be done in this order:

        1. Initial blood drawing (20 ml), 18-24 hours after the 5th shot of Neupogen. Blood samples
           will be sent to Dr. Bartholomew Lab for biochemical analysis.

        2. Patients will then wear PPCD for 2 hours in seated position.

        3. Just prior to the end of the 2-hour use of the PPCD, another blood draw will be done (20
           ml).

        4. Patient will return the empty vials of Neupogen.

        5. Patient will be given ample time to fill out the quality of life (QOL) questionnaires
           (SF36, EQ5D, VascQoL-6) and a study coordinator will be available at this time to assist
           the patient. Each questionnaire will take about 10 minutes to fill out.

      Day30 (Clinical Resource Center, University of Illinois at Chicago): The following procedures
      will be done in this order:

        1. Initial blood drawing (20 ml), 18-24 hours after the 10th shot of Neupogen. Blood
           samples will be sent to Dr. Bartholomew Lab for biochemical analysis.

        2. Patients will then wear PPCD for 2 hours in seated position.

        3. Just prior to the end of the 2-hour use of the PPCD, another blood draw will be done (20
           ml).

        4. Patient will be given ample time to fill out the quality of life (QOL) questionnaires
           (SF36, EQ5D, VascQoL-6) and a study coordinator will be available at this time to assist
           the patient. Each questionnaire will take about 10 minutes to fill out.

        5. Patient will return the empty vials of Neupogen.

      Monthly Follow-up (Clinical Resource Center, University of Illinois at Chicago):

        1. After the completion of the initial 30 day treatment period, the patient will follow-up
           in clinic at 1 month intervals for ongoing clinical assessment. The patient will
           continue using the device alone daily until wounds are healed and forefoot rest pain has
           resolved.

        2. At 6 month visit, the patient will fill out QOL questionnaires. Each patient will be
           followed for a total of 6 months. Repeat hemodynamic testing will occur in our
           Intersocietal Accreditation Commission certified non-invasive ultrasound laboratory at
           the 6 month visit.

      Unscheduled visits and early termination:

      1. Enrolled subjects will be given the contact information for the principal investigator so
      that they can have access to the study organizers should any questions or concerns arise at
      home in-between clinic visits. Patients wishing to terminate their enrollment in the study
      can contact the principal investigator in the same manner.
    

Intervention name(s): Pneumatic calf compression; Filgrastim
Intervention type(s): Device; Drug
Intervention description(s): Application of a pneumatic calf compression device for two hours per day, every day for 30 days.; Administration of Filgrastim 10 mcg/kg every 3rd day for 30 days
Other intervention name(s): Art Assist Device; Neupogen
Intervention MeSH terms: Lenograstim
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment