Proteomics and Stem Cell Therapy as a New Vascularization Strategy

NCT02802852 | Completed DMC

• 1 other identifier: 2015-1244
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Critical Limb Ischemia

Outcome Measures

Primary Outcomes (22)

• Hepatocyte Growth Factor

  Change between 1 day, 14 days, and 30 days

• Insulin Growth Factor

  Change between 1 day, 14 days, and 30 days

• Vascular Endothelial Growth Factor A

  Change between 1 day, 14 days, and 30 days

• Vascular Endothelial Growth Factor B

  Change between 1 day, 14 days, and 30 days

• Vascular Endothelial Growth Factor C

  Change between 1 day, 14 days, and 30 days

• Vascular Endothelial Growth Factor 165b

  Change between 1 day, 14 days, and 30 days

• Matrix Metalloproteinase 9

  Change between 1 day, 14 days, and 30 days

• Tissue Necrosis Factor alpha

  Change between 1 day, 14 days, and 30 days

• Placental Growth Factor

  Change between 1 day, 14 days, and 30 days

• Platelet Derived Growth Factor AA

  Change between 1 day, 14 days, and 30 days

• Platelet Derived Growth Factor BB

  Change between 1 day, 14 days, and 30 days

• Angiopoietin

  Change between 1 day, 14 days, and 30 days

• Tissue Growth Factor beta

  Change between 1 day, 14 days, and 30 days

• Plasmin

  Change between 1 day, 14 days, and 30 days

• Fibrin Degradation Products

  Change between 1 day, 14 days, and 30 days

• Interleukin 6

  Change between 1 day, 14 days, and 30 days

• Interleukin 8

  Change between 1 day, 14 days, and 30 days

• CD 34+ Cytometry

  Change between 1 day, 14 days, and 30 days

• Vascular Endothelial Growth Factor Receptor 2+ Cytometry

  Change between 1 day, 14 days, and 30 days

• CD 14+ Cytometry

  Change between 1 day, 14 days, and 30 days

• CD 31+ Cytometry

  Change between 1 day, 14 days, and 30 days

• Serum Nitrate

  Change between 1 day, 14 days, and 30 days

Secondary Outcomes (3)

• Medical Outcomes Study 36-Item Short Form Health Survey (SF-36)

  14 days, 30 days, 6 months

• Vascular Quality of Life Questionnaire

  14 days, 30 days, 6 months

• EuroQol-5D

  14 days, 30 days, 6 months

Study Arms (1)

Calf Compression, Filgrastim injection

EXPERIMENTAL

All patients enrolled in the study will undergo pneumatic calf compression though use of the Art Assist device as well as stem cell mobilization through administration of Filgrastim 10 mcg/kg subcutaneously, every 3rd day for 30 days.

Device: Pneumatic calf compression; Drug: Filgrastim

Interventions

Pneumatic calf compression DEVICE

Application of a pneumatic calf compression device for two hours per day, every day for 30 days.

Also known as: Art Assist Device

Calf Compression, Filgrastim injection

Filgrastim DRUG

Administration of Filgrastim 10 mcg/kg every 3rd day for 30 days

Also known as: Neupogen

Calf Compression, Filgrastim injection

Eligibility Criteria

• Age: 35 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female between the ages of 35 and 85.
• Chronic limb ischemia Fontaine Class III (ischemic forefoot rest pain) and Class IV (non-healing ischemic ulcers, gangrene) with confirmatory non-invasive vascular testing.
• English or Spanish speaking patients

You may not qualify if:

• Acute limb ischemia requiring emergency treatment.
• Non-salvageable foot (e.g. extensive gangrene, advanced infection, rigor mortis, knee/hip flexion contracture, post-stroke paralysis, and hemiparesis).
• Untreated hypercoagulability disorder, sickle cell anemia, myeloproliferative disorder.
• Dialysis, and/or sustained elevated Creatinine \>3.6 mg/dl.
• Severe dementia; bed-ridden; non-compliance; unlikely to follow-up; unreliable.
• Intolerance of PPCD compression
• Morbid obesity (Body Mass Index \> 34)
• Severe venous insufficiency causing venous stasis ulceration and dermatitis.
• Uncorrected significant aorto-iliac, common femoral, and profunda femoral arterial disease
• Ulceration precluding PPCD placement.
• Active cancer.
• Allergy to Neupogen.
• Uncorrected symptomatic coronary artery disease
• History of lymphoma or leukemia

Sponsors & Collaborators

• University of Illinois at Chicago: lead

Study Sites (1)

University of Illinois at Chicago

Chicago, Illinois, 60612, United States

Location

Related Publications (5)

• Eton D, Yu H. Enhanced cell therapy strategy to treat chronic limb-threatening ischemia. J Vasc Surg. 2010 Jul;52(1):199-204. doi: 10.1016/j.jvs.2009.12.048. Epub 2010 Mar 28.

  PMID: 20347552 BACKGROUND

• Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, Pippen AM, Annex BH, Dong C, Taylor DA. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation. 2003 Jul 29;108(4):457-63. doi: 10.1161/01.CIR.0000082924.75945.48. Epub 2003 Jul 14.

  PMID: 12860902 BACKGROUND

• Fadini GP, Avogaro A. Autologous transplantation of granulocyte colony-stimulating factor- mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care. 2006 Feb;29(2):478-9; author reply 479-80. doi: 10.2337/diacare.29.02.06.dc05-1770. No abstract available.

  PMID: 16482702 BACKGROUND

• Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999 Apr;5(4):434-8. doi: 10.1038/7434.

  PMID: 10202935 BACKGROUND

• Eton D, Zhou G, He TC, Bartholomew A, Patil R. Filgrastim, fibrinolysis, and neovascularization. J Tissue Eng Regen Med. 2022 May;16(5):496-510. doi: 10.1002/term.3284. Epub 2022 Feb 17.

  PMID: 35175691 DERIVED

MeSH Terms

Conditions

Chronic Limb-Threatening Ischemia

Interventions

Filgrastim

Condition Hierarchy (Ancestors)

Peripheral Arterial Disease; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Peripheral Vascular Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Ischemia

Intervention Hierarchy (Ancestors)

Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• George E Havelka, MD

  University of Illinois at Chicago

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Surgery

Study Record Dates

• First Submitted: April 21, 2016
• First Posted: June 16, 2016
• Study Start: June 1, 2016
• Primary Completion: March 1, 2018
• Study Completion: March 1, 2019
• Last Updated: November 15, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)